Embryology - User contributions [en-gb]

2017 Group Project 1

2017-10-26T04:38:39Z

Z5177691: /* Timeline of Corticogenesis */

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Intro section cortex.jpg|thumb|right|350px|'''Figure1. Cerebral cortex is the outermost layer of the cerebrum''' <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex is part of the brain which surrounds the cerebral hemispheres. It has a very large surface area (largest part of human brain). The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres (Figure 1). It is a layer of gray matter around 2-4 mm in thickness, and consists of approximately 10 billion nerve cell bodies and dendrites. It appears gray because of the cell bodies (Figure 2). 
[[File:Brain sectin showing cortex.jpg|thumb|left|300px|'''Figure 2. Section of the human brain''' <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]]

The cerebral cortex is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The development of the cerebral cortex involves 3 main stages:
*Proliferation (or growth or differentiation)
*Migration of neurons
*Maturation (or organisation or folding). 
 
The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. Xxternal pyramidal, IV. Internal granular layer, V. Internal pyramidal layer, VI. Multiform layer. These individual layers organise the capacity for interconnections between both input and output signals. <ref>Dartmouth.edu. (2006). Chapter 11: The Cerebral Cortex. [online] Available at: http://www.dartmouth.edu/~rswenson/NeuroSci/chapter_11.html.</ref> 

This project will explore the various embryologic aspects of the cerebral cortex, including early development of the brain, development of the cerebral cortex, anatomy and functions of the cortex, and abnormalities associated with cortical development. 
<ref>Moore, K., Persaud, T. and Torchia, M. (2011). The Developing Human. London: Elsevier Health Sciences, pp.The Nervous System; 379-414.</ref><ref>Van Essen, D. (2005). A Population-Average, Landmark- and Surface-based (PALS) atlas of human cerebral cortex. NeuroImage, 28(3), pp.635-662.</ref><ref>Differencebetween.com. (2017). Difference Between Cerebrum and Cerebral Cortex. [online] Available at: http://www.differencebetween.com/difference-between-cerebrum-and-vs-cerebral-cortex/ [Accessed 26 Oct. 2017].</ref><ref name="first">Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
 

==Early Development of the Brain==

 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
[[File:Brain Development 2.png|thumb|400px|right|'''Figure 3. A longitudinal perspective of the neural tube, showing the primary brain vesicles divided into the five secondary subdivisions'''. <ref name="image">Vanderah, T., Gould, D. and Nolte, J. (2016). Nolte's The human brain. Philadelphia, PA: Elsevier, p.44. </ref>]]

*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five, as depicted in Figure 3. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.

'''Brain Flexures'''
[[File:Brain Development.png|thumb|400px|right|'''Figure 4. Lateral perspective of the neural tube, showing the three flexures, and five secondary subdivisions'''.<ref name="image"/>]]
During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures, as depicted in Figure 4, in proximity to the five secondary vesicles. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

Through the foundation of structures and processes in during the early developmental brain, the fetus' brain is able to further develop into a much more complex organ.

 

==Later Development: Development of the Cerebral Cortex==
[[File:Neural- cortex Cajal drawing 01.jpg |thumb|right|200px|'''Figure 5. Laminar and columnar organization of the cerebral cortex (Historical drawing by Cajal)''']]
 
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes. The diversity in neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned in above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contributes to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|400px|super|'''Figure 6. Key developmental zones in the human cortex'''.]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone
**Subplate
*Cortical Plate: establishment of the 6 cortical layers form in this region between the subplate and the marginal zone

===Timeline of Corticogenesis===
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (e.g fate) of the neurons so that specific connections and cortical structure are achieved. "E" relates to embryonic day in relation to corticogenesis.
 

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along in order to expand the neocortex. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area as well as the preplate and many of the cells in the SVZ contribute to the later cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to the target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layers 6 is populated before layer 5; layer 5 is populated before layer 4 and so on <ref name="boulder"/>. Each layer condenses and the neurons are closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex such as sensory and motor function.
[[File:Corticogenesis.png|center|thumb|700px|super|'''Figure 7. Corticogenesis from E30 to adult human brain''']]

===Signalling involved in Cerebral Cortex Development===
 
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 8. Shh signalling increases the number of proliferating cells''']]
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.

[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 9. Cortex development in wild-type and ''reeler'' mice''']]

'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 8) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 9). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|500px|'''Figure 10. Cortical thickness in the absence of Bmp7''']]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers, (Fig. 10) Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.
 

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref> 
 
[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|'''Figure 11. Anatomy of the human cerebral cortex''' <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]] 

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull (see figure 11). The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri, as shown in figure 11. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri (see figure 11). Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>
 
'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}
 

==Functions of the Cerebral Cortex==
 
[[File:Cortical areas.png|thumb|right|text-top|450px|'''Figure 12. Cortical areas human cortex''' <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]
[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|'''Figure 13. Cortical Homonculus'''<ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]
The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas, as shown in Figure 12. <ref name="overall function"><pubmed>21653723</pubmed></ref>

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body (see figure 13). The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

 

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>
 

==Abnormalities associated with Cerebral Cortex Development==
[[File:Stages of development.png|thumb|right|text-top||520px|'''Figure 14. Main stages of cortical development where abnormalities may arise'''.<ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>]]
 

The embryologic development of the cerebral cortex involves highly organised and complex events. As mentioned in the 'Introduction', these events are generally divided by scientists into 3 major stages in cortical formation where crucial changes occur in neuronal cells; these stages include: 
1. Proliferation (or Growth), 
2. Migration, 
3. Organisation (or Maturation or Differentiation).

Disruptions can occur in these stages of cortical development due to multiple causes, and these disruptions give rise to malformations or irregularities in the cerebral cortex (Figure 13). 

Although multitudinous and/or severe effects ensue from such disorders, epilepsy and mental retardation (of varying degrees) are almost always present with these disorders. 

This section will explore some abnormalities that are commonly discussed in scientific literature. <ref name="first"/><ref name="second">Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref><ref name="third">Christopher A, C. (1999). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 
 
===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder that results because neuroblasts are not able to successfully complete the proliferation stage of cortical development. Mechanism of development of this disorder is not well understood and FCD is categorised as due to uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers (lamination disorganisation). Very large dysmorphic cells called 'balloon' cells are also seen due to abnormal regulation of cell growth. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

If symptoms do present, then these are associated with epilepsy ( tonic-clonic, tonic, simple partial and complex partial seizures). In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. <ref name="first"/><ref name="second"/> 
[[File:Hemimegalencephaly2.png|thumb|left|upright=1.42|'''Figure 15. Observable radiographic features in Hemimegalencephaly'''. <ref name="imaging"/> ]]
 
<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form tumour-like, benign malformation(s) ) of one cerebral hemisphere, part of a hemisphere or one hemisphere with partial involvement of the other hemisphere. MRI findings usually show enlargement of one hemisphere or at least one lobe and abnormal white matter (Figure 15).

Clinical symptoms of this disease may include developmental delay, mental retardation, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. 
<ref name="imaging"/><ref name="second"/>
[[File:Image.png|thumb|right|upright=1.45|'''Figure 16. Possible clinical features of Microcephaly in a newborn'''. <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]] 
<big><big>'''3) Microcephaly Vera'''</big></big>

Amongst cortical congenital disorders, Microcephaly Vera is a relatively common disorder. Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs, and can be caused by genetic or non-genetic factors. 

'''Microcephaly Vera or Primary Microcephaly''' is genetic and does not involve other organs. It from abnormal cortical development, specifically cell division or proliferation. In this malformation the circumference of the head (and so the brain) is much less than normal, while the rest of the body is of normal size. Microcephaly Vera clinically most frequently presents with mental retardation and sometimes epilepsy, although some other features can be observed ocassionally (Figure 16). 
<ref name="imaging"/><ref name="second"/><ref name="third"/> 
 

<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms), which can occur in several tissues of the body, including cerebral cortex. In the cortical gray matter, cortical tubers and bizarre cells are seen because laminar disorganisation occurs (like Focal Cortical Dyplasia). TSC is thus called because at the scientists thought that the lesions seen resembled potato tubers. 

No signs or symptoms are known to be observed for TSC, and diagnosis is determined after a brain scan. 
<ref name="imaging"/><ref name="third"/> 

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:Heteroptopia.png|thumb|upright=1.85|right|'''Figure 17. Observable radiographic features of subcortical band heterotopia'''. <ref name="imaging"/> ]]
For neurons to successfully execute the migration stage of development, some steps have to be completed including departure from the ventricular zone, migration to the cortical plate and then arrest of movement at the appropriate layer. 
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex (Figure 17). 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 
<ref name="imaging"/><ref name="second"/><ref name="third"/> 
<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 
Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. Type II Lissencephaly also includes:
#Muscle-Eye-Brain Disease
#Walker-Warburg Syndrome
#Fukuyama Syndrome 
*'''Microlissencephaly''' 
Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly(discussed previously), and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span. 
<ref name="first"/><ref name="imaging"/><ref name="second"/><ref name="third"/> 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Clinical presentation of Kallman Syndrome includes Archinencephaly, which is hypoplasia (underdevelopment or incomplete development) of the olfactory cortex and olfactory bulb, and deficient or absent sense of smell. 
<ref name="imaging"/><ref name="third"/> 

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

Affected patients can have varying degrees of symptoms, including epilepsy and developmental delay. For example, bilateral poylmicrogyria causes developmental delay, hypertonicity, ataxia, and refractory seizures. 
<ref name="first"/><ref name="second"/> 
[[File:SchizencephalicB.jpg|thumb|left|upright=1.45|'''Figure 18. Coronal and axial sections of the brain of a patient with Schizencephaly'''.<ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]
 

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder classified within the same group as Polymicrogyria. It is characterised by a cleft(s) or lesion(s) on the brain surface,extending from the cerebral cortex to the ventricle and is typically filled with CSF (cerebrospinal fluid) and lined by cortex gray matter. These lesions or clefts are thought to be 'destructive'. 

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly. Type I presents with partial seizures or spastic hemiparesis, while Type II presents with epilepsy or seizures, spasticity, severe developmental delay and microcephaly.

Schizencephaly can be bilateral or unilateral; and commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
<ref name="first"/><ref name="imaging"/><ref name="second"/> 
 
 
 
 
 
{| role="presentation" class="wikitable mw-collapsible mw-collapsed"
| <big><big><big>Other disorders of varying etiology</big></big></big>
|-
| <big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right|'''Figure 19. Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD)'''.<ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome. 
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

The corpus callosum is a structure present in the brain which connects both the hemispheres of the brain. The video below briefly describes this:

<html5media height="350" width="550">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref> 
Agenesis of the corpus callosum (ACC) occurs when the corpus callosum is partially or completely absent. It is thought to be due to a disruption of brain cell migration during fetal development.
<ref>Ninds.nih.gov. (2017). Agenesis of the Corpus Callosum Information Page. [online] Available at: https://www.ninds.nih.gov/Disorders/All-Disorders/Agenesis-Corpus-Callosum-Information-Page [Accessed 26 Oct. 2017].</ref> 
Some clinical symptoms include epilepsy or seizures, developmental delay, vision and hearing impairment, trouble in motor coordination and language skills and difficulty in muscle coordination and tone coordination.
<ref>Vasudevan, C., McKechnie, L. and Levene, M. (2012). Long-term outcome of antenatally diagnosed agenesis of corpus callosum and cerebellar malformations. Seminars in Fetal and Neonatal Medicine, 17(5), pp.295-300. </ref>
|}
 

==Models and Research==
===Animal Models===
[[File:Corticogenesis of mouse and humans.jpeg|thumb|right|text-top|590px|'''Figure 20. Mouse vs Human Neurogenesis''']]

====Mice Model====
Mice have often been used to study corticogenesis in mammals. Corticogenesis lasts from E11 to E19 in mice and lasts eight days, which is far shorter than human corticogenesis. While there are many similarities between human corticogenesis, the rodent brain is much smaller than that of a human’s and therefore, there are different types of progenitor cells involved in mice and the cortex does not expand as greatly. <ref name="control">Dehay, C. and Kennedy, H. (2007). Cell-cycle control and cortical development. Nature Reviews Neuroscience, 8(6),438-450.</ref>Humans have greater numbers of intermediate precursor cells (to aid in further differentiation) and outer radial glial cells compared those of mice. <ref name="cerebral"/> In addition, the SVZ does not split into the inner and outer subventricular zone, but stays intact as one. <ref name="control"/> The importance of reelin has also been greatly studied in mice. Studies showed that mutant mice have disruptions in the migration of neurons into their subsequent layers. By injecting thymidine at various time points of gestation into the female mice, researchers were able to track the development of various populations of neurons. Later developing neurons were unable to ascend past the already early formed neurons due to disruptions in reelin signaling (in the marginal zone). Instead, superficial layer neurons resided below the older, deep layer neurons. This inverted lamination comprises sensory and motor function.<ref> Caviness, V. (1982). Neocortical histogenesis in normal and reeler mice: A developmental study based upon [3H]thymidine autoradiography. Developmental Brain Research, 4(3), 293-302.</ref>
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Figure 21. Timeline and protocol of cerebral organoid development''']]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

The development of these brain organoids has allowed more comprehensive understanding of the self-organisational properties of the brain, and is quickly advancing, however the lack of vasculature in cultured organoids restricts their ability to be used for specific neurological disorders. Furthermore there are still challenges associated with the generation of individual, discrete brain regions, which should be addressed in the future. <ref><pubmed>28822354</pubmed></ref>

==Glossary==

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
|'''Agenesis'''|| The total absence of a tissue or organ
|-bgcolor="FAF5FF"
|'''Cajal-Retzius (CR) cells'''|| Cortical neurons that develop early on, at the same time as the preplate, and express an important glycoprotein known as reelin, which helps with the proper migration of neurons into their respective layers.
|-bgcolor="FAF5FF"
|'''Cortical Plate'''|| Forms in between the marginal zone and subplate and gives rise to the 6 layers of the cortex involved in sensory and motor function.
|-bgcolor="FAF5FF"
|'''Corticogenesis'''|| The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes.
|-bgcolor="FAF5FF"
|'''Fissures'''|| Large sulci.
|-bgcolor="FAF5FF"
|'''GABAergic Neurons'''|| Generate gamma aminobutyric acid (GABA) as their output, one of the two inhibitory neurotransmitters in the central nervous system (CNS).
|-bgcolor="FAF5FF"
|'''Gyrus '''|| Gyri (plural) are folds/ridges in the cerebral cortex.
|-bgcolor="FAF5FF"
|'''Hypoplasia'''|| Underdevelopment or incomplete development of a tissue or organ
|-bgcolor="FAF5FF"
|'''Intermediate zone'''|| Forms below the subplate between E50-55 and contains only migrating cells and no intermediate precursor cells.
|-bgcolor="FAF5FF"
|'''Marginal Zone (MZ)'''|| A subsection of the preplate that forms around E50-55. It lies at the uppermost area of the cortex nearest the pial surface.
|-bgcolor="FAF5FF"
|'''Neural Plate'''|| Main developmental structure required for the development of the nervous system.
|-bgcolor="FAF5FF"
|'''Neural Tube|| Structure of the embryo that evolves into the spinal cord and brain.
|-bgcolor="FAF5FF"
|'''Pachygyria'''|| Gyri can be seen but are very few compared to normal brain
|-bgcolor="FAF5FF"
|'''Preplate'''|| First "pioneer neurons" from dividing cells in the ventricular zone for this layer above the ventricular zone
|-bgcolor="FAF5FF"
|'''Radial glial cells '''|| A class of distinct nonneuronal cells that are bipolar shaped and span the entire width of the cortex during development.
|-bgcolor="FAF5FF"
|'''Subplate'''|| A subsection of the preplate that forms around E50-55.
|-bgcolor="FAF5FF"
|'''Subventricular zone (SVZ)'''|| Cells in the VZ continue to divide symmetrically and give rise to another zone above the VZ known as the SVZ. This zone later splits into an inner (ISVZ) and outer ventricular zone (OSVZ)
|-bgcolor="FAF5FF"
|'''Sulcus'''|| Sulci (plural) are grooves in the cerebral cortex.
|-bgcolor="FAF5FF"
|'''Total agyria'''||Gyri and sulci absent resulting in 'smooth brain'
|-bgcolor="FAF5FF"
|'''Ventricular zone (VZ)'''|| First formed single-celled layer in the cortex, arising from progenitors in the dorsal telencephalon that divide symmetrically. It lies adjacent to the ventricular surface.
|-bgcolor="FAF5FF"
|}

==References==

2017 Group Project 1

2017-10-26T04:37:33Z

Z5177691: /* Later Development: Development of the Cerebral Cortex */

2017 Group Project 1

2017-10-26T04:36:52Z

Z5177691: /* Early Development of the Brain */

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Intro section cortex.jpg|thumb|right|350px|'''Figure1. Cerebral cortex is the outermost layer of the cerebrum''' <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex is part of the brain which surrounds the cerebral hemispheres. It has a very large surface area (largest part of human brain). The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres (Figure 1). It is a layer of gray matter around 2-4 mm in thickness, and consists of approximately 10 billion nerve cell bodies and dendrites. It appears gray because of the cell bodies (Figure 2). 
[[File:Brain sectin showing cortex.jpg|thumb|left|300px|'''Figure 2. Section of the human brain''' <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]]

The cerebral cortex is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The development of the cerebral cortex involves 3 main stages:
*Proliferation (or growth or differentiation)
*Migration of neurons
*Maturation (or organisation or folding). 
 
The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. Xxternal pyramidal, IV. Internal granular layer, V. Internal pyramidal layer, VI. Multiform layer. These individual layers organise the capacity for interconnections between both input and output signals. <ref>Dartmouth.edu. (2006). Chapter 11: The Cerebral Cortex. [online] Available at: http://www.dartmouth.edu/~rswenson/NeuroSci/chapter_11.html.</ref> 

This project will explore the various embryologic aspects of the cerebral cortex, including early development of the brain, development of the cerebral cortex, anatomy and functions of the cortex, and abnormalities associated with cortical development. 
<ref>Moore, K., Persaud, T. and Torchia, M. (2011). The Developing Human. London: Elsevier Health Sciences, pp.The Nervous System; 379-414.</ref><ref>Van Essen, D. (2005). A Population-Average, Landmark- and Surface-based (PALS) atlas of human cerebral cortex. NeuroImage, 28(3), pp.635-662.</ref><ref>Differencebetween.com. (2017). Difference Between Cerebrum and Cerebral Cortex. [online] Available at: http://www.differencebetween.com/difference-between-cerebrum-and-vs-cerebral-cortex/ [Accessed 26 Oct. 2017].</ref><ref name="first">Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
 

==Early Development of the Brain==

 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
[[File:Brain Development 2.png|thumb|400px|right|'''Figure 3. A longitudinal perspective of the neural tube, showing the primary brain vesicles divided into the five secondary subdivisions'''. <ref name="image">Vanderah, T., Gould, D. and Nolte, J. (2016). Nolte's The human brain. Philadelphia, PA: Elsevier, p.44. </ref>]]

*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five, as depicted in Figure 3. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.

'''Brain Flexures'''
[[File:Brain Development.png|thumb|400px|right|'''Figure 4. Lateral perspective of the neural tube, showing the three flexures, and five secondary subdivisions'''.<ref name="image"/>]]
During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures, as depicted in Figure 4, in proximity to the five secondary vesicles. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

Through the foundation of structures and processes in during the early developmental brain, the fetus' brain is able to further develop into a much more complex organ.

 

==Later Development: Development of the Cerebral Cortex==
 
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes. The diversity in neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned in above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contributes to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|400px|super|'''Figure 6. Key developmental zones in the human cortex'''.]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone
**Subplate
*Cortical Plate: establishment of the 6 cortical layers form in this region between the subplate and the marginal zone

===Timeline of Corticogenesis===
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (e.g fate) of the neurons so that specific connections and cortical structure are achieved. "E" relates to embryonic day in relation to corticogenesis.
 

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along in order to expand the neocortex. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area as well as the preplate and many of the cells in the SVZ contribute to the later cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to the target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layers 6 is populated before layer 5; layer 5 is populated before layer 4 and so on <ref name="boulder"/>. Each layer condenses and the neurons are closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex such as sensory and motor function.
[[File:Corticogenesis.png|center|thumb|700px|super|'''Figure 7. Corticogenesis from E30 to adult human brain''']]

===Signalling involved in Cerebral Cortex Development===
 
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 8. Shh signalling increases the number of proliferating cells''']]
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.

[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 9. Cortex development in wild-type and ''reeler'' mice''']]

'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 8) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 9). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|500px|'''Figure 10. Cortical thickness in the absence of Bmp7''']]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers, (Fig. 10) Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.
 

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref> 
 
[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|'''Figure 11. Anatomy of the human cerebral cortex''' <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]] 

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull (see figure 11). The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri, as shown in figure 11. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri (see figure 11). Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>
 
'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}
 

==Functions of the Cerebral Cortex==
 
[[File:Cortical areas.png|thumb|right|text-top|450px|'''Figure 12. Cortical areas human cortex''' <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]
[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|'''Figure 13. Cortical Homonculus'''<ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]
The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas, as shown in Figure 12. <ref name="overall function"><pubmed>21653723</pubmed></ref>

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body (see figure 13). The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

 

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>
 

==Abnormalities associated with Cerebral Cortex Development==
[[File:Stages of development.png|thumb|right|text-top||520px|'''Figure 14. Main stages of cortical development where abnormalities may arise'''.<ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>]]
 

The embryologic development of the cerebral cortex involves highly organised and complex events. As mentioned in the 'Introduction', these events are generally divided by scientists into 3 major stages in cortical formation where crucial changes occur in neuronal cells; these stages include: 
1. Proliferation (or Growth), 
2. Migration, 
3. Organisation (or Maturation or Differentiation).

Disruptions can occur in these stages of cortical development due to multiple causes, and these disruptions give rise to malformations or irregularities in the cerebral cortex (Figure 13). 

Although multitudinous and/or severe effects ensue from such disorders, epilepsy and mental retardation (of varying degrees) are almost always present with these disorders. 

This section will explore some abnormalities that are commonly discussed in scientific literature. <ref name="first"/><ref name="second">Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref><ref name="third">Christopher A, C. (1999). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 
 
===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder that results because neuroblasts are not able to successfully complete the proliferation stage of cortical development. Mechanism of development of this disorder is not well understood and FCD is categorised as due to uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers (lamination disorganisation). Very large dysmorphic cells called 'balloon' cells are also seen due to abnormal regulation of cell growth. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

If symptoms do present, then these are associated with epilepsy ( tonic-clonic, tonic, simple partial and complex partial seizures). In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. <ref name="first"/><ref name="second"/> 
[[File:Hemimegalencephaly2.png|thumb|left|upright=1.42|'''Figure 15. Observable radiographic features in Hemimegalencephaly'''. <ref name="imaging"/> ]]
 
<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form tumour-like, benign malformation(s) ) of one cerebral hemisphere, part of a hemisphere or one hemisphere with partial involvement of the other hemisphere. MRI findings usually show enlargement of one hemisphere or at least one lobe and abnormal white matter (Figure 15).

Clinical symptoms of this disease may include developmental delay, mental retardation, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. 
<ref name="imaging"/><ref name="second"/>
[[File:Image.png|thumb|right|upright=1.45|'''Figure 16. Possible clinical features of Microcephaly in a newborn'''. <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]] 
<big><big>'''3) Microcephaly Vera'''</big></big>

Amongst cortical congenital disorders, Microcephaly Vera is a relatively common disorder. Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs, and can be caused by genetic or non-genetic factors. 

'''Microcephaly Vera or Primary Microcephaly''' is genetic and does not involve other organs. It from abnormal cortical development, specifically cell division or proliferation. In this malformation the circumference of the head (and so the brain) is much less than normal, while the rest of the body is of normal size. Microcephaly Vera clinically most frequently presents with mental retardation and sometimes epilepsy, although some other features can be observed ocassionally (Figure 16). 
<ref name="imaging"/><ref name="second"/><ref name="third"/> 
 

<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms), which can occur in several tissues of the body, including cerebral cortex. In the cortical gray matter, cortical tubers and bizarre cells are seen because laminar disorganisation occurs (like Focal Cortical Dyplasia). TSC is thus called because at the scientists thought that the lesions seen resembled potato tubers. 

No signs or symptoms are known to be observed for TSC, and diagnosis is determined after a brain scan. 
<ref name="imaging"/><ref name="third"/> 

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:Heteroptopia.png|thumb|upright=1.85|right|'''Figure 17. Observable radiographic features of subcortical band heterotopia'''. <ref name="imaging"/> ]]
For neurons to successfully execute the migration stage of development, some steps have to be completed including departure from the ventricular zone, migration to the cortical plate and then arrest of movement at the appropriate layer. 
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex (Figure 17). 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 
<ref name="imaging"/><ref name="second"/><ref name="third"/> 
<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 
Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. Type II Lissencephaly also includes:
#Muscle-Eye-Brain Disease
#Walker-Warburg Syndrome
#Fukuyama Syndrome 
*'''Microlissencephaly''' 
Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly(discussed previously), and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span. 
<ref name="first"/><ref name="imaging"/><ref name="second"/><ref name="third"/> 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Clinical presentation of Kallman Syndrome includes Archinencephaly, which is hypoplasia (underdevelopment or incomplete development) of the olfactory cortex and olfactory bulb, and deficient or absent sense of smell. 
<ref name="imaging"/><ref name="third"/> 

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

Affected patients can have varying degrees of symptoms, including epilepsy and developmental delay. For example, bilateral poylmicrogyria causes developmental delay, hypertonicity, ataxia, and refractory seizures. 
<ref name="first"/><ref name="second"/> 
[[File:SchizencephalicB.jpg|thumb|left|upright=1.45|'''Figure 18. Coronal and axial sections of the brain of a patient with Schizencephaly'''.<ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]
 

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder classified within the same group as Polymicrogyria. It is characterised by a cleft(s) or lesion(s) on the brain surface,extending from the cerebral cortex to the ventricle and is typically filled with CSF (cerebrospinal fluid) and lined by cortex gray matter. These lesions or clefts are thought to be 'destructive'. 

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly. Type I presents with partial seizures or spastic hemiparesis, while Type II presents with epilepsy or seizures, spasticity, severe developmental delay and microcephaly.

Schizencephaly can be bilateral or unilateral; and commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
<ref name="first"/><ref name="imaging"/><ref name="second"/> 
 
 
 
 
 
{| role="presentation" class="wikitable mw-collapsible mw-collapsed"
| <big><big><big>Other disorders of varying etiology</big></big></big>
|-
| <big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right|'''Figure 19. Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD)'''.<ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome. 
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

The corpus callosum is a structure present in the brain which connects both the hemispheres of the brain. The video below briefly describes this:

<html5media height="350" width="550">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref> 
Agenesis of the corpus callosum (ACC) occurs when the corpus callosum is partially or completely absent. It is thought to be due to a disruption of brain cell migration during fetal development.
<ref>Ninds.nih.gov. (2017). Agenesis of the Corpus Callosum Information Page. [online] Available at: https://www.ninds.nih.gov/Disorders/All-Disorders/Agenesis-Corpus-Callosum-Information-Page [Accessed 26 Oct. 2017].</ref> 
Some clinical symptoms include epilepsy or seizures, developmental delay, vision and hearing impairment, trouble in motor coordination and language skills and difficulty in muscle coordination and tone coordination.
<ref>Vasudevan, C., McKechnie, L. and Levene, M. (2012). Long-term outcome of antenatally diagnosed agenesis of corpus callosum and cerebellar malformations. Seminars in Fetal and Neonatal Medicine, 17(5), pp.295-300. </ref>
|}
 

==Models and Research==
===Animal Models===
[[File:Corticogenesis of mouse and humans.jpeg|thumb|right|text-top|590px|'''Figure 20. Mouse vs Human Neurogenesis''']]

====Mice Model====
Mice have often been used to study corticogenesis in mammals. Corticogenesis lasts from E11 to E19 in mice and lasts eight days, which is far shorter than human corticogenesis. While there are many similarities between human corticogenesis, the rodent brain is much smaller than that of a human’s and therefore, there are different types of progenitor cells involved in mice and the cortex does not expand as greatly. <ref name="control">Dehay, C. and Kennedy, H. (2007). Cell-cycle control and cortical development. Nature Reviews Neuroscience, 8(6),438-450.</ref>Humans have greater numbers of intermediate precursor cells (to aid in further differentiation) and outer radial glial cells compared those of mice. <ref name="cerebral"/> In addition, the SVZ does not split into the inner and outer subventricular zone, but stays intact as one. <ref name="control"/> The importance of reelin has also been greatly studied in mice. Studies showed that mutant mice have disruptions in the migration of neurons into their subsequent layers. By injecting thymidine at various time points of gestation into the female mice, researchers were able to track the development of various populations of neurons. Later developing neurons were unable to ascend past the already early formed neurons due to disruptions in reelin signaling (in the marginal zone). Instead, superficial layer neurons resided below the older, deep layer neurons. This inverted lamination comprises sensory and motor function.<ref> Caviness, V. (1982). Neocortical histogenesis in normal and reeler mice: A developmental study based upon [3H]thymidine autoradiography. Developmental Brain Research, 4(3), 293-302.</ref>
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Figure 21. Timeline and protocol of cerebral organoid development''']]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

The development of these brain organoids has allowed more comprehensive understanding of the self-organisational properties of the brain, and is quickly advancing, however the lack of vasculature in cultured organoids restricts their ability to be used for specific neurological disorders. Furthermore there are still challenges associated with the generation of individual, discrete brain regions, which should be addressed in the future. <ref><pubmed>28822354</pubmed></ref>

==Glossary==

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
|'''Agenesis'''|| The total absence of a tissue or organ
|-bgcolor="FAF5FF"
|'''Cajal-Retzius (CR) cells'''|| Cortical neurons that develop early on, at the same time as the preplate, and express an important glycoprotein known as reelin, which helps with the proper migration of neurons into their respective layers.
|-bgcolor="FAF5FF"
|'''Cortical Plate'''|| Forms in between the marginal zone and subplate and gives rise to the 6 layers of the cortex involved in sensory and motor function.
|-bgcolor="FAF5FF"
|'''Corticogenesis'''|| The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes.
|-bgcolor="FAF5FF"
|'''Fissures'''|| Large sulci.
|-bgcolor="FAF5FF"
|'''GABAergic Neurons'''|| Generate gamma aminobutyric acid (GABA) as their output, one of the two inhibitory neurotransmitters in the central nervous system (CNS).
|-bgcolor="FAF5FF"
|'''Gyrus '''|| Gyri (plural) are folds/ridges in the cerebral cortex.
|-bgcolor="FAF5FF"
|'''Hypoplasia'''|| Underdevelopment or incomplete development of a tissue or organ
|-bgcolor="FAF5FF"
|'''Intermediate zone'''|| Forms below the subplate between E50-55 and contains only migrating cells and no intermediate precursor cells.
|-bgcolor="FAF5FF"
|'''Marginal Zone (MZ)'''|| A subsection of the preplate that forms around E50-55. It lies at the uppermost area of the cortex nearest the pial surface.
|-bgcolor="FAF5FF"
|'''Neural Plate'''|| Main developmental structure required for the development of the nervous system.
|-bgcolor="FAF5FF"
|'''Neural Tube|| Structure of the embryo that evolves into the spinal cord and brain.
|-bgcolor="FAF5FF"
|'''Pachygyria'''|| Gyri can be seen but are very few compared to normal brain
|-bgcolor="FAF5FF"
|'''Preplate'''|| First "pioneer neurons" from dividing cells in the ventricular zone for this layer above the ventricular zone
|-bgcolor="FAF5FF"
|'''Radial glial cells '''|| A class of distinct nonneuronal cells that are bipolar shaped and span the entire width of the cortex during development.
|-bgcolor="FAF5FF"
|'''Subplate'''|| A subsection of the preplate that forms around E50-55.
|-bgcolor="FAF5FF"
|'''Subventricular zone (SVZ)'''|| Cells in the VZ continue to divide symmetrically and give rise to another zone above the VZ known as the SVZ. This zone later splits into an inner (ISVZ) and outer ventricular zone (OSVZ)
|-bgcolor="FAF5FF"
|'''Sulcus'''|| Sulci (plural) are grooves in the cerebral cortex.
|-bgcolor="FAF5FF"
|'''Total agyria'''||Gyri and sulci absent resulting in 'smooth brain'
|-bgcolor="FAF5FF"
|'''Ventricular zone (VZ)'''|| First formed single-celled layer in the cortex, arising from progenitors in the dorsal telencephalon that divide symmetrically. It lies adjacent to the ventricular surface.
|-bgcolor="FAF5FF"
|}

==References==

Talk:2017 Group Project 1

2017-10-26T04:30:19Z

Z5177691: /* 6 Layers */

{{ANAT2341Project2017discussion}}



=Image Use=
File:Neural- cortex Cajal drawing 01.jpg uploaded by z5177691

File:Stage 22 image 217.jpg uploaded by z5177691

=Cerebral Cortex=
==Introduction==
https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024757/ [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:37, 23 August 2017 (AEST)

==Lobes and Function==
4 Lobes: parietal, temporal, frontal, occipital
Video Overview: [https://www.khanacademy.org/science/health-and-medicine/human-anatomy-and-physiology/nervous-system-introduction/v/cerebral-cortex "Cerebral Histology"]
[[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:32, 23 August 2017 (AEST)

==Neocortical Development==
Nature article: https://www.nature.com/nrn/journal/v9/n2/full/nrn2252.html [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:57, 23 August 2017 (AEST)

==Anatomy and Function==

to do:

-change from dot points

-add images

-references

-finish function information

==Abnormalities==
PubMed Article: [https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024757/ "Developmental Disorders"] [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:41, 23 August 2017 (AEST)

=Peer Reviews=

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This page is very well structured and sequential. It provides a very detailed explanation of development under chronological subheadings. Subpages under images are well informed, but some images lack a proper Copyright phrase and Student Image Template to indicate reproducibility. On the main page, some subheadings need to be capitalised (formatting) and student signatures need to be provided on relevant sections, rather than student numbers . The "Anatomy of the Cerebral Cortex" section is filled with dot points, and could be improved using paragraphs, images and Wiki formatting. The layout of the Abnormalities section could be improved, by changing the headings and subheadings. The images and videos on the page are all very relevant to the topic, but I don't think the screenshots from youtube are appropriate of reputable. The page could benefit from a glossary list and 'Future Research' section. However, the reference list was well constructed. Overall the the page addresses the brief very well.

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Be careful in how the sentences are expressed for example in the introduction ‘the cerebral cortex is actually the outermost layer’; avoid using ‘actually’ in this sentence. Don’t forget to remove the student numbers from the posts. Minor grammatical errors; no use of commas in long sentences. The images do include copyright however the team has forgotten to place the Student Image Template that is required. The team should add a small description of the images that are on their webpage so readers will see immediately what the image is showing. The team could do a further questions subheading or an animal model subheading to explore more on the research of the Cerebral Cortex.

Subheadings and content that have been used show a good understanding of the topic area. The use of dot points where necessary are done well which makes the project easier to understand and read through. The use of tables to demonstrate the ‘Timeline of Corticogenesis’ is done comprehensively; maybe an image for each day that is explained should be added to show consistency (as only the last row has an image). The team has used their own diagrams which shows that the team was innovative in displaying their research. The references used are cited correctly, however, there are links at the bottom where they need to fix up and place it under references.

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Overall, the page is has nice structuring making it relatively easy to follow. But they are missing major topics necessary including historical discoveries, developmental signalling processes, current research and animal models. The introduction was short and concise, which provided a relevant amount of background knowledge. The anatomy and functions of the cerebral cortex could be put before the development so that it ties in with the introduction. The images and videos were relevant to the topic, which aided in understanding the content. However, labelling, adding a description and citing is necessary for images and videos which has not been done. A table would be a great feature for the timeline because right now its annoying to read and has a messy, unfinished look. References need fixing.

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The page has good structure and formatting, however there is a significant unfinished touch. Anatomy of the Cerebral Cortex heading could place all the information in a table to make it easier to read as well as images to help the viewer visualise the process. Maybe remove the student numbers because they are unnecessary and make the page look not as professional. figures and tables need to be labelled as well as referencing and copyright claims. The diagram under the statement "Migration and division of all six layers of the cortex is completed during the third trimester. Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex." needs to be further explained because I had a hard time understanding the image and what each section meant. The video is a nice touch to help understand the function and placement of the cerebral cortex. Developmental abnormalities was well written, easy to understand and flowed nicely.

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Well-structured and provides a vast amount of background information on the functions and structure of the cortex before delving into the details of development. However, the anatomy of the cerebral cortex and the layers are difficult to understand due to heavy use of dot points – perhaps images would be of good use in this section. There is consistently limited evidence of in-text references or citations throughout the information (rather than at the beginning of some of the sections) which makes it harder to link or follow where information was gathered. Headings are concise and easy to follow however the “other info to add” subheading under “Anatomy of the Cerebral Cortex” needs to be reworded for efficiency. Under the subheading “A) Disorders due to …” the disorders are inconsistently numbered – a 2 needs to be placed with “Hemimegalencephaly” as well as 8 with Schizencephaly. Functions of the cerebral cortex is hard to follow as dot points are used with lacking descriptions or expansion. Perhaps further discussing the actions of each functional area would provide more sufficient information in this part.

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The layout is looking very good, pictures could be a little smaller. I like the choice of headings, they explain well what is going to be talked about. I feel like you need to add headings like animal models and current research needs to be fixed but I’m sure that’s what is intended. I have some minor points for some of the headings:
Early development:
Spelling: Rhomboncephalon, and the instead of three at the beginning of a paragraph. Overall this heading was covered well
Development of cerebral cortex:
With images, you can add figure titles and this could make your page flow better!! Maybe expand a bit more on the key developmental zones in the human cortex, a brief explanation of what happens could help. The table is very well explained, however for E50-55 I can’t see a reference for all the information, also for the picture in the table for E50-55, you haven’t copied the copyright information so you should add that so it can be used in the page and also add the student template. I really like the drawn picture, but again a figure description would be helpful. This section is very well done.
Anatomy of the cerebral cortex
Some great points but needs to be broken up into paragraphs. Your Wikipedia link for the image is a good image however you should find the original, I recognize it from Cajal’s drawings so I think it could be in a paper about the cerebellum with Cajal. You have good ideas for this heading, also maybe add another image.
Functions of the cerebral cortex
For functional areas, I think a 2 sentence description of each area would be good and maybe a picture for reference.
Abnormalities
Intext referencing would be better. For images, add the student template to each!! Im not entirely sure how I feel about the youtube screenshots as images, maybe use one but try and find some in research articles aswell.
Overall, I think you’ve done a really good job at summarizing abnormalities.

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The introduction was a good opening to the Cortex page as it gives a brief overview and understanding of the cortex generally. The next subheading, “Early development of the Brain”, provides of a simple and clear explanation of the early development process however images would be a great addition to help visualise the text. Try having a look at some images that were shown to us in previous lectures on the brain development where it showed the neural plate, neuroectoderm and subsequent developments.
The next subheading, “Development of Cerebral Cortex”, would probably do better to be called “Later Development of Cerebral Cortex” as it would be a seamless flow from the previous subheading of “Early development…”. It was good that a labelled image was used and information was added for explanation. It helped orient me as I was going on to read about the timeline of corticogenesis. The timeline was detailed and the use of bold helped highlight key terms. However, I would suggest making another column for images on each day. Visual reinforcement just makes the information easier to absorb and make more sense.
The subheading, “Anatomy of the Cerebral Cortex”, is clearly in the editing process. I would just once again definitely recommend the use of images in this section, both hand-drawn diagrams and labelled images from the internet. I thought the use of a video was a clever way to cover the cerebral cortex functions. A bit of general text that briefly covers the functions of the main parts would be a good addition in this section, as a segue into the video.
The “Abnormalities” subheading was a good balance of text and images. It was easier to read because it was split into categories. I would only suggest that you mention at the beginning of the section that abnormalities associated with the cerebral cortex development can be divided into the following categories… I can see the references were placed at the beginning of the section and I’m assuming that is temporary. It is better if they are dispersed within the text where appropriate. There are a good bunch of references but you could probably aim for 25-30 for this page.

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This page needs some more information about current research, signaling processes, future questions and references to animal models. It would also be good with a table or quick overview of developmental origin. There has been a good use of pictures and tables. The setup of the section about abnormalities is really good. This page needs to use more references during the sections and not only at the start of a section. A glossary list would also be good for the reader to understand the page.

*'''Introduction''': Gives a quick knowledge of the cerebral cortex. A picture would be good to support this introduction and maybe a bit more description of the different terms. This section also needs references.
*'''Early Development:''' Good setup with bulleting. I find some of the context a bit confusing to read - especially these two sentences "From there three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five" and "During the fifth week, the embryonic brain undergoes rapid growth folding the neural tube and consequently resulting in three brain flexures" Maybe you can rephrase this.
*'''Development of Cerebral Cortex:''' Good section! Good overview.
*'''Timeline of Corticogenesis:''' Please give a short introduction of what Corticogenesis and Neurogenesis means. Good picture supporting the E50-55, maybe you can put this picture already in the section called "Key developmental zones in the human cortex" since this is the first time we get introduced to the different zones and plates and it would give a better basic knowledge before getting into Corticogenesis.
*'''Anatomy and Function of the Cerebral Cortex''': These two sections should maybe be earlier on the project page together with the introduction since it's a basic understanding of the Cerebral Cortex. Both sections look a bit messy, try to work on making it more simple and easier to read - it kind of looks like personal notes and not a proper information site :-) These sections also need some references. The video in this section gives a good understanding. Good idea putting a video on the page.
*'''Abnormalities associated with Cerebral Cortex Development:''' This section is really good. Great overview of the different scenarios and a lot of pictures to support the reading. Instead of mentioning all the references in the start of the section, you should add the specific reference used for each subsection, this will make it easier for the reader to look up references for specific sections.

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In the introduction section, it was not referenced where the information facts are from. This section should introduce a brief information on the topic, what you are going to discuss on the whole wiki page, introduce current researches and animal models to support the new findings and understandings. Also, don't use "actually" in the sentence.
On the page, It is better to write in full sentences instead of dot points as I've seen a lot of them and include any of scientific words in the glossary section at the end of the page. Where you've inserted picture, it will be clearer to also include it within the text in brackets for example (Figure 1).
Any figures or pictures on this page needs references as well.
In the abnormality section, it is well written with supporting pictures, but in my opinion, it is easier to read if the the figures/pictures are on the same side and texts on the other side instead of alternating. This section was very thoroughly referenced too. I think a small paragraph under the heading introducing the different type of disorders before going into greater details.
Don't focus too much on the anatomy as I can see this section is not finished nor written in paragraph and no pictures or figures, would be better to swap anatomy with some other embryology discussion for example, signalling processes.
Touch on current researches, animal model if any and future questions as they were not seen on the page. Also include a glossary table. References section is looking good but more is needed.

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Overall, a really informative and well-written wiki. The information was well presented and was understandable. The abnormalities section of the wiki, was particularly well done, as it was a good idea to group each abnormality with the disruption of the main event that lead to the abnormality, as it informs the reader that different abnormalities arise from a disruption of different processes that occur in the development of the cerebral cortex. The diagrams and pictures were useful as it functions as a reference point.

Overall, the layout was good, however maybe use more of a dot-point layout in the Anatomy section and maybe add some diagrams of pictures to enhance the information given. Also the sub-title "what is it?" is probably not needed as the introduction itself suggests that you will be describing what the cerebral cortex is and what is does. The Functions of Cerebral cortex may also need a bit more text as the video should just be a supplement rather than the main source for information in that section. Overall, well done as it was an informative and well written wiki.

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Overall I find the information provided to be concise and easy to understand. The introduction was great in giving us a brief overview of page. The layout of the early development of the brain and the development of the cerebral cortex was really nice. I like the use of bullet points as this makes it easier to read. Also good amount of referencing is seen in this area. The use of the table is also a nice touch to the page and I like the picture used for E50-55. However, it could help to have another column with pictures for each row. That would help with the understanding of the text. For the anatomy of the cerebral cortex, it seems a little messy and hard to read as it is too point form. Perhaps these could be phrased into proper sentences with certain parts placed into bullet points to make it easier to read. Also, with the anatomy, pictures would be very helpful to aid in the explanation. For the functions of the cerebral cortex, it lists the functional areas but not the functions of those areas. Although it is stated in the video, which is a nice addition to the page, this could be improved by adding short sentences that state these functions that were mentioned as well. For Sections 1.4 and 1.5, references are also needed to state where the information was obtained from. The abnormalities section provides detailed explanations of the various disorders associated with the development of the cerebral cortex. There is also a good amount of pictures used. One thing I noticed was the references which was placed on the top of the section instead of throughout the text.

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Overall, the page has a good structure and flow with good headings and subheadings. The information provided was concise and easy to comprehend. The introduction provides a brief overview and sufficient background knowledge about the cerebral cortex. I like how the team thought of mentioning about the early development of the brain before narrowing it down to the cerebral cortex. However these two sections do not seem to flow well. Maybe you could have 2-3 sentences that could help ease into the development of the cerebral cortex. I really love the timeline of corticogenesis. This part has been done really well. One minor improvement that could be made is to add images under each embryonic stage instead of just the last stage to better aid the reader into understanding the development. Also, a brief description of what corticogenesis is could be included before the table. For these two sections, there were a good amount of references.

For the anatomy of the cerebral cortex, it seems a little messy and hard to understand as its written in point forms. Perhaps, the dot points could be changed to proper sentences with histological images to tie it together. For the functions of the cerebral cortex, I think you could use a table to list down the areas and then provide a brief description of the functions of that particular part. The video is a good addition to the page. These two sections are lacking citations and references.The abnormalities section was well done. However, the citations should be added within the text instead of at the top of the page. Since there are a lot of abnormalities, maybe the team could list in a few sentences about all the abnormalities that they are going to discuss to have a better start to the section. For the images that are used on this page, the images should be labelled as “figure 1” or “table 1”. Maybe, sections on the “animal models” and “current research” could be added to wrap the page up.

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Overall the project was very good and clear. Pictures were well placed and bullet points spaced out information, making the page easy to look at and follow. The layout of the beginning and end sections with the short paragraphs and interspersed bullet points broke up the information and highlighted key facts. The introduction was a good overview of the page, including a quick summary of the anatomy, function, and development of the cerebral cortex.

There were some basic grammatical and spelling errors (e.g. “neurons” is spelled wrong under the subheading “Layer 4”), but for the most part did not take away from the clarity of the page. One sentence, “From there three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five,” seems to be missing something at the beginning that would increase clarity.

Some pictures had a lot of information in the summary when clicking on them while others lacked sufficient information. Some pictures that could benefit from more information are Corticogenesis of mouse and humans.jpeg, SBH.png, Disorders of Cortical Formation2.png, Symptoms of microcephaly.png, Hemimegalencephaly.png, and SchizencephalicBrain.jpg. These pictures are relevant to the topic and are pretty self-explanatory so this does not take away much clarity from the page but for the parameters of the project, additional summary should be added. The picture Stage22 HPA2L.jpg has good information in the summary but it is oddly structured. FASface.jpeg does not have any copyright information included. Having Gray754.png displayed on the page rather than as a link would look better.

The video describing the functions of the cerebral cortex was a good introduction to that topic. The video was easy to watch and understand. The first video about corpus callosum agenesis was a good introduction to the topic, but the second video about corpus callosum agenesis was long and the lecturer was hard to understand. That subheading would benefit from a brief description of that topic rather that a long video explanation.

The switch from a mix of bullets and short paragraphs to all bullet points in Anatomy of the Cerebral Cortex makes the page look less cohesive. The last bullet point in Layer 4 is hard to understand and the last 2 bullet points in Layer 5 would flow better if they were combined. The information in these sections are good and relatively easy to follow.

Overall the project is very good. The table explaining the timetable of cortex development is a clear way to break down the topic. Breaking down the information of abnormal development into what went wrong in the embryology (e.g. migration problems vs. differentiation problems) highlights importance of embryology in congenital disorders. There is a lot of information about the abnormal development of the cortex but could use some information about past and current research and animal studies. Reference list at the end looks good but the in-text citations of abnormal development should be interspersed with the information rather than all at the beginning.

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*Overall, the page is well structured and relatively easy to follow with the headings and subheadings relevant to the topic area (embryology of the cerebral cortex).

*The introduction was short and concise, which provided a relevant amount of background knowledge before delving straight into the development.

*Perhaps the Anatomy and Functions of the cerebral cortex could be put before the development so that it ties in with the introduction.

*The use of dot points under Anatomy and Function of the Cerebral Cortex was excessive and gives off an unfinished feel. Perhaps you could add in a couple of images to make these dot points easier to understand. Also, it might be better to use the * function to create these dot points.

*The use of the table on the "Timeline of Corticogenesis” was quite clever and made it easier to understand, however I suggest that you add photos in E30, E31-32 and E40-45 since there seems to only be one photo in E50-55. The page is lacking a "further questions" section which would be quite informative in understanding the research gap to date.

*I think the Disorders was nicely done and was very informative. The use of images in the left and right side of the page made it aesthetically pleasing to read. However this section lacks references, which I think you should add to avoid plagiarism.

*The images and videos that are on the page are very relevant to the topic, which aided in understanding the content. However perhaps you could label them using "Figure 1", or "Table 1" etc as well as putting an appropriate description under the image/video. Also, the link of an wiki image under Layers was not inserted properly, so be sure to check that for next time.

*References were inconsistent throughout the page, however most were done properly.

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The chosen headings for the development of the cerebral cortex were very suitable to highlight the key topics in providing a page of summarised information. It was then easy to navigate through the page using the shortcuts and finding information. Although, there was one sub sub heading “Timeline of Corticogenesis” that was formatted to be in bold while the rest were not.

The disorders listed seems to be really interesting and it covers the whole spectrum of the case abnormalities. But I suggest to get rid of the letter bullets (e.g. A), B), C) ) for the breakdown of the abnormalities.

The introduction had a quick and concise text, however, an image of the cerebellum would be suitable in this section on the side. While the sub sub heading stated that the introduction section will talk about the features of a cerebellum, a paragraph about the development and its stages were written down in this section as well. This could be moved into the ‘Early Development of the Brain’ subheading underneath. Bullet points of the brain layers as well as a diagram would be helpful for the visualisation of the brain.

For the sections that explain the development in specific weeks, a table would be advisable to make it neater and easier to look at. Also, an image was left inside the table grids and it was confusing whether it was meant to be there or not. Perhaps adding a photo gallery showing the stages at the bottom of the table would be better.

Hand drawn diagrams were really precise, neat and was very visually appealing. It was taking up all the space and unless it is intentional, I suggest to resize the drawing into a smaller one that fits the page as well as the accompanying text and content of the drawing.

The variety of visual aids were really entertaining and were referenced properly.

Finally, the reference list at the bottom of the page did not have a consistent format. It was mostly APA format however the others looked like a different format.

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The most obvious flaw was the lack of polish in formatting of some of the page. Bullet points are only so useful when it comes to writing a wiki page, instead of taking notes. The page is unfinished, but, the content included especially in the "Development of Cerebral Cortex" and "Abnormalities associated with Cerebral Cortex Development" was extensive and well done. The large table that linked the development with the time period was very useful and the choice of bolding key words allowed the main idea in the paragraph to be quickly understood from a glance. The use of images very much enhanced the descriptions and checker-like the layout of the different abnormalities was refreshing. Some subheadings, such as the Anatomy and Function of the cerebral cortex, could be elaborated on but the overall structure of the page is logical and fluid, and the writing is clear and concise without being superficial.

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Strengths: 
• The page has an excellent structure covering a broad variety of topics regarding the cerebral cortex. It was great to see how you also explored abnormalities associated with the cerebral cortex. Furthermore the use of various subheadings and headings related to cerebral cortex development meets criteria 1 and 2 of the assessment. 
• The presentation of the wiki page was excellent in that a variety of images, videos and tables were utilized. The use of such sources of information helps present information in a much more clear and concise manner, whilst also providing a thorough explanation to visual learners. Hence the wiki page has an element of teaching at a peer level (criteria 4 is satisfied). 
• A large number of references have also been included within the wiki page, a characteristic which helps increase the reliability of information presented. Furthermore, most sources are recent which another great characteristic. Thus, it appears that the group has satisfied criteria 3 for the assessment. 
• Each topic appears to show a significant amount of detail which is excellent. In addition, the use of images alongside the text is a great tool as the audience is able to better visualize the concept being described. 

Areas of improvement: 
• Although you have provided a variety of recent references, to improve you may avoid using sources as old as 1977 as results presented from this study may be outdated. 
• It was excellent that the functional areas of the brain were listed, however to improve you may wish to elaborate on the specific functions of these areas. You may also explore how abnormalities of these areas during development may impact upon the behaviour of the individual following birth 
• Whilst a variety of topics have been covered, you may wish to also describe the importance of signaling throughout the process of cortical development. For example, you may investigate different growth factors and receptors involved in the process. 
• Another possible improvement would be to perhaps include a timeline of different researchers who contributed to the in-depth understanding of the developing cortex that we have today. You may also describe what each researcher discovered. 
• In order to completely satisfy criteria 5, you may wish to conduct further research beyond the scope of formal teaching activities. For example you may explore the contribution of animal models towards our understanding of cortical development. 

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This peer review is based on the relevant dot points of the ‘Group Assessment Criteria’, as well as subheadings suggested by Mark. This information can be found on the student page.

{| border="1" align="left"
|-
|Criteria
|Strengths
|Weaknesses
|-
| 1. The choice of content shows a good understanding of the topic area
| The developmental origin of the cerebral cortex is addressed well under the sub-heading ‘Early development of the brain’.

The development timeline of the cerebral cortex is described clearly and in detail in the table of the ‘Timeline of corticogenesis’.

Abnormal development of the cerebral cortex and the associated conditions are covered in an immense amount of detail. The accompanying images and videos enhance the written information, as well as making it easier for the reader to comprehend. In addition, the sub-headings of this section compartmentalize the congenital diseases in a logical manner that highlights the link between abnormal development and specific diseases.
| There are several key topic areas missing from the page:
*There is no section covering key historical discoveries relevant to the cerebral cortex and its embryological development.
*There is no information relating to developmental signalling processes
*There is no section on current research in fields relevant to the embryological development of the cerebral cortex.
*There is no section on animal models that have been used to advance scientific understanding of the cerebral cortex.
*There is no section on future questions regarding the development of the cerebral cortex.
*A glossary of terms has not been included.

Some sections that have been included are somewhat irrelevant to the subject matter. For example, there is a large (unfinished) section on the anatomy and functions of the cerebral cortex. While it is important to provide a bit of an anatomical background on the subject, it shouldn’t be a major focus of this assignment. Focus more on the sections mentioned above, and keep the project focused on the embryology of the cerebral cortex.
|-
|2. Content is correctly cited and referenced
|There have been attempts at referencing throughout the assignment. A reference list has been produced and appears mostly correct. References have not been repeated throughout the list.

Peer-reviewed primary research articles have been used in this assignment.

The student-drawn image has been cited correctly, as have most of the images used in the ‘abnormal development’ section.
|Overall, referencing in this assignment is very poor. Most of the content is completely devoid of any references (see ‘introduction’, ‘anatomy of the cortex’ and ‘abnormal development), and sections that have been referenced have been referenced “by paragraph” (see ‘timeline of corticogenesis’)

Many of the sources used in this assignment are inappropriate and/or unreliable. Try to rely more on primary research articles and less on textbooks or websites.

Many of the images have been cited incorrectly and used without permission. Remember to include the full reference, the original summary and the copyright license information for each image.
|-
|3. The wiki has an element of teaching at a peer level
|The information presented is mostly at a level appropriate for peers. Images and hand-drawn diagrams have been included to facilitate the readers understanding of the subject matter. Some of the images contain useful descriptions of the subject matter, and aid in understanding of the topic.
|Many of the acronyms and terms used in this assignment are not well explained. Include a glossary of terms to make some of the content easier to follow and understand.
|-
|4. Relates the topic and content of the Wiki entry to learning aims of embryology
|The development of the cerebral cortex was covered extensively, which is a very important learning aim of embryology.
|There are certain learning aims of embryology that have not been included in this assignment, such as developmental signaling processes (see criteria 1 for more information). There has been no discussion of relevant historical or current research (adding in the subheadings “key developments” and “current research” would help rectify this).
|-
|5. The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic
|Certain aspects have been researched and presented well (such as embryological development).

Links to other pages of the UNSW embryology wiki have been included, however they have been used as references rather than just links.
|Information from the UNSW embryology wiki has been used as direct sources of information. Instead they should be included to relate this particular wiki page to other areas of learning.

The small number of sources cited in the reference list demonstrates a poor and narrow approach to researching this topic. A greater library of sources should be used to create this page (mainly primary research articles).
|}

Grade: FAIL

General Comment:
While some aspects of the wiki page have been done well, the page is largely unfinished. Many sections still need to be added, and others are in need of improvement.

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The introduction of this page gives a good general background but could benefit from adding bullet points to describe the six horizontal layers of the cortex and maybe a short summary of its clinical significance. 'Early Development' was well written, easy to follow and well referenced. 'Development of Cerebral Cortex' would benefit from a short introductory statement instead of going straight into the 'Main classes of neurons'. Pictures and tables in this section were informative and engaging to the reader. Hand-drawn picture was well done, colourful and easy to interpret. 'Anatomy of the Cerebral Cortex' looks unfinished and isn't easy to read as it doesn't flow or show a clear structure. No references can be seen and no pictures or tables to make for easier reading or understanding. The different layers of the cortex would greatly benefit from a table with structure/function format or a clear diagram. The same is true for 'Functions of the Cerebral Cortex'. 'Abnormalities associated with Cerebral Cortex Development' I liked the setup of this section because of its clear headings and subheadings as well as its informative pictures. The captions on some of these pictures need to be elaborated on. Also couldn't see any in text referencing which really needs to be present. Content is clear and concise and easy to follow. This section was engaging and well done. 'INFO/Research Links' was not finished yet but shows lots of research articles that could be promising.
----

'''Peer review project 1:'''

I have some general comments which applies to almost all of the sections in the project:
* The referencing is not proper. A lot of the sections do not have reference or all of the reference are at the bottom of the section.
* Some of the sections have bullet points instead of text. It feels like you are reading somebodies notes not a project.
* It would be nice with more pictures to get a better understanding. The pictures there are good, but it does not have any caption. The size is to big as well for some of the pictures (the drawing with the mouse and human model)
* The project does not have a current research, future questions section or animal, which is a requirement for the project.
* I think it would be better for the project if the anatomy and function sections stood before the development part. It would give a better understanding or at least I think so.
* In general, I don’t feel like the project is connected, and expressions like cortigenesis and neurogenesis is not defined.
* I really think the timeline is nice. But a lot of the text within the timeline would have been more appropriate to write in the cortex development section. It should contain some key discoveries instead. But the text there is good, makes sense to me and is well written.
* In the early development of the brain section I don’t understand some of the sentence like: “From there three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five. These are fundamental divisions of the adult brain and communicate freely with each other”. Some of it should properly be rephrased.
* There are some repetions during the project. The text could be compromised.
* In general, the language is neutral and written in a good scientific way.

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- Covers only development, anatomy, functions and abnormalities, more subheadings could be better and exploring other areas of the embryology of the cerebral cortex

- Nice introduction that summarises what the cerebral cortex does and some of its structural layers. Would be nice to see a diagram with the layers of the cerebral cortex or a diagram of the cerebral cortex in the introduction.

- Development of the brain was covered really well and was detailed and also proper and good amount of referencing in this section. Good use of lot of pictures in this section, which made it much easier to understand.

- Timeline of corticogenesis was explained very well in a straightforward manner and use of the table helped.

- Anatomy of cerebral cortex as well as functions of the cerebral cortex is still incomplete and is mainly in dot points and no referencing

- Abnormalities was done well and very detailed and covered many types of abnormalities. Disorders were also divided into categories which is good.

- Good use of pictures in the abnormalities of the section for each abnormalities but use of videos were probably not necessary in this section

- Overall, introduction, development and abnormalities were all done well and good grammar and spelling. Other main headings definitely needed more work and referencing was done incorrectly or absent in some parts. There could be more subheadings and there is no glossary.

- References are from proper journal articles/peer reviewed journals which is good.

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- Introduction provides a good summary, however the list of layers is quite long so maybe adding a diagram would make all that information a bit easier to take in? Or perhaps, listing the layers in dot point form rather than a long sentence.
- Early development of the brain is very detailed, well researched as evidenced by the many references. Perhaps a short table summarising all that information could be added. Some formatting issues, but nothing that can't be easily fixed.
- Development of cerebral cortex section very well done. Good use of diagrams and the table; they made the information easier to understand. However maybe the drawn diagram could be smaller (good job though!). Easy to follow.
- Anatomy and functions sections are obviously unfinished, but it is clear that extensive research has been done to produce all that in the first place. So good job, once it is all formatted, I'm sure it will look great. All the dot points were easy to understand anyway.
- Abnormalities section was very well researched. Great use of diagrams. Personally, I found the subheadings easy to grasp in the Contents, however it was a bit overwhelming to scroll through it all.

Overall, a good job. It is clear that some sections are incomplete, but it seems like there is a clear direction of where it is going. I would recommend a glossary of terms, just because the cerebral cortex is so complex and all the terms can become overwhelming. Tables in the development would help with this also just to provide a quick and easily accesible summary of development.

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* Introduction
** Could have been linked together with anatomy and function for better structuring of page
** Simple diagram could have been used to provide context on body location
* Development of the cerebral cortex
** Section should be expanded upon to give context to the content
*** Seemed like a sudden introduction of neuronal classes and key developmental zones without much expansion
** Section seemed to be more about components of the developing cerebral cortex rather than development itself – could update subheading to reflect this or update content to focus more on development
* Timeline of corticogenesis
** Could have been its own subheading
* Anatomy
** Should be moved up towards start of the page with introduction
* Functions
** Should be moved up towards start of page with introduction
** Functional areas should be expanded upon to briefly discuss their different roles
** Should not rely too much on linked video
* Abnormalities
** Diagram “disorders of cortical formation” gave little information relating to section – seemed like illustration related little to the mentioned stages. Instead, could have mentioned that abnormalities arise during proliferation, migration and organisation during cortical development
** Lettering and numbering of subheadings in this section should be switched for clarity
* Overall was well done. However:
** Some diagrams lacked descriptions and figure legends/abbreviation definitions – diagrams should be self-explanatory and be understandable in combination with their descriptions, when taken out of their contexts within the page
** Minor grammatical errors present throughout the page
** Mostly well-structured but some subheadings can be shifted around - see above for specific feedback
** Remember to clear zIDs before final submission

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*Introduction
**References are missing.
**Labeled images could be included to illustrate the relative position of cerebral cortex and cerebrum in the human brain and the organization of cerebral cortex into the six horizontal layers.

*Early development of the brain
**Written expression could be clearer. For example, L1: “The brain begins to develop during the third week (of pregnancy) when the neural plate and (neural) tube (are derived) from the outermost layer of embryonic cells, (that is) the neuroectoderm.”.
**A table listing the major development occurring at each week (i.e. week 3 – start of development of brain, week 4 – fusion of the neural folds) could be included for easier understanding of the developmental timeline
**Labeled images should be included for clear illustration of the relative positions and development of various parts of the cerebral cortex.

*Development of cerebral cortex
**Appropriate inclusion of images that aid in understanding the content. However, there is little reference or explanation to the images in the text. No caption is included for the images. The first image and the second image are redundant to each other as they are both illustrating the key developmental zones in the human cortex. Author may want to consider taking one of them out.
**Good use of a table in summarising the developmental timeline for corticogenesis. Clear explanation of corticogenesis.

*Anatomy of the cerebral cortex
**Content could be better organized in paragraphs instead of point forms.
**Labelled images should be included for clear illustration

*Functions of the cerebral cortex
**More content could be added to each of the functional areas listed.
**Video is appropriate and useful in facilitating understanding.

*Abnormalities associated with cerebral cortex development
**References should be included where appropriate instead of generalizing as “references used to write”.
**The amount of content seems slightly overwhelming as compared to other sections of the page which are equally important as well. Nonetheless, good effort in explaining the abnormalities in great details.
**Some references are missing.

*References
**Good effort in for having both journal and book references. However, it would be good to adhere to either APA or BJP style of referencing.

__

GROUP 1

Early Development of the Brain: Well written, maybe a little concise, there are some great images which could be useful for this section also Development of Cerebral Cortex: Lots of good information, maybe try to make this section a bit more fluid - comes of a little disjointed Anatomy of the Cerebral Cortex/Functions of the Cerebral Cortex: This section does not read well to the eye - that's not to say it is incorrect - I would try putting this into a friendly format Abnormalities associated with Cerebral Cortex Development: This section is huge, but each condition has a fairly concise explanation so well done

Overall: There is lots of sound information on the page - main emphasis would be giving the page a clean up of the format and trying to make the sections flow together a little nicer

Talk:2017 Group Project 1

2017-10-26T04:30:10Z

Z5177691: /* Cell Types */

{{ANAT2341Project2017discussion}}



=Image Use=
File:Neural- cortex Cajal drawing 01.jpg uploaded by z5177691

File:Stage 22 image 217.jpg uploaded by z5177691

=Cerebral Cortex=
==Introduction==
https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024757/ [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:37, 23 August 2017 (AEST)

==Lobes and Function==
4 Lobes: parietal, temporal, frontal, occipital
Video Overview: [https://www.khanacademy.org/science/health-and-medicine/human-anatomy-and-physiology/nervous-system-introduction/v/cerebral-cortex "Cerebral Histology"]
[[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:32, 23 August 2017 (AEST)

==Neocortical Development==
Nature article: https://www.nature.com/nrn/journal/v9/n2/full/nrn2252.html [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:57, 23 August 2017 (AEST)

===6 Layers===
Layers I, II, III, IV, V, VI (see [http://www.ruf.rice.edu/~lngbrain/Sidhya/ "Cortical Layer Review"] [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:57, 23 August 2017 (AEST)

==Anatomy and Function==

to do:

-change from dot points

-add images

-references

-finish function information

==Abnormalities==
PubMed Article: [https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024757/ "Developmental Disorders"] [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:41, 23 August 2017 (AEST)

=Peer Reviews=

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This page is very well structured and sequential. It provides a very detailed explanation of development under chronological subheadings. Subpages under images are well informed, but some images lack a proper Copyright phrase and Student Image Template to indicate reproducibility. On the main page, some subheadings need to be capitalised (formatting) and student signatures need to be provided on relevant sections, rather than student numbers . The "Anatomy of the Cerebral Cortex" section is filled with dot points, and could be improved using paragraphs, images and Wiki formatting. The layout of the Abnormalities section could be improved, by changing the headings and subheadings. The images and videos on the page are all very relevant to the topic, but I don't think the screenshots from youtube are appropriate of reputable. The page could benefit from a glossary list and 'Future Research' section. However, the reference list was well constructed. Overall the the page addresses the brief very well.

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Be careful in how the sentences are expressed for example in the introduction ‘the cerebral cortex is actually the outermost layer’; avoid using ‘actually’ in this sentence. Don’t forget to remove the student numbers from the posts. Minor grammatical errors; no use of commas in long sentences. The images do include copyright however the team has forgotten to place the Student Image Template that is required. The team should add a small description of the images that are on their webpage so readers will see immediately what the image is showing. The team could do a further questions subheading or an animal model subheading to explore more on the research of the Cerebral Cortex.

Subheadings and content that have been used show a good understanding of the topic area. The use of dot points where necessary are done well which makes the project easier to understand and read through. The use of tables to demonstrate the ‘Timeline of Corticogenesis’ is done comprehensively; maybe an image for each day that is explained should be added to show consistency (as only the last row has an image). The team has used their own diagrams which shows that the team was innovative in displaying their research. The references used are cited correctly, however, there are links at the bottom where they need to fix up and place it under references.

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Overall, the page is has nice structuring making it relatively easy to follow. But they are missing major topics necessary including historical discoveries, developmental signalling processes, current research and animal models. The introduction was short and concise, which provided a relevant amount of background knowledge. The anatomy and functions of the cerebral cortex could be put before the development so that it ties in with the introduction. The images and videos were relevant to the topic, which aided in understanding the content. However, labelling, adding a description and citing is necessary for images and videos which has not been done. A table would be a great feature for the timeline because right now its annoying to read and has a messy, unfinished look. References need fixing.

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The page has good structure and formatting, however there is a significant unfinished touch. Anatomy of the Cerebral Cortex heading could place all the information in a table to make it easier to read as well as images to help the viewer visualise the process. Maybe remove the student numbers because they are unnecessary and make the page look not as professional. figures and tables need to be labelled as well as referencing and copyright claims. The diagram under the statement "Migration and division of all six layers of the cortex is completed during the third trimester. Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex." needs to be further explained because I had a hard time understanding the image and what each section meant. The video is a nice touch to help understand the function and placement of the cerebral cortex. Developmental abnormalities was well written, easy to understand and flowed nicely.

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Well-structured and provides a vast amount of background information on the functions and structure of the cortex before delving into the details of development. However, the anatomy of the cerebral cortex and the layers are difficult to understand due to heavy use of dot points – perhaps images would be of good use in this section. There is consistently limited evidence of in-text references or citations throughout the information (rather than at the beginning of some of the sections) which makes it harder to link or follow where information was gathered. Headings are concise and easy to follow however the “other info to add” subheading under “Anatomy of the Cerebral Cortex” needs to be reworded for efficiency. Under the subheading “A) Disorders due to …” the disorders are inconsistently numbered – a 2 needs to be placed with “Hemimegalencephaly” as well as 8 with Schizencephaly. Functions of the cerebral cortex is hard to follow as dot points are used with lacking descriptions or expansion. Perhaps further discussing the actions of each functional area would provide more sufficient information in this part.

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The layout is looking very good, pictures could be a little smaller. I like the choice of headings, they explain well what is going to be talked about. I feel like you need to add headings like animal models and current research needs to be fixed but I’m sure that’s what is intended. I have some minor points for some of the headings:
Early development:
Spelling: Rhomboncephalon, and the instead of three at the beginning of a paragraph. Overall this heading was covered well
Development of cerebral cortex:
With images, you can add figure titles and this could make your page flow better!! Maybe expand a bit more on the key developmental zones in the human cortex, a brief explanation of what happens could help. The table is very well explained, however for E50-55 I can’t see a reference for all the information, also for the picture in the table for E50-55, you haven’t copied the copyright information so you should add that so it can be used in the page and also add the student template. I really like the drawn picture, but again a figure description would be helpful. This section is very well done.
Anatomy of the cerebral cortex
Some great points but needs to be broken up into paragraphs. Your Wikipedia link for the image is a good image however you should find the original, I recognize it from Cajal’s drawings so I think it could be in a paper about the cerebellum with Cajal. You have good ideas for this heading, also maybe add another image.
Functions of the cerebral cortex
For functional areas, I think a 2 sentence description of each area would be good and maybe a picture for reference.
Abnormalities
Intext referencing would be better. For images, add the student template to each!! Im not entirely sure how I feel about the youtube screenshots as images, maybe use one but try and find some in research articles aswell.
Overall, I think you’ve done a really good job at summarizing abnormalities.

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The introduction was a good opening to the Cortex page as it gives a brief overview and understanding of the cortex generally. The next subheading, “Early development of the Brain”, provides of a simple and clear explanation of the early development process however images would be a great addition to help visualise the text. Try having a look at some images that were shown to us in previous lectures on the brain development where it showed the neural plate, neuroectoderm and subsequent developments.
The next subheading, “Development of Cerebral Cortex”, would probably do better to be called “Later Development of Cerebral Cortex” as it would be a seamless flow from the previous subheading of “Early development…”. It was good that a labelled image was used and information was added for explanation. It helped orient me as I was going on to read about the timeline of corticogenesis. The timeline was detailed and the use of bold helped highlight key terms. However, I would suggest making another column for images on each day. Visual reinforcement just makes the information easier to absorb and make more sense.
The subheading, “Anatomy of the Cerebral Cortex”, is clearly in the editing process. I would just once again definitely recommend the use of images in this section, both hand-drawn diagrams and labelled images from the internet. I thought the use of a video was a clever way to cover the cerebral cortex functions. A bit of general text that briefly covers the functions of the main parts would be a good addition in this section, as a segue into the video.
The “Abnormalities” subheading was a good balance of text and images. It was easier to read because it was split into categories. I would only suggest that you mention at the beginning of the section that abnormalities associated with the cerebral cortex development can be divided into the following categories… I can see the references were placed at the beginning of the section and I’m assuming that is temporary. It is better if they are dispersed within the text where appropriate. There are a good bunch of references but you could probably aim for 25-30 for this page.

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This page needs some more information about current research, signaling processes, future questions and references to animal models. It would also be good with a table or quick overview of developmental origin. There has been a good use of pictures and tables. The setup of the section about abnormalities is really good. This page needs to use more references during the sections and not only at the start of a section. A glossary list would also be good for the reader to understand the page.

*'''Introduction''': Gives a quick knowledge of the cerebral cortex. A picture would be good to support this introduction and maybe a bit more description of the different terms. This section also needs references.
*'''Early Development:''' Good setup with bulleting. I find some of the context a bit confusing to read - especially these two sentences "From there three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five" and "During the fifth week, the embryonic brain undergoes rapid growth folding the neural tube and consequently resulting in three brain flexures" Maybe you can rephrase this.
*'''Development of Cerebral Cortex:''' Good section! Good overview.
*'''Timeline of Corticogenesis:''' Please give a short introduction of what Corticogenesis and Neurogenesis means. Good picture supporting the E50-55, maybe you can put this picture already in the section called "Key developmental zones in the human cortex" since this is the first time we get introduced to the different zones and plates and it would give a better basic knowledge before getting into Corticogenesis.
*'''Anatomy and Function of the Cerebral Cortex''': These two sections should maybe be earlier on the project page together with the introduction since it's a basic understanding of the Cerebral Cortex. Both sections look a bit messy, try to work on making it more simple and easier to read - it kind of looks like personal notes and not a proper information site :-) These sections also need some references. The video in this section gives a good understanding. Good idea putting a video on the page.
*'''Abnormalities associated with Cerebral Cortex Development:''' This section is really good. Great overview of the different scenarios and a lot of pictures to support the reading. Instead of mentioning all the references in the start of the section, you should add the specific reference used for each subsection, this will make it easier for the reader to look up references for specific sections.

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In the introduction section, it was not referenced where the information facts are from. This section should introduce a brief information on the topic, what you are going to discuss on the whole wiki page, introduce current researches and animal models to support the new findings and understandings. Also, don't use "actually" in the sentence.
On the page, It is better to write in full sentences instead of dot points as I've seen a lot of them and include any of scientific words in the glossary section at the end of the page. Where you've inserted picture, it will be clearer to also include it within the text in brackets for example (Figure 1).
Any figures or pictures on this page needs references as well.
In the abnormality section, it is well written with supporting pictures, but in my opinion, it is easier to read if the the figures/pictures are on the same side and texts on the other side instead of alternating. This section was very thoroughly referenced too. I think a small paragraph under the heading introducing the different type of disorders before going into greater details.
Don't focus too much on the anatomy as I can see this section is not finished nor written in paragraph and no pictures or figures, would be better to swap anatomy with some other embryology discussion for example, signalling processes.
Touch on current researches, animal model if any and future questions as they were not seen on the page. Also include a glossary table. References section is looking good but more is needed.

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Overall, a really informative and well-written wiki. The information was well presented and was understandable. The abnormalities section of the wiki, was particularly well done, as it was a good idea to group each abnormality with the disruption of the main event that lead to the abnormality, as it informs the reader that different abnormalities arise from a disruption of different processes that occur in the development of the cerebral cortex. The diagrams and pictures were useful as it functions as a reference point.

Overall, the layout was good, however maybe use more of a dot-point layout in the Anatomy section and maybe add some diagrams of pictures to enhance the information given. Also the sub-title "what is it?" is probably not needed as the introduction itself suggests that you will be describing what the cerebral cortex is and what is does. The Functions of Cerebral cortex may also need a bit more text as the video should just be a supplement rather than the main source for information in that section. Overall, well done as it was an informative and well written wiki.

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Overall I find the information provided to be concise and easy to understand. The introduction was great in giving us a brief overview of page. The layout of the early development of the brain and the development of the cerebral cortex was really nice. I like the use of bullet points as this makes it easier to read. Also good amount of referencing is seen in this area. The use of the table is also a nice touch to the page and I like the picture used for E50-55. However, it could help to have another column with pictures for each row. That would help with the understanding of the text. For the anatomy of the cerebral cortex, it seems a little messy and hard to read as it is too point form. Perhaps these could be phrased into proper sentences with certain parts placed into bullet points to make it easier to read. Also, with the anatomy, pictures would be very helpful to aid in the explanation. For the functions of the cerebral cortex, it lists the functional areas but not the functions of those areas. Although it is stated in the video, which is a nice addition to the page, this could be improved by adding short sentences that state these functions that were mentioned as well. For Sections 1.4 and 1.5, references are also needed to state where the information was obtained from. The abnormalities section provides detailed explanations of the various disorders associated with the development of the cerebral cortex. There is also a good amount of pictures used. One thing I noticed was the references which was placed on the top of the section instead of throughout the text.

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Overall, the page has a good structure and flow with good headings and subheadings. The information provided was concise and easy to comprehend. The introduction provides a brief overview and sufficient background knowledge about the cerebral cortex. I like how the team thought of mentioning about the early development of the brain before narrowing it down to the cerebral cortex. However these two sections do not seem to flow well. Maybe you could have 2-3 sentences that could help ease into the development of the cerebral cortex. I really love the timeline of corticogenesis. This part has been done really well. One minor improvement that could be made is to add images under each embryonic stage instead of just the last stage to better aid the reader into understanding the development. Also, a brief description of what corticogenesis is could be included before the table. For these two sections, there were a good amount of references.

For the anatomy of the cerebral cortex, it seems a little messy and hard to understand as its written in point forms. Perhaps, the dot points could be changed to proper sentences with histological images to tie it together. For the functions of the cerebral cortex, I think you could use a table to list down the areas and then provide a brief description of the functions of that particular part. The video is a good addition to the page. These two sections are lacking citations and references.The abnormalities section was well done. However, the citations should be added within the text instead of at the top of the page. Since there are a lot of abnormalities, maybe the team could list in a few sentences about all the abnormalities that they are going to discuss to have a better start to the section. For the images that are used on this page, the images should be labelled as “figure 1” or “table 1”. Maybe, sections on the “animal models” and “current research” could be added to wrap the page up.

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Overall the project was very good and clear. Pictures were well placed and bullet points spaced out information, making the page easy to look at and follow. The layout of the beginning and end sections with the short paragraphs and interspersed bullet points broke up the information and highlighted key facts. The introduction was a good overview of the page, including a quick summary of the anatomy, function, and development of the cerebral cortex.

There were some basic grammatical and spelling errors (e.g. “neurons” is spelled wrong under the subheading “Layer 4”), but for the most part did not take away from the clarity of the page. One sentence, “From there three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five,” seems to be missing something at the beginning that would increase clarity.

Some pictures had a lot of information in the summary when clicking on them while others lacked sufficient information. Some pictures that could benefit from more information are Corticogenesis of mouse and humans.jpeg, SBH.png, Disorders of Cortical Formation2.png, Symptoms of microcephaly.png, Hemimegalencephaly.png, and SchizencephalicBrain.jpg. These pictures are relevant to the topic and are pretty self-explanatory so this does not take away much clarity from the page but for the parameters of the project, additional summary should be added. The picture Stage22 HPA2L.jpg has good information in the summary but it is oddly structured. FASface.jpeg does not have any copyright information included. Having Gray754.png displayed on the page rather than as a link would look better.

The video describing the functions of the cerebral cortex was a good introduction to that topic. The video was easy to watch and understand. The first video about corpus callosum agenesis was a good introduction to the topic, but the second video about corpus callosum agenesis was long and the lecturer was hard to understand. That subheading would benefit from a brief description of that topic rather that a long video explanation.

The switch from a mix of bullets and short paragraphs to all bullet points in Anatomy of the Cerebral Cortex makes the page look less cohesive. The last bullet point in Layer 4 is hard to understand and the last 2 bullet points in Layer 5 would flow better if they were combined. The information in these sections are good and relatively easy to follow.

Overall the project is very good. The table explaining the timetable of cortex development is a clear way to break down the topic. Breaking down the information of abnormal development into what went wrong in the embryology (e.g. migration problems vs. differentiation problems) highlights importance of embryology in congenital disorders. There is a lot of information about the abnormal development of the cortex but could use some information about past and current research and animal studies. Reference list at the end looks good but the in-text citations of abnormal development should be interspersed with the information rather than all at the beginning.

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*Overall, the page is well structured and relatively easy to follow with the headings and subheadings relevant to the topic area (embryology of the cerebral cortex).

*The introduction was short and concise, which provided a relevant amount of background knowledge before delving straight into the development.

*Perhaps the Anatomy and Functions of the cerebral cortex could be put before the development so that it ties in with the introduction.

*The use of dot points under Anatomy and Function of the Cerebral Cortex was excessive and gives off an unfinished feel. Perhaps you could add in a couple of images to make these dot points easier to understand. Also, it might be better to use the * function to create these dot points.

*The use of the table on the "Timeline of Corticogenesis” was quite clever and made it easier to understand, however I suggest that you add photos in E30, E31-32 and E40-45 since there seems to only be one photo in E50-55. The page is lacking a "further questions" section which would be quite informative in understanding the research gap to date.

*I think the Disorders was nicely done and was very informative. The use of images in the left and right side of the page made it aesthetically pleasing to read. However this section lacks references, which I think you should add to avoid plagiarism.

*The images and videos that are on the page are very relevant to the topic, which aided in understanding the content. However perhaps you could label them using "Figure 1", or "Table 1" etc as well as putting an appropriate description under the image/video. Also, the link of an wiki image under Layers was not inserted properly, so be sure to check that for next time.

*References were inconsistent throughout the page, however most were done properly.

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The chosen headings for the development of the cerebral cortex were very suitable to highlight the key topics in providing a page of summarised information. It was then easy to navigate through the page using the shortcuts and finding information. Although, there was one sub sub heading “Timeline of Corticogenesis” that was formatted to be in bold while the rest were not.

The disorders listed seems to be really interesting and it covers the whole spectrum of the case abnormalities. But I suggest to get rid of the letter bullets (e.g. A), B), C) ) for the breakdown of the abnormalities.

The introduction had a quick and concise text, however, an image of the cerebellum would be suitable in this section on the side. While the sub sub heading stated that the introduction section will talk about the features of a cerebellum, a paragraph about the development and its stages were written down in this section as well. This could be moved into the ‘Early Development of the Brain’ subheading underneath. Bullet points of the brain layers as well as a diagram would be helpful for the visualisation of the brain.

For the sections that explain the development in specific weeks, a table would be advisable to make it neater and easier to look at. Also, an image was left inside the table grids and it was confusing whether it was meant to be there or not. Perhaps adding a photo gallery showing the stages at the bottom of the table would be better.

Hand drawn diagrams were really precise, neat and was very visually appealing. It was taking up all the space and unless it is intentional, I suggest to resize the drawing into a smaller one that fits the page as well as the accompanying text and content of the drawing.

The variety of visual aids were really entertaining and were referenced properly.

Finally, the reference list at the bottom of the page did not have a consistent format. It was mostly APA format however the others looked like a different format.

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The most obvious flaw was the lack of polish in formatting of some of the page. Bullet points are only so useful when it comes to writing a wiki page, instead of taking notes. The page is unfinished, but, the content included especially in the "Development of Cerebral Cortex" and "Abnormalities associated with Cerebral Cortex Development" was extensive and well done. The large table that linked the development with the time period was very useful and the choice of bolding key words allowed the main idea in the paragraph to be quickly understood from a glance. The use of images very much enhanced the descriptions and checker-like the layout of the different abnormalities was refreshing. Some subheadings, such as the Anatomy and Function of the cerebral cortex, could be elaborated on but the overall structure of the page is logical and fluid, and the writing is clear and concise without being superficial.

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Strengths: 
• The page has an excellent structure covering a broad variety of topics regarding the cerebral cortex. It was great to see how you also explored abnormalities associated with the cerebral cortex. Furthermore the use of various subheadings and headings related to cerebral cortex development meets criteria 1 and 2 of the assessment. 
• The presentation of the wiki page was excellent in that a variety of images, videos and tables were utilized. The use of such sources of information helps present information in a much more clear and concise manner, whilst also providing a thorough explanation to visual learners. Hence the wiki page has an element of teaching at a peer level (criteria 4 is satisfied). 
• A large number of references have also been included within the wiki page, a characteristic which helps increase the reliability of information presented. Furthermore, most sources are recent which another great characteristic. Thus, it appears that the group has satisfied criteria 3 for the assessment. 
• Each topic appears to show a significant amount of detail which is excellent. In addition, the use of images alongside the text is a great tool as the audience is able to better visualize the concept being described. 

Areas of improvement: 
• Although you have provided a variety of recent references, to improve you may avoid using sources as old as 1977 as results presented from this study may be outdated. 
• It was excellent that the functional areas of the brain were listed, however to improve you may wish to elaborate on the specific functions of these areas. You may also explore how abnormalities of these areas during development may impact upon the behaviour of the individual following birth 
• Whilst a variety of topics have been covered, you may wish to also describe the importance of signaling throughout the process of cortical development. For example, you may investigate different growth factors and receptors involved in the process. 
• Another possible improvement would be to perhaps include a timeline of different researchers who contributed to the in-depth understanding of the developing cortex that we have today. You may also describe what each researcher discovered. 
• In order to completely satisfy criteria 5, you may wish to conduct further research beyond the scope of formal teaching activities. For example you may explore the contribution of animal models towards our understanding of cortical development. 

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This peer review is based on the relevant dot points of the ‘Group Assessment Criteria’, as well as subheadings suggested by Mark. This information can be found on the student page.

{| border="1" align="left"
|-
|Criteria
|Strengths
|Weaknesses
|-
| 1. The choice of content shows a good understanding of the topic area
| The developmental origin of the cerebral cortex is addressed well under the sub-heading ‘Early development of the brain’.

The development timeline of the cerebral cortex is described clearly and in detail in the table of the ‘Timeline of corticogenesis’.

Abnormal development of the cerebral cortex and the associated conditions are covered in an immense amount of detail. The accompanying images and videos enhance the written information, as well as making it easier for the reader to comprehend. In addition, the sub-headings of this section compartmentalize the congenital diseases in a logical manner that highlights the link between abnormal development and specific diseases.
| There are several key topic areas missing from the page:
*There is no section covering key historical discoveries relevant to the cerebral cortex and its embryological development.
*There is no information relating to developmental signalling processes
*There is no section on current research in fields relevant to the embryological development of the cerebral cortex.
*There is no section on animal models that have been used to advance scientific understanding of the cerebral cortex.
*There is no section on future questions regarding the development of the cerebral cortex.
*A glossary of terms has not been included.

Some sections that have been included are somewhat irrelevant to the subject matter. For example, there is a large (unfinished) section on the anatomy and functions of the cerebral cortex. While it is important to provide a bit of an anatomical background on the subject, it shouldn’t be a major focus of this assignment. Focus more on the sections mentioned above, and keep the project focused on the embryology of the cerebral cortex.
|-
|2. Content is correctly cited and referenced
|There have been attempts at referencing throughout the assignment. A reference list has been produced and appears mostly correct. References have not been repeated throughout the list.

Peer-reviewed primary research articles have been used in this assignment.

The student-drawn image has been cited correctly, as have most of the images used in the ‘abnormal development’ section.
|Overall, referencing in this assignment is very poor. Most of the content is completely devoid of any references (see ‘introduction’, ‘anatomy of the cortex’ and ‘abnormal development), and sections that have been referenced have been referenced “by paragraph” (see ‘timeline of corticogenesis’)

Many of the sources used in this assignment are inappropriate and/or unreliable. Try to rely more on primary research articles and less on textbooks or websites.

Many of the images have been cited incorrectly and used without permission. Remember to include the full reference, the original summary and the copyright license information for each image.
|-
|3. The wiki has an element of teaching at a peer level
|The information presented is mostly at a level appropriate for peers. Images and hand-drawn diagrams have been included to facilitate the readers understanding of the subject matter. Some of the images contain useful descriptions of the subject matter, and aid in understanding of the topic.
|Many of the acronyms and terms used in this assignment are not well explained. Include a glossary of terms to make some of the content easier to follow and understand.
|-
|4. Relates the topic and content of the Wiki entry to learning aims of embryology
|The development of the cerebral cortex was covered extensively, which is a very important learning aim of embryology.
|There are certain learning aims of embryology that have not been included in this assignment, such as developmental signaling processes (see criteria 1 for more information). There has been no discussion of relevant historical or current research (adding in the subheadings “key developments” and “current research” would help rectify this).
|-
|5. The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic
|Certain aspects have been researched and presented well (such as embryological development).

Links to other pages of the UNSW embryology wiki have been included, however they have been used as references rather than just links.
|Information from the UNSW embryology wiki has been used as direct sources of information. Instead they should be included to relate this particular wiki page to other areas of learning.

The small number of sources cited in the reference list demonstrates a poor and narrow approach to researching this topic. A greater library of sources should be used to create this page (mainly primary research articles).
|}

Grade: FAIL

General Comment:
While some aspects of the wiki page have been done well, the page is largely unfinished. Many sections still need to be added, and others are in need of improvement.

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The introduction of this page gives a good general background but could benefit from adding bullet points to describe the six horizontal layers of the cortex and maybe a short summary of its clinical significance. 'Early Development' was well written, easy to follow and well referenced. 'Development of Cerebral Cortex' would benefit from a short introductory statement instead of going straight into the 'Main classes of neurons'. Pictures and tables in this section were informative and engaging to the reader. Hand-drawn picture was well done, colourful and easy to interpret. 'Anatomy of the Cerebral Cortex' looks unfinished and isn't easy to read as it doesn't flow or show a clear structure. No references can be seen and no pictures or tables to make for easier reading or understanding. The different layers of the cortex would greatly benefit from a table with structure/function format or a clear diagram. The same is true for 'Functions of the Cerebral Cortex'. 'Abnormalities associated with Cerebral Cortex Development' I liked the setup of this section because of its clear headings and subheadings as well as its informative pictures. The captions on some of these pictures need to be elaborated on. Also couldn't see any in text referencing which really needs to be present. Content is clear and concise and easy to follow. This section was engaging and well done. 'INFO/Research Links' was not finished yet but shows lots of research articles that could be promising.
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'''Peer review project 1:'''

I have some general comments which applies to almost all of the sections in the project:
* The referencing is not proper. A lot of the sections do not have reference or all of the reference are at the bottom of the section.
* Some of the sections have bullet points instead of text. It feels like you are reading somebodies notes not a project.
* It would be nice with more pictures to get a better understanding. The pictures there are good, but it does not have any caption. The size is to big as well for some of the pictures (the drawing with the mouse and human model)
* The project does not have a current research, future questions section or animal, which is a requirement for the project.
* I think it would be better for the project if the anatomy and function sections stood before the development part. It would give a better understanding or at least I think so.
* In general, I don’t feel like the project is connected, and expressions like cortigenesis and neurogenesis is not defined.
* I really think the timeline is nice. But a lot of the text within the timeline would have been more appropriate to write in the cortex development section. It should contain some key discoveries instead. But the text there is good, makes sense to me and is well written.
* In the early development of the brain section I don’t understand some of the sentence like: “From there three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five. These are fundamental divisions of the adult brain and communicate freely with each other”. Some of it should properly be rephrased.
* There are some repetions during the project. The text could be compromised.
* In general, the language is neutral and written in a good scientific way.

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- Covers only development, anatomy, functions and abnormalities, more subheadings could be better and exploring other areas of the embryology of the cerebral cortex

- Nice introduction that summarises what the cerebral cortex does and some of its structural layers. Would be nice to see a diagram with the layers of the cerebral cortex or a diagram of the cerebral cortex in the introduction.

- Development of the brain was covered really well and was detailed and also proper and good amount of referencing in this section. Good use of lot of pictures in this section, which made it much easier to understand.

- Timeline of corticogenesis was explained very well in a straightforward manner and use of the table helped.

- Anatomy of cerebral cortex as well as functions of the cerebral cortex is still incomplete and is mainly in dot points and no referencing

- Abnormalities was done well and very detailed and covered many types of abnormalities. Disorders were also divided into categories which is good.

- Good use of pictures in the abnormalities of the section for each abnormalities but use of videos were probably not necessary in this section

- Overall, introduction, development and abnormalities were all done well and good grammar and spelling. Other main headings definitely needed more work and referencing was done incorrectly or absent in some parts. There could be more subheadings and there is no glossary.

- References are from proper journal articles/peer reviewed journals which is good.

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- Introduction provides a good summary, however the list of layers is quite long so maybe adding a diagram would make all that information a bit easier to take in? Or perhaps, listing the layers in dot point form rather than a long sentence.
- Early development of the brain is very detailed, well researched as evidenced by the many references. Perhaps a short table summarising all that information could be added. Some formatting issues, but nothing that can't be easily fixed.
- Development of cerebral cortex section very well done. Good use of diagrams and the table; they made the information easier to understand. However maybe the drawn diagram could be smaller (good job though!). Easy to follow.
- Anatomy and functions sections are obviously unfinished, but it is clear that extensive research has been done to produce all that in the first place. So good job, once it is all formatted, I'm sure it will look great. All the dot points were easy to understand anyway.
- Abnormalities section was very well researched. Great use of diagrams. Personally, I found the subheadings easy to grasp in the Contents, however it was a bit overwhelming to scroll through it all.

Overall, a good job. It is clear that some sections are incomplete, but it seems like there is a clear direction of where it is going. I would recommend a glossary of terms, just because the cerebral cortex is so complex and all the terms can become overwhelming. Tables in the development would help with this also just to provide a quick and easily accesible summary of development.

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* Introduction
** Could have been linked together with anatomy and function for better structuring of page
** Simple diagram could have been used to provide context on body location
* Development of the cerebral cortex
** Section should be expanded upon to give context to the content
*** Seemed like a sudden introduction of neuronal classes and key developmental zones without much expansion
** Section seemed to be more about components of the developing cerebral cortex rather than development itself – could update subheading to reflect this or update content to focus more on development
* Timeline of corticogenesis
** Could have been its own subheading
* Anatomy
** Should be moved up towards start of the page with introduction
* Functions
** Should be moved up towards start of page with introduction
** Functional areas should be expanded upon to briefly discuss their different roles
** Should not rely too much on linked video
* Abnormalities
** Diagram “disorders of cortical formation” gave little information relating to section – seemed like illustration related little to the mentioned stages. Instead, could have mentioned that abnormalities arise during proliferation, migration and organisation during cortical development
** Lettering and numbering of subheadings in this section should be switched for clarity
* Overall was well done. However:
** Some diagrams lacked descriptions and figure legends/abbreviation definitions – diagrams should be self-explanatory and be understandable in combination with their descriptions, when taken out of their contexts within the page
** Minor grammatical errors present throughout the page
** Mostly well-structured but some subheadings can be shifted around - see above for specific feedback
** Remember to clear zIDs before final submission

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*Introduction
**References are missing.
**Labeled images could be included to illustrate the relative position of cerebral cortex and cerebrum in the human brain and the organization of cerebral cortex into the six horizontal layers.

*Early development of the brain
**Written expression could be clearer. For example, L1: “The brain begins to develop during the third week (of pregnancy) when the neural plate and (neural) tube (are derived) from the outermost layer of embryonic cells, (that is) the neuroectoderm.”.
**A table listing the major development occurring at each week (i.e. week 3 – start of development of brain, week 4 – fusion of the neural folds) could be included for easier understanding of the developmental timeline
**Labeled images should be included for clear illustration of the relative positions and development of various parts of the cerebral cortex.

*Development of cerebral cortex
**Appropriate inclusion of images that aid in understanding the content. However, there is little reference or explanation to the images in the text. No caption is included for the images. The first image and the second image are redundant to each other as they are both illustrating the key developmental zones in the human cortex. Author may want to consider taking one of them out.
**Good use of a table in summarising the developmental timeline for corticogenesis. Clear explanation of corticogenesis.

*Anatomy of the cerebral cortex
**Content could be better organized in paragraphs instead of point forms.
**Labelled images should be included for clear illustration

*Functions of the cerebral cortex
**More content could be added to each of the functional areas listed.
**Video is appropriate and useful in facilitating understanding.

*Abnormalities associated with cerebral cortex development
**References should be included where appropriate instead of generalizing as “references used to write”.
**The amount of content seems slightly overwhelming as compared to other sections of the page which are equally important as well. Nonetheless, good effort in explaining the abnormalities in great details.
**Some references are missing.

*References
**Good effort in for having both journal and book references. However, it would be good to adhere to either APA or BJP style of referencing.

__

GROUP 1

Early Development of the Brain: Well written, maybe a little concise, there are some great images which could be useful for this section also Development of Cerebral Cortex: Lots of good information, maybe try to make this section a bit more fluid - comes of a little disjointed Anatomy of the Cerebral Cortex/Functions of the Cerebral Cortex: This section does not read well to the eye - that's not to say it is incorrect - I would try putting this into a friendly format Abnormalities associated with Cerebral Cortex Development: This section is huge, but each condition has a fairly concise explanation so well done

Overall: There is lots of sound information on the page - main emphasis would be giving the page a clean up of the format and trying to make the sections flow together a little nicer

Talk:2017 Group Project 1

2017-10-26T04:29:56Z

Z5177691: /* Image Use */

{{ANAT2341Project2017discussion}}



=Image Use=
File:Neural- cortex Cajal drawing 01.jpg uploaded by z5177691

File:Stage 22 image 217.jpg uploaded by z5177691

=Cerebral Cortex=
==Introduction==
https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024757/ [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:37, 23 August 2017 (AEST)

==Lobes and Function==
4 Lobes: parietal, temporal, frontal, occipital
Video Overview: [https://www.khanacademy.org/science/health-and-medicine/human-anatomy-and-physiology/nervous-system-introduction/v/cerebral-cortex "Cerebral Histology"]
[[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:32, 23 August 2017 (AEST)

==Neocortical Development==
Nature article: https://www.nature.com/nrn/journal/v9/n2/full/nrn2252.html [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:57, 23 August 2017 (AEST)

===6 Layers===
Layers I, II, III, IV, V, VI (see [http://www.ruf.rice.edu/~lngbrain/Sidhya/ "Cortical Layer Review"] [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:57, 23 August 2017 (AEST)

==Anatomy and Function==

to do:

-change from dot points

-add images

-references

-finish function information

===Cell Types===
http://www.ruf.rice.edu/~lngbrain/Sidhya/ [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:57, 23 August 2017 (AEST)

==Abnormalities==
PubMed Article: [https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024757/ "Developmental Disorders"] [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:41, 23 August 2017 (AEST)

=Peer Reviews=

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This page is very well structured and sequential. It provides a very detailed explanation of development under chronological subheadings. Subpages under images are well informed, but some images lack a proper Copyright phrase and Student Image Template to indicate reproducibility. On the main page, some subheadings need to be capitalised (formatting) and student signatures need to be provided on relevant sections, rather than student numbers . The "Anatomy of the Cerebral Cortex" section is filled with dot points, and could be improved using paragraphs, images and Wiki formatting. The layout of the Abnormalities section could be improved, by changing the headings and subheadings. The images and videos on the page are all very relevant to the topic, but I don't think the screenshots from youtube are appropriate of reputable. The page could benefit from a glossary list and 'Future Research' section. However, the reference list was well constructed. Overall the the page addresses the brief very well.

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Be careful in how the sentences are expressed for example in the introduction ‘the cerebral cortex is actually the outermost layer’; avoid using ‘actually’ in this sentence. Don’t forget to remove the student numbers from the posts. Minor grammatical errors; no use of commas in long sentences. The images do include copyright however the team has forgotten to place the Student Image Template that is required. The team should add a small description of the images that are on their webpage so readers will see immediately what the image is showing. The team could do a further questions subheading or an animal model subheading to explore more on the research of the Cerebral Cortex.

Subheadings and content that have been used show a good understanding of the topic area. The use of dot points where necessary are done well which makes the project easier to understand and read through. The use of tables to demonstrate the ‘Timeline of Corticogenesis’ is done comprehensively; maybe an image for each day that is explained should be added to show consistency (as only the last row has an image). The team has used their own diagrams which shows that the team was innovative in displaying their research. The references used are cited correctly, however, there are links at the bottom where they need to fix up and place it under references.

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Overall, the page is has nice structuring making it relatively easy to follow. But they are missing major topics necessary including historical discoveries, developmental signalling processes, current research and animal models. The introduction was short and concise, which provided a relevant amount of background knowledge. The anatomy and functions of the cerebral cortex could be put before the development so that it ties in with the introduction. The images and videos were relevant to the topic, which aided in understanding the content. However, labelling, adding a description and citing is necessary for images and videos which has not been done. A table would be a great feature for the timeline because right now its annoying to read and has a messy, unfinished look. References need fixing.

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The page has good structure and formatting, however there is a significant unfinished touch. Anatomy of the Cerebral Cortex heading could place all the information in a table to make it easier to read as well as images to help the viewer visualise the process. Maybe remove the student numbers because they are unnecessary and make the page look not as professional. figures and tables need to be labelled as well as referencing and copyright claims. The diagram under the statement "Migration and division of all six layers of the cortex is completed during the third trimester. Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex." needs to be further explained because I had a hard time understanding the image and what each section meant. The video is a nice touch to help understand the function and placement of the cerebral cortex. Developmental abnormalities was well written, easy to understand and flowed nicely.

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Well-structured and provides a vast amount of background information on the functions and structure of the cortex before delving into the details of development. However, the anatomy of the cerebral cortex and the layers are difficult to understand due to heavy use of dot points – perhaps images would be of good use in this section. There is consistently limited evidence of in-text references or citations throughout the information (rather than at the beginning of some of the sections) which makes it harder to link or follow where information was gathered. Headings are concise and easy to follow however the “other info to add” subheading under “Anatomy of the Cerebral Cortex” needs to be reworded for efficiency. Under the subheading “A) Disorders due to …” the disorders are inconsistently numbered – a 2 needs to be placed with “Hemimegalencephaly” as well as 8 with Schizencephaly. Functions of the cerebral cortex is hard to follow as dot points are used with lacking descriptions or expansion. Perhaps further discussing the actions of each functional area would provide more sufficient information in this part.

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The layout is looking very good, pictures could be a little smaller. I like the choice of headings, they explain well what is going to be talked about. I feel like you need to add headings like animal models and current research needs to be fixed but I’m sure that’s what is intended. I have some minor points for some of the headings:
Early development:
Spelling: Rhomboncephalon, and the instead of three at the beginning of a paragraph. Overall this heading was covered well
Development of cerebral cortex:
With images, you can add figure titles and this could make your page flow better!! Maybe expand a bit more on the key developmental zones in the human cortex, a brief explanation of what happens could help. The table is very well explained, however for E50-55 I can’t see a reference for all the information, also for the picture in the table for E50-55, you haven’t copied the copyright information so you should add that so it can be used in the page and also add the student template. I really like the drawn picture, but again a figure description would be helpful. This section is very well done.
Anatomy of the cerebral cortex
Some great points but needs to be broken up into paragraphs. Your Wikipedia link for the image is a good image however you should find the original, I recognize it from Cajal’s drawings so I think it could be in a paper about the cerebellum with Cajal. You have good ideas for this heading, also maybe add another image.
Functions of the cerebral cortex
For functional areas, I think a 2 sentence description of each area would be good and maybe a picture for reference.
Abnormalities
Intext referencing would be better. For images, add the student template to each!! Im not entirely sure how I feel about the youtube screenshots as images, maybe use one but try and find some in research articles aswell.
Overall, I think you’ve done a really good job at summarizing abnormalities.

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The introduction was a good opening to the Cortex page as it gives a brief overview and understanding of the cortex generally. The next subheading, “Early development of the Brain”, provides of a simple and clear explanation of the early development process however images would be a great addition to help visualise the text. Try having a look at some images that were shown to us in previous lectures on the brain development where it showed the neural plate, neuroectoderm and subsequent developments.
The next subheading, “Development of Cerebral Cortex”, would probably do better to be called “Later Development of Cerebral Cortex” as it would be a seamless flow from the previous subheading of “Early development…”. It was good that a labelled image was used and information was added for explanation. It helped orient me as I was going on to read about the timeline of corticogenesis. The timeline was detailed and the use of bold helped highlight key terms. However, I would suggest making another column for images on each day. Visual reinforcement just makes the information easier to absorb and make more sense.
The subheading, “Anatomy of the Cerebral Cortex”, is clearly in the editing process. I would just once again definitely recommend the use of images in this section, both hand-drawn diagrams and labelled images from the internet. I thought the use of a video was a clever way to cover the cerebral cortex functions. A bit of general text that briefly covers the functions of the main parts would be a good addition in this section, as a segue into the video.
The “Abnormalities” subheading was a good balance of text and images. It was easier to read because it was split into categories. I would only suggest that you mention at the beginning of the section that abnormalities associated with the cerebral cortex development can be divided into the following categories… I can see the references were placed at the beginning of the section and I’m assuming that is temporary. It is better if they are dispersed within the text where appropriate. There are a good bunch of references but you could probably aim for 25-30 for this page.

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This page needs some more information about current research, signaling processes, future questions and references to animal models. It would also be good with a table or quick overview of developmental origin. There has been a good use of pictures and tables. The setup of the section about abnormalities is really good. This page needs to use more references during the sections and not only at the start of a section. A glossary list would also be good for the reader to understand the page.

*'''Introduction''': Gives a quick knowledge of the cerebral cortex. A picture would be good to support this introduction and maybe a bit more description of the different terms. This section also needs references.
*'''Early Development:''' Good setup with bulleting. I find some of the context a bit confusing to read - especially these two sentences "From there three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five" and "During the fifth week, the embryonic brain undergoes rapid growth folding the neural tube and consequently resulting in three brain flexures" Maybe you can rephrase this.
*'''Development of Cerebral Cortex:''' Good section! Good overview.
*'''Timeline of Corticogenesis:''' Please give a short introduction of what Corticogenesis and Neurogenesis means. Good picture supporting the E50-55, maybe you can put this picture already in the section called "Key developmental zones in the human cortex" since this is the first time we get introduced to the different zones and plates and it would give a better basic knowledge before getting into Corticogenesis.
*'''Anatomy and Function of the Cerebral Cortex''': These two sections should maybe be earlier on the project page together with the introduction since it's a basic understanding of the Cerebral Cortex. Both sections look a bit messy, try to work on making it more simple and easier to read - it kind of looks like personal notes and not a proper information site :-) These sections also need some references. The video in this section gives a good understanding. Good idea putting a video on the page.
*'''Abnormalities associated with Cerebral Cortex Development:''' This section is really good. Great overview of the different scenarios and a lot of pictures to support the reading. Instead of mentioning all the references in the start of the section, you should add the specific reference used for each subsection, this will make it easier for the reader to look up references for specific sections.

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In the introduction section, it was not referenced where the information facts are from. This section should introduce a brief information on the topic, what you are going to discuss on the whole wiki page, introduce current researches and animal models to support the new findings and understandings. Also, don't use "actually" in the sentence.
On the page, It is better to write in full sentences instead of dot points as I've seen a lot of them and include any of scientific words in the glossary section at the end of the page. Where you've inserted picture, it will be clearer to also include it within the text in brackets for example (Figure 1).
Any figures or pictures on this page needs references as well.
In the abnormality section, it is well written with supporting pictures, but in my opinion, it is easier to read if the the figures/pictures are on the same side and texts on the other side instead of alternating. This section was very thoroughly referenced too. I think a small paragraph under the heading introducing the different type of disorders before going into greater details.
Don't focus too much on the anatomy as I can see this section is not finished nor written in paragraph and no pictures or figures, would be better to swap anatomy with some other embryology discussion for example, signalling processes.
Touch on current researches, animal model if any and future questions as they were not seen on the page. Also include a glossary table. References section is looking good but more is needed.

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Overall, a really informative and well-written wiki. The information was well presented and was understandable. The abnormalities section of the wiki, was particularly well done, as it was a good idea to group each abnormality with the disruption of the main event that lead to the abnormality, as it informs the reader that different abnormalities arise from a disruption of different processes that occur in the development of the cerebral cortex. The diagrams and pictures were useful as it functions as a reference point.

Overall, the layout was good, however maybe use more of a dot-point layout in the Anatomy section and maybe add some diagrams of pictures to enhance the information given. Also the sub-title "what is it?" is probably not needed as the introduction itself suggests that you will be describing what the cerebral cortex is and what is does. The Functions of Cerebral cortex may also need a bit more text as the video should just be a supplement rather than the main source for information in that section. Overall, well done as it was an informative and well written wiki.

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Overall I find the information provided to be concise and easy to understand. The introduction was great in giving us a brief overview of page. The layout of the early development of the brain and the development of the cerebral cortex was really nice. I like the use of bullet points as this makes it easier to read. Also good amount of referencing is seen in this area. The use of the table is also a nice touch to the page and I like the picture used for E50-55. However, it could help to have another column with pictures for each row. That would help with the understanding of the text. For the anatomy of the cerebral cortex, it seems a little messy and hard to read as it is too point form. Perhaps these could be phrased into proper sentences with certain parts placed into bullet points to make it easier to read. Also, with the anatomy, pictures would be very helpful to aid in the explanation. For the functions of the cerebral cortex, it lists the functional areas but not the functions of those areas. Although it is stated in the video, which is a nice addition to the page, this could be improved by adding short sentences that state these functions that were mentioned as well. For Sections 1.4 and 1.5, references are also needed to state where the information was obtained from. The abnormalities section provides detailed explanations of the various disorders associated with the development of the cerebral cortex. There is also a good amount of pictures used. One thing I noticed was the references which was placed on the top of the section instead of throughout the text.

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Overall, the page has a good structure and flow with good headings and subheadings. The information provided was concise and easy to comprehend. The introduction provides a brief overview and sufficient background knowledge about the cerebral cortex. I like how the team thought of mentioning about the early development of the brain before narrowing it down to the cerebral cortex. However these two sections do not seem to flow well. Maybe you could have 2-3 sentences that could help ease into the development of the cerebral cortex. I really love the timeline of corticogenesis. This part has been done really well. One minor improvement that could be made is to add images under each embryonic stage instead of just the last stage to better aid the reader into understanding the development. Also, a brief description of what corticogenesis is could be included before the table. For these two sections, there were a good amount of references.

For the anatomy of the cerebral cortex, it seems a little messy and hard to understand as its written in point forms. Perhaps, the dot points could be changed to proper sentences with histological images to tie it together. For the functions of the cerebral cortex, I think you could use a table to list down the areas and then provide a brief description of the functions of that particular part. The video is a good addition to the page. These two sections are lacking citations and references.The abnormalities section was well done. However, the citations should be added within the text instead of at the top of the page. Since there are a lot of abnormalities, maybe the team could list in a few sentences about all the abnormalities that they are going to discuss to have a better start to the section. For the images that are used on this page, the images should be labelled as “figure 1” or “table 1”. Maybe, sections on the “animal models” and “current research” could be added to wrap the page up.

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Overall the project was very good and clear. Pictures were well placed and bullet points spaced out information, making the page easy to look at and follow. The layout of the beginning and end sections with the short paragraphs and interspersed bullet points broke up the information and highlighted key facts. The introduction was a good overview of the page, including a quick summary of the anatomy, function, and development of the cerebral cortex.

There were some basic grammatical and spelling errors (e.g. “neurons” is spelled wrong under the subheading “Layer 4”), but for the most part did not take away from the clarity of the page. One sentence, “From there three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five,” seems to be missing something at the beginning that would increase clarity.

Some pictures had a lot of information in the summary when clicking on them while others lacked sufficient information. Some pictures that could benefit from more information are Corticogenesis of mouse and humans.jpeg, SBH.png, Disorders of Cortical Formation2.png, Symptoms of microcephaly.png, Hemimegalencephaly.png, and SchizencephalicBrain.jpg. These pictures are relevant to the topic and are pretty self-explanatory so this does not take away much clarity from the page but for the parameters of the project, additional summary should be added. The picture Stage22 HPA2L.jpg has good information in the summary but it is oddly structured. FASface.jpeg does not have any copyright information included. Having Gray754.png displayed on the page rather than as a link would look better.

The video describing the functions of the cerebral cortex was a good introduction to that topic. The video was easy to watch and understand. The first video about corpus callosum agenesis was a good introduction to the topic, but the second video about corpus callosum agenesis was long and the lecturer was hard to understand. That subheading would benefit from a brief description of that topic rather that a long video explanation.

The switch from a mix of bullets and short paragraphs to all bullet points in Anatomy of the Cerebral Cortex makes the page look less cohesive. The last bullet point in Layer 4 is hard to understand and the last 2 bullet points in Layer 5 would flow better if they were combined. The information in these sections are good and relatively easy to follow.

Overall the project is very good. The table explaining the timetable of cortex development is a clear way to break down the topic. Breaking down the information of abnormal development into what went wrong in the embryology (e.g. migration problems vs. differentiation problems) highlights importance of embryology in congenital disorders. There is a lot of information about the abnormal development of the cortex but could use some information about past and current research and animal studies. Reference list at the end looks good but the in-text citations of abnormal development should be interspersed with the information rather than all at the beginning.

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*Overall, the page is well structured and relatively easy to follow with the headings and subheadings relevant to the topic area (embryology of the cerebral cortex).

*The introduction was short and concise, which provided a relevant amount of background knowledge before delving straight into the development.

*Perhaps the Anatomy and Functions of the cerebral cortex could be put before the development so that it ties in with the introduction.

*The use of dot points under Anatomy and Function of the Cerebral Cortex was excessive and gives off an unfinished feel. Perhaps you could add in a couple of images to make these dot points easier to understand. Also, it might be better to use the * function to create these dot points.

*The use of the table on the "Timeline of Corticogenesis” was quite clever and made it easier to understand, however I suggest that you add photos in E30, E31-32 and E40-45 since there seems to only be one photo in E50-55. The page is lacking a "further questions" section which would be quite informative in understanding the research gap to date.

*I think the Disorders was nicely done and was very informative. The use of images in the left and right side of the page made it aesthetically pleasing to read. However this section lacks references, which I think you should add to avoid plagiarism.

*The images and videos that are on the page are very relevant to the topic, which aided in understanding the content. However perhaps you could label them using "Figure 1", or "Table 1" etc as well as putting an appropriate description under the image/video. Also, the link of an wiki image under Layers was not inserted properly, so be sure to check that for next time.

*References were inconsistent throughout the page, however most were done properly.

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The chosen headings for the development of the cerebral cortex were very suitable to highlight the key topics in providing a page of summarised information. It was then easy to navigate through the page using the shortcuts and finding information. Although, there was one sub sub heading “Timeline of Corticogenesis” that was formatted to be in bold while the rest were not.

The disorders listed seems to be really interesting and it covers the whole spectrum of the case abnormalities. But I suggest to get rid of the letter bullets (e.g. A), B), C) ) for the breakdown of the abnormalities.

The introduction had a quick and concise text, however, an image of the cerebellum would be suitable in this section on the side. While the sub sub heading stated that the introduction section will talk about the features of a cerebellum, a paragraph about the development and its stages were written down in this section as well. This could be moved into the ‘Early Development of the Brain’ subheading underneath. Bullet points of the brain layers as well as a diagram would be helpful for the visualisation of the brain.

For the sections that explain the development in specific weeks, a table would be advisable to make it neater and easier to look at. Also, an image was left inside the table grids and it was confusing whether it was meant to be there or not. Perhaps adding a photo gallery showing the stages at the bottom of the table would be better.

Hand drawn diagrams were really precise, neat and was very visually appealing. It was taking up all the space and unless it is intentional, I suggest to resize the drawing into a smaller one that fits the page as well as the accompanying text and content of the drawing.

The variety of visual aids were really entertaining and were referenced properly.

Finally, the reference list at the bottom of the page did not have a consistent format. It was mostly APA format however the others looked like a different format.

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The most obvious flaw was the lack of polish in formatting of some of the page. Bullet points are only so useful when it comes to writing a wiki page, instead of taking notes. The page is unfinished, but, the content included especially in the "Development of Cerebral Cortex" and "Abnormalities associated with Cerebral Cortex Development" was extensive and well done. The large table that linked the development with the time period was very useful and the choice of bolding key words allowed the main idea in the paragraph to be quickly understood from a glance. The use of images very much enhanced the descriptions and checker-like the layout of the different abnormalities was refreshing. Some subheadings, such as the Anatomy and Function of the cerebral cortex, could be elaborated on but the overall structure of the page is logical and fluid, and the writing is clear and concise without being superficial.

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Strengths: 
• The page has an excellent structure covering a broad variety of topics regarding the cerebral cortex. It was great to see how you also explored abnormalities associated with the cerebral cortex. Furthermore the use of various subheadings and headings related to cerebral cortex development meets criteria 1 and 2 of the assessment. 
• The presentation of the wiki page was excellent in that a variety of images, videos and tables were utilized. The use of such sources of information helps present information in a much more clear and concise manner, whilst also providing a thorough explanation to visual learners. Hence the wiki page has an element of teaching at a peer level (criteria 4 is satisfied). 
• A large number of references have also been included within the wiki page, a characteristic which helps increase the reliability of information presented. Furthermore, most sources are recent which another great characteristic. Thus, it appears that the group has satisfied criteria 3 for the assessment. 
• Each topic appears to show a significant amount of detail which is excellent. In addition, the use of images alongside the text is a great tool as the audience is able to better visualize the concept being described. 

Areas of improvement: 
• Although you have provided a variety of recent references, to improve you may avoid using sources as old as 1977 as results presented from this study may be outdated. 
• It was excellent that the functional areas of the brain were listed, however to improve you may wish to elaborate on the specific functions of these areas. You may also explore how abnormalities of these areas during development may impact upon the behaviour of the individual following birth 
• Whilst a variety of topics have been covered, you may wish to also describe the importance of signaling throughout the process of cortical development. For example, you may investigate different growth factors and receptors involved in the process. 
• Another possible improvement would be to perhaps include a timeline of different researchers who contributed to the in-depth understanding of the developing cortex that we have today. You may also describe what each researcher discovered. 
• In order to completely satisfy criteria 5, you may wish to conduct further research beyond the scope of formal teaching activities. For example you may explore the contribution of animal models towards our understanding of cortical development. 

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This peer review is based on the relevant dot points of the ‘Group Assessment Criteria’, as well as subheadings suggested by Mark. This information can be found on the student page.

{| border="1" align="left"
|-
|Criteria
|Strengths
|Weaknesses
|-
| 1. The choice of content shows a good understanding of the topic area
| The developmental origin of the cerebral cortex is addressed well under the sub-heading ‘Early development of the brain’.

The development timeline of the cerebral cortex is described clearly and in detail in the table of the ‘Timeline of corticogenesis’.

Abnormal development of the cerebral cortex and the associated conditions are covered in an immense amount of detail. The accompanying images and videos enhance the written information, as well as making it easier for the reader to comprehend. In addition, the sub-headings of this section compartmentalize the congenital diseases in a logical manner that highlights the link between abnormal development and specific diseases.
| There are several key topic areas missing from the page:
*There is no section covering key historical discoveries relevant to the cerebral cortex and its embryological development.
*There is no information relating to developmental signalling processes
*There is no section on current research in fields relevant to the embryological development of the cerebral cortex.
*There is no section on animal models that have been used to advance scientific understanding of the cerebral cortex.
*There is no section on future questions regarding the development of the cerebral cortex.
*A glossary of terms has not been included.

Some sections that have been included are somewhat irrelevant to the subject matter. For example, there is a large (unfinished) section on the anatomy and functions of the cerebral cortex. While it is important to provide a bit of an anatomical background on the subject, it shouldn’t be a major focus of this assignment. Focus more on the sections mentioned above, and keep the project focused on the embryology of the cerebral cortex.
|-
|2. Content is correctly cited and referenced
|There have been attempts at referencing throughout the assignment. A reference list has been produced and appears mostly correct. References have not been repeated throughout the list.

Peer-reviewed primary research articles have been used in this assignment.

The student-drawn image has been cited correctly, as have most of the images used in the ‘abnormal development’ section.
|Overall, referencing in this assignment is very poor. Most of the content is completely devoid of any references (see ‘introduction’, ‘anatomy of the cortex’ and ‘abnormal development), and sections that have been referenced have been referenced “by paragraph” (see ‘timeline of corticogenesis’)

Many of the sources used in this assignment are inappropriate and/or unreliable. Try to rely more on primary research articles and less on textbooks or websites.

Many of the images have been cited incorrectly and used without permission. Remember to include the full reference, the original summary and the copyright license information for each image.
|-
|3. The wiki has an element of teaching at a peer level
|The information presented is mostly at a level appropriate for peers. Images and hand-drawn diagrams have been included to facilitate the readers understanding of the subject matter. Some of the images contain useful descriptions of the subject matter, and aid in understanding of the topic.
|Many of the acronyms and terms used in this assignment are not well explained. Include a glossary of terms to make some of the content easier to follow and understand.
|-
|4. Relates the topic and content of the Wiki entry to learning aims of embryology
|The development of the cerebral cortex was covered extensively, which is a very important learning aim of embryology.
|There are certain learning aims of embryology that have not been included in this assignment, such as developmental signaling processes (see criteria 1 for more information). There has been no discussion of relevant historical or current research (adding in the subheadings “key developments” and “current research” would help rectify this).
|-
|5. The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic
|Certain aspects have been researched and presented well (such as embryological development).

Links to other pages of the UNSW embryology wiki have been included, however they have been used as references rather than just links.
|Information from the UNSW embryology wiki has been used as direct sources of information. Instead they should be included to relate this particular wiki page to other areas of learning.

The small number of sources cited in the reference list demonstrates a poor and narrow approach to researching this topic. A greater library of sources should be used to create this page (mainly primary research articles).
|}

Grade: FAIL

General Comment:
While some aspects of the wiki page have been done well, the page is largely unfinished. Many sections still need to be added, and others are in need of improvement.

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The introduction of this page gives a good general background but could benefit from adding bullet points to describe the six horizontal layers of the cortex and maybe a short summary of its clinical significance. 'Early Development' was well written, easy to follow and well referenced. 'Development of Cerebral Cortex' would benefit from a short introductory statement instead of going straight into the 'Main classes of neurons'. Pictures and tables in this section were informative and engaging to the reader. Hand-drawn picture was well done, colourful and easy to interpret. 'Anatomy of the Cerebral Cortex' looks unfinished and isn't easy to read as it doesn't flow or show a clear structure. No references can be seen and no pictures or tables to make for easier reading or understanding. The different layers of the cortex would greatly benefit from a table with structure/function format or a clear diagram. The same is true for 'Functions of the Cerebral Cortex'. 'Abnormalities associated with Cerebral Cortex Development' I liked the setup of this section because of its clear headings and subheadings as well as its informative pictures. The captions on some of these pictures need to be elaborated on. Also couldn't see any in text referencing which really needs to be present. Content is clear and concise and easy to follow. This section was engaging and well done. 'INFO/Research Links' was not finished yet but shows lots of research articles that could be promising.
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'''Peer review project 1:'''

I have some general comments which applies to almost all of the sections in the project:
* The referencing is not proper. A lot of the sections do not have reference or all of the reference are at the bottom of the section.
* Some of the sections have bullet points instead of text. It feels like you are reading somebodies notes not a project.
* It would be nice with more pictures to get a better understanding. The pictures there are good, but it does not have any caption. The size is to big as well for some of the pictures (the drawing with the mouse and human model)
* The project does not have a current research, future questions section or animal, which is a requirement for the project.
* I think it would be better for the project if the anatomy and function sections stood before the development part. It would give a better understanding or at least I think so.
* In general, I don’t feel like the project is connected, and expressions like cortigenesis and neurogenesis is not defined.
* I really think the timeline is nice. But a lot of the text within the timeline would have been more appropriate to write in the cortex development section. It should contain some key discoveries instead. But the text there is good, makes sense to me and is well written.
* In the early development of the brain section I don’t understand some of the sentence like: “From there three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five. These are fundamental divisions of the adult brain and communicate freely with each other”. Some of it should properly be rephrased.
* There are some repetions during the project. The text could be compromised.
* In general, the language is neutral and written in a good scientific way.

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- Covers only development, anatomy, functions and abnormalities, more subheadings could be better and exploring other areas of the embryology of the cerebral cortex

- Nice introduction that summarises what the cerebral cortex does and some of its structural layers. Would be nice to see a diagram with the layers of the cerebral cortex or a diagram of the cerebral cortex in the introduction.

- Development of the brain was covered really well and was detailed and also proper and good amount of referencing in this section. Good use of lot of pictures in this section, which made it much easier to understand.

- Timeline of corticogenesis was explained very well in a straightforward manner and use of the table helped.

- Anatomy of cerebral cortex as well as functions of the cerebral cortex is still incomplete and is mainly in dot points and no referencing

- Abnormalities was done well and very detailed and covered many types of abnormalities. Disorders were also divided into categories which is good.

- Good use of pictures in the abnormalities of the section for each abnormalities but use of videos were probably not necessary in this section

- Overall, introduction, development and abnormalities were all done well and good grammar and spelling. Other main headings definitely needed more work and referencing was done incorrectly or absent in some parts. There could be more subheadings and there is no glossary.

- References are from proper journal articles/peer reviewed journals which is good.

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- Introduction provides a good summary, however the list of layers is quite long so maybe adding a diagram would make all that information a bit easier to take in? Or perhaps, listing the layers in dot point form rather than a long sentence.
- Early development of the brain is very detailed, well researched as evidenced by the many references. Perhaps a short table summarising all that information could be added. Some formatting issues, but nothing that can't be easily fixed.
- Development of cerebral cortex section very well done. Good use of diagrams and the table; they made the information easier to understand. However maybe the drawn diagram could be smaller (good job though!). Easy to follow.
- Anatomy and functions sections are obviously unfinished, but it is clear that extensive research has been done to produce all that in the first place. So good job, once it is all formatted, I'm sure it will look great. All the dot points were easy to understand anyway.
- Abnormalities section was very well researched. Great use of diagrams. Personally, I found the subheadings easy to grasp in the Contents, however it was a bit overwhelming to scroll through it all.

Overall, a good job. It is clear that some sections are incomplete, but it seems like there is a clear direction of where it is going. I would recommend a glossary of terms, just because the cerebral cortex is so complex and all the terms can become overwhelming. Tables in the development would help with this also just to provide a quick and easily accesible summary of development.

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* Introduction
** Could have been linked together with anatomy and function for better structuring of page
** Simple diagram could have been used to provide context on body location
* Development of the cerebral cortex
** Section should be expanded upon to give context to the content
*** Seemed like a sudden introduction of neuronal classes and key developmental zones without much expansion
** Section seemed to be more about components of the developing cerebral cortex rather than development itself – could update subheading to reflect this or update content to focus more on development
* Timeline of corticogenesis
** Could have been its own subheading
* Anatomy
** Should be moved up towards start of the page with introduction
* Functions
** Should be moved up towards start of page with introduction
** Functional areas should be expanded upon to briefly discuss their different roles
** Should not rely too much on linked video
* Abnormalities
** Diagram “disorders of cortical formation” gave little information relating to section – seemed like illustration related little to the mentioned stages. Instead, could have mentioned that abnormalities arise during proliferation, migration and organisation during cortical development
** Lettering and numbering of subheadings in this section should be switched for clarity
* Overall was well done. However:
** Some diagrams lacked descriptions and figure legends/abbreviation definitions – diagrams should be self-explanatory and be understandable in combination with their descriptions, when taken out of their contexts within the page
** Minor grammatical errors present throughout the page
** Mostly well-structured but some subheadings can be shifted around - see above for specific feedback
** Remember to clear zIDs before final submission

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*Introduction
**References are missing.
**Labeled images could be included to illustrate the relative position of cerebral cortex and cerebrum in the human brain and the organization of cerebral cortex into the six horizontal layers.

*Early development of the brain
**Written expression could be clearer. For example, L1: “The brain begins to develop during the third week (of pregnancy) when the neural plate and (neural) tube (are derived) from the outermost layer of embryonic cells, (that is) the neuroectoderm.”.
**A table listing the major development occurring at each week (i.e. week 3 – start of development of brain, week 4 – fusion of the neural folds) could be included for easier understanding of the developmental timeline
**Labeled images should be included for clear illustration of the relative positions and development of various parts of the cerebral cortex.

*Development of cerebral cortex
**Appropriate inclusion of images that aid in understanding the content. However, there is little reference or explanation to the images in the text. No caption is included for the images. The first image and the second image are redundant to each other as they are both illustrating the key developmental zones in the human cortex. Author may want to consider taking one of them out.
**Good use of a table in summarising the developmental timeline for corticogenesis. Clear explanation of corticogenesis.

*Anatomy of the cerebral cortex
**Content could be better organized in paragraphs instead of point forms.
**Labelled images should be included for clear illustration

*Functions of the cerebral cortex
**More content could be added to each of the functional areas listed.
**Video is appropriate and useful in facilitating understanding.

*Abnormalities associated with cerebral cortex development
**References should be included where appropriate instead of generalizing as “references used to write”.
**The amount of content seems slightly overwhelming as compared to other sections of the page which are equally important as well. Nonetheless, good effort in explaining the abnormalities in great details.
**Some references are missing.

*References
**Good effort in for having both journal and book references. However, it would be good to adhere to either APA or BJP style of referencing.

__

GROUP 1

Early Development of the Brain: Well written, maybe a little concise, there are some great images which could be useful for this section also Development of Cerebral Cortex: Lots of good information, maybe try to make this section a bit more fluid - comes of a little disjointed Anatomy of the Cerebral Cortex/Functions of the Cerebral Cortex: This section does not read well to the eye - that's not to say it is incorrect - I would try putting this into a friendly format Abnormalities associated with Cerebral Cortex Development: This section is huge, but each condition has a fairly concise explanation so well done

Overall: There is lots of sound information on the page - main emphasis would be giving the page a clean up of the format and trying to make the sections flow together a little nicer

Talk:2017 Group Project 1

2017-10-26T04:29:18Z

Z5177691: /* Image Use */

{{ANAT2341Project2017discussion}}



==Image Use==
File:Neural- cortex Cajal drawing 01.jpg uploaded by z5177691

File:Stage 22 image 217.jpg uploaded by z5177691

=Cerebral Cortex=
==Introduction==
https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024757/ [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:37, 23 August 2017 (AEST)

==Lobes and Function==
4 Lobes: parietal, temporal, frontal, occipital
Video Overview: [https://www.khanacademy.org/science/health-and-medicine/human-anatomy-and-physiology/nervous-system-introduction/v/cerebral-cortex "Cerebral Histology"]
[[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:32, 23 August 2017 (AEST)

==Neocortical Development==
Nature article: https://www.nature.com/nrn/journal/v9/n2/full/nrn2252.html [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:57, 23 August 2017 (AEST)

===6 Layers===
Layers I, II, III, IV, V, VI (see [http://www.ruf.rice.edu/~lngbrain/Sidhya/ "Cortical Layer Review"] [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:57, 23 August 2017 (AEST)

==Anatomy and Function==

to do:

-change from dot points

-add images

-references

-finish function information

===Cell Types===
http://www.ruf.rice.edu/~lngbrain/Sidhya/ [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:57, 23 August 2017 (AEST)

==Abnormalities==
PubMed Article: [https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024757/ "Developmental Disorders"] [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:41, 23 August 2017 (AEST)

=Peer Reviews=

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This page is very well structured and sequential. It provides a very detailed explanation of development under chronological subheadings. Subpages under images are well informed, but some images lack a proper Copyright phrase and Student Image Template to indicate reproducibility. On the main page, some subheadings need to be capitalised (formatting) and student signatures need to be provided on relevant sections, rather than student numbers . The "Anatomy of the Cerebral Cortex" section is filled with dot points, and could be improved using paragraphs, images and Wiki formatting. The layout of the Abnormalities section could be improved, by changing the headings and subheadings. The images and videos on the page are all very relevant to the topic, but I don't think the screenshots from youtube are appropriate of reputable. The page could benefit from a glossary list and 'Future Research' section. However, the reference list was well constructed. Overall the the page addresses the brief very well.

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Be careful in how the sentences are expressed for example in the introduction ‘the cerebral cortex is actually the outermost layer’; avoid using ‘actually’ in this sentence. Don’t forget to remove the student numbers from the posts. Minor grammatical errors; no use of commas in long sentences. The images do include copyright however the team has forgotten to place the Student Image Template that is required. The team should add a small description of the images that are on their webpage so readers will see immediately what the image is showing. The team could do a further questions subheading or an animal model subheading to explore more on the research of the Cerebral Cortex.

Subheadings and content that have been used show a good understanding of the topic area. The use of dot points where necessary are done well which makes the project easier to understand and read through. The use of tables to demonstrate the ‘Timeline of Corticogenesis’ is done comprehensively; maybe an image for each day that is explained should be added to show consistency (as only the last row has an image). The team has used their own diagrams which shows that the team was innovative in displaying their research. The references used are cited correctly, however, there are links at the bottom where they need to fix up and place it under references.

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Overall, the page is has nice structuring making it relatively easy to follow. But they are missing major topics necessary including historical discoveries, developmental signalling processes, current research and animal models. The introduction was short and concise, which provided a relevant amount of background knowledge. The anatomy and functions of the cerebral cortex could be put before the development so that it ties in with the introduction. The images and videos were relevant to the topic, which aided in understanding the content. However, labelling, adding a description and citing is necessary for images and videos which has not been done. A table would be a great feature for the timeline because right now its annoying to read and has a messy, unfinished look. References need fixing.

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The page has good structure and formatting, however there is a significant unfinished touch. Anatomy of the Cerebral Cortex heading could place all the information in a table to make it easier to read as well as images to help the viewer visualise the process. Maybe remove the student numbers because they are unnecessary and make the page look not as professional. figures and tables need to be labelled as well as referencing and copyright claims. The diagram under the statement "Migration and division of all six layers of the cortex is completed during the third trimester. Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex." needs to be further explained because I had a hard time understanding the image and what each section meant. The video is a nice touch to help understand the function and placement of the cerebral cortex. Developmental abnormalities was well written, easy to understand and flowed nicely.

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Well-structured and provides a vast amount of background information on the functions and structure of the cortex before delving into the details of development. However, the anatomy of the cerebral cortex and the layers are difficult to understand due to heavy use of dot points – perhaps images would be of good use in this section. There is consistently limited evidence of in-text references or citations throughout the information (rather than at the beginning of some of the sections) which makes it harder to link or follow where information was gathered. Headings are concise and easy to follow however the “other info to add” subheading under “Anatomy of the Cerebral Cortex” needs to be reworded for efficiency. Under the subheading “A) Disorders due to …” the disorders are inconsistently numbered – a 2 needs to be placed with “Hemimegalencephaly” as well as 8 with Schizencephaly. Functions of the cerebral cortex is hard to follow as dot points are used with lacking descriptions or expansion. Perhaps further discussing the actions of each functional area would provide more sufficient information in this part.

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The layout is looking very good, pictures could be a little smaller. I like the choice of headings, they explain well what is going to be talked about. I feel like you need to add headings like animal models and current research needs to be fixed but I’m sure that’s what is intended. I have some minor points for some of the headings:
Early development:
Spelling: Rhomboncephalon, and the instead of three at the beginning of a paragraph. Overall this heading was covered well
Development of cerebral cortex:
With images, you can add figure titles and this could make your page flow better!! Maybe expand a bit more on the key developmental zones in the human cortex, a brief explanation of what happens could help. The table is very well explained, however for E50-55 I can’t see a reference for all the information, also for the picture in the table for E50-55, you haven’t copied the copyright information so you should add that so it can be used in the page and also add the student template. I really like the drawn picture, but again a figure description would be helpful. This section is very well done.
Anatomy of the cerebral cortex
Some great points but needs to be broken up into paragraphs. Your Wikipedia link for the image is a good image however you should find the original, I recognize it from Cajal’s drawings so I think it could be in a paper about the cerebellum with Cajal. You have good ideas for this heading, also maybe add another image.
Functions of the cerebral cortex
For functional areas, I think a 2 sentence description of each area would be good and maybe a picture for reference.
Abnormalities
Intext referencing would be better. For images, add the student template to each!! Im not entirely sure how I feel about the youtube screenshots as images, maybe use one but try and find some in research articles aswell.
Overall, I think you’ve done a really good job at summarizing abnormalities.

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The introduction was a good opening to the Cortex page as it gives a brief overview and understanding of the cortex generally. The next subheading, “Early development of the Brain”, provides of a simple and clear explanation of the early development process however images would be a great addition to help visualise the text. Try having a look at some images that were shown to us in previous lectures on the brain development where it showed the neural plate, neuroectoderm and subsequent developments.
The next subheading, “Development of Cerebral Cortex”, would probably do better to be called “Later Development of Cerebral Cortex” as it would be a seamless flow from the previous subheading of “Early development…”. It was good that a labelled image was used and information was added for explanation. It helped orient me as I was going on to read about the timeline of corticogenesis. The timeline was detailed and the use of bold helped highlight key terms. However, I would suggest making another column for images on each day. Visual reinforcement just makes the information easier to absorb and make more sense.
The subheading, “Anatomy of the Cerebral Cortex”, is clearly in the editing process. I would just once again definitely recommend the use of images in this section, both hand-drawn diagrams and labelled images from the internet. I thought the use of a video was a clever way to cover the cerebral cortex functions. A bit of general text that briefly covers the functions of the main parts would be a good addition in this section, as a segue into the video.
The “Abnormalities” subheading was a good balance of text and images. It was easier to read because it was split into categories. I would only suggest that you mention at the beginning of the section that abnormalities associated with the cerebral cortex development can be divided into the following categories… I can see the references were placed at the beginning of the section and I’m assuming that is temporary. It is better if they are dispersed within the text where appropriate. There are a good bunch of references but you could probably aim for 25-30 for this page.

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This page needs some more information about current research, signaling processes, future questions and references to animal models. It would also be good with a table or quick overview of developmental origin. There has been a good use of pictures and tables. The setup of the section about abnormalities is really good. This page needs to use more references during the sections and not only at the start of a section. A glossary list would also be good for the reader to understand the page.

*'''Introduction''': Gives a quick knowledge of the cerebral cortex. A picture would be good to support this introduction and maybe a bit more description of the different terms. This section also needs references.
*'''Early Development:''' Good setup with bulleting. I find some of the context a bit confusing to read - especially these two sentences "From there three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five" and "During the fifth week, the embryonic brain undergoes rapid growth folding the neural tube and consequently resulting in three brain flexures" Maybe you can rephrase this.
*'''Development of Cerebral Cortex:''' Good section! Good overview.
*'''Timeline of Corticogenesis:''' Please give a short introduction of what Corticogenesis and Neurogenesis means. Good picture supporting the E50-55, maybe you can put this picture already in the section called "Key developmental zones in the human cortex" since this is the first time we get introduced to the different zones and plates and it would give a better basic knowledge before getting into Corticogenesis.
*'''Anatomy and Function of the Cerebral Cortex''': These two sections should maybe be earlier on the project page together with the introduction since it's a basic understanding of the Cerebral Cortex. Both sections look a bit messy, try to work on making it more simple and easier to read - it kind of looks like personal notes and not a proper information site :-) These sections also need some references. The video in this section gives a good understanding. Good idea putting a video on the page.
*'''Abnormalities associated with Cerebral Cortex Development:''' This section is really good. Great overview of the different scenarios and a lot of pictures to support the reading. Instead of mentioning all the references in the start of the section, you should add the specific reference used for each subsection, this will make it easier for the reader to look up references for specific sections.

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In the introduction section, it was not referenced where the information facts are from. This section should introduce a brief information on the topic, what you are going to discuss on the whole wiki page, introduce current researches and animal models to support the new findings and understandings. Also, don't use "actually" in the sentence.
On the page, It is better to write in full sentences instead of dot points as I've seen a lot of them and include any of scientific words in the glossary section at the end of the page. Where you've inserted picture, it will be clearer to also include it within the text in brackets for example (Figure 1).
Any figures or pictures on this page needs references as well.
In the abnormality section, it is well written with supporting pictures, but in my opinion, it is easier to read if the the figures/pictures are on the same side and texts on the other side instead of alternating. This section was very thoroughly referenced too. I think a small paragraph under the heading introducing the different type of disorders before going into greater details.
Don't focus too much on the anatomy as I can see this section is not finished nor written in paragraph and no pictures or figures, would be better to swap anatomy with some other embryology discussion for example, signalling processes.
Touch on current researches, animal model if any and future questions as they were not seen on the page. Also include a glossary table. References section is looking good but more is needed.

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Overall, a really informative and well-written wiki. The information was well presented and was understandable. The abnormalities section of the wiki, was particularly well done, as it was a good idea to group each abnormality with the disruption of the main event that lead to the abnormality, as it informs the reader that different abnormalities arise from a disruption of different processes that occur in the development of the cerebral cortex. The diagrams and pictures were useful as it functions as a reference point.

Overall, the layout was good, however maybe use more of a dot-point layout in the Anatomy section and maybe add some diagrams of pictures to enhance the information given. Also the sub-title "what is it?" is probably not needed as the introduction itself suggests that you will be describing what the cerebral cortex is and what is does. The Functions of Cerebral cortex may also need a bit more text as the video should just be a supplement rather than the main source for information in that section. Overall, well done as it was an informative and well written wiki.

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Overall I find the information provided to be concise and easy to understand. The introduction was great in giving us a brief overview of page. The layout of the early development of the brain and the development of the cerebral cortex was really nice. I like the use of bullet points as this makes it easier to read. Also good amount of referencing is seen in this area. The use of the table is also a nice touch to the page and I like the picture used for E50-55. However, it could help to have another column with pictures for each row. That would help with the understanding of the text. For the anatomy of the cerebral cortex, it seems a little messy and hard to read as it is too point form. Perhaps these could be phrased into proper sentences with certain parts placed into bullet points to make it easier to read. Also, with the anatomy, pictures would be very helpful to aid in the explanation. For the functions of the cerebral cortex, it lists the functional areas but not the functions of those areas. Although it is stated in the video, which is a nice addition to the page, this could be improved by adding short sentences that state these functions that were mentioned as well. For Sections 1.4 and 1.5, references are also needed to state where the information was obtained from. The abnormalities section provides detailed explanations of the various disorders associated with the development of the cerebral cortex. There is also a good amount of pictures used. One thing I noticed was the references which was placed on the top of the section instead of throughout the text.

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Overall, the page has a good structure and flow with good headings and subheadings. The information provided was concise and easy to comprehend. The introduction provides a brief overview and sufficient background knowledge about the cerebral cortex. I like how the team thought of mentioning about the early development of the brain before narrowing it down to the cerebral cortex. However these two sections do not seem to flow well. Maybe you could have 2-3 sentences that could help ease into the development of the cerebral cortex. I really love the timeline of corticogenesis. This part has been done really well. One minor improvement that could be made is to add images under each embryonic stage instead of just the last stage to better aid the reader into understanding the development. Also, a brief description of what corticogenesis is could be included before the table. For these two sections, there were a good amount of references.

For the anatomy of the cerebral cortex, it seems a little messy and hard to understand as its written in point forms. Perhaps, the dot points could be changed to proper sentences with histological images to tie it together. For the functions of the cerebral cortex, I think you could use a table to list down the areas and then provide a brief description of the functions of that particular part. The video is a good addition to the page. These two sections are lacking citations and references.The abnormalities section was well done. However, the citations should be added within the text instead of at the top of the page. Since there are a lot of abnormalities, maybe the team could list in a few sentences about all the abnormalities that they are going to discuss to have a better start to the section. For the images that are used on this page, the images should be labelled as “figure 1” or “table 1”. Maybe, sections on the “animal models” and “current research” could be added to wrap the page up.

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Overall the project was very good and clear. Pictures were well placed and bullet points spaced out information, making the page easy to look at and follow. The layout of the beginning and end sections with the short paragraphs and interspersed bullet points broke up the information and highlighted key facts. The introduction was a good overview of the page, including a quick summary of the anatomy, function, and development of the cerebral cortex.

There were some basic grammatical and spelling errors (e.g. “neurons” is spelled wrong under the subheading “Layer 4”), but for the most part did not take away from the clarity of the page. One sentence, “From there three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five,” seems to be missing something at the beginning that would increase clarity.

Some pictures had a lot of information in the summary when clicking on them while others lacked sufficient information. Some pictures that could benefit from more information are Corticogenesis of mouse and humans.jpeg, SBH.png, Disorders of Cortical Formation2.png, Symptoms of microcephaly.png, Hemimegalencephaly.png, and SchizencephalicBrain.jpg. These pictures are relevant to the topic and are pretty self-explanatory so this does not take away much clarity from the page but for the parameters of the project, additional summary should be added. The picture Stage22 HPA2L.jpg has good information in the summary but it is oddly structured. FASface.jpeg does not have any copyright information included. Having Gray754.png displayed on the page rather than as a link would look better.

The video describing the functions of the cerebral cortex was a good introduction to that topic. The video was easy to watch and understand. The first video about corpus callosum agenesis was a good introduction to the topic, but the second video about corpus callosum agenesis was long and the lecturer was hard to understand. That subheading would benefit from a brief description of that topic rather that a long video explanation.

The switch from a mix of bullets and short paragraphs to all bullet points in Anatomy of the Cerebral Cortex makes the page look less cohesive. The last bullet point in Layer 4 is hard to understand and the last 2 bullet points in Layer 5 would flow better if they were combined. The information in these sections are good and relatively easy to follow.

Overall the project is very good. The table explaining the timetable of cortex development is a clear way to break down the topic. Breaking down the information of abnormal development into what went wrong in the embryology (e.g. migration problems vs. differentiation problems) highlights importance of embryology in congenital disorders. There is a lot of information about the abnormal development of the cortex but could use some information about past and current research and animal studies. Reference list at the end looks good but the in-text citations of abnormal development should be interspersed with the information rather than all at the beginning.

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*Overall, the page is well structured and relatively easy to follow with the headings and subheadings relevant to the topic area (embryology of the cerebral cortex).

*The introduction was short and concise, which provided a relevant amount of background knowledge before delving straight into the development.

*Perhaps the Anatomy and Functions of the cerebral cortex could be put before the development so that it ties in with the introduction.

*The use of dot points under Anatomy and Function of the Cerebral Cortex was excessive and gives off an unfinished feel. Perhaps you could add in a couple of images to make these dot points easier to understand. Also, it might be better to use the * function to create these dot points.

*The use of the table on the "Timeline of Corticogenesis” was quite clever and made it easier to understand, however I suggest that you add photos in E30, E31-32 and E40-45 since there seems to only be one photo in E50-55. The page is lacking a "further questions" section which would be quite informative in understanding the research gap to date.

*I think the Disorders was nicely done and was very informative. The use of images in the left and right side of the page made it aesthetically pleasing to read. However this section lacks references, which I think you should add to avoid plagiarism.

*The images and videos that are on the page are very relevant to the topic, which aided in understanding the content. However perhaps you could label them using "Figure 1", or "Table 1" etc as well as putting an appropriate description under the image/video. Also, the link of an wiki image under Layers was not inserted properly, so be sure to check that for next time.

*References were inconsistent throughout the page, however most were done properly.

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The chosen headings for the development of the cerebral cortex were very suitable to highlight the key topics in providing a page of summarised information. It was then easy to navigate through the page using the shortcuts and finding information. Although, there was one sub sub heading “Timeline of Corticogenesis” that was formatted to be in bold while the rest were not.

The disorders listed seems to be really interesting and it covers the whole spectrum of the case abnormalities. But I suggest to get rid of the letter bullets (e.g. A), B), C) ) for the breakdown of the abnormalities.

The introduction had a quick and concise text, however, an image of the cerebellum would be suitable in this section on the side. While the sub sub heading stated that the introduction section will talk about the features of a cerebellum, a paragraph about the development and its stages were written down in this section as well. This could be moved into the ‘Early Development of the Brain’ subheading underneath. Bullet points of the brain layers as well as a diagram would be helpful for the visualisation of the brain.

For the sections that explain the development in specific weeks, a table would be advisable to make it neater and easier to look at. Also, an image was left inside the table grids and it was confusing whether it was meant to be there or not. Perhaps adding a photo gallery showing the stages at the bottom of the table would be better.

Hand drawn diagrams were really precise, neat and was very visually appealing. It was taking up all the space and unless it is intentional, I suggest to resize the drawing into a smaller one that fits the page as well as the accompanying text and content of the drawing.

The variety of visual aids were really entertaining and were referenced properly.

Finally, the reference list at the bottom of the page did not have a consistent format. It was mostly APA format however the others looked like a different format.

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The most obvious flaw was the lack of polish in formatting of some of the page. Bullet points are only so useful when it comes to writing a wiki page, instead of taking notes. The page is unfinished, but, the content included especially in the "Development of Cerebral Cortex" and "Abnormalities associated with Cerebral Cortex Development" was extensive and well done. The large table that linked the development with the time period was very useful and the choice of bolding key words allowed the main idea in the paragraph to be quickly understood from a glance. The use of images very much enhanced the descriptions and checker-like the layout of the different abnormalities was refreshing. Some subheadings, such as the Anatomy and Function of the cerebral cortex, could be elaborated on but the overall structure of the page is logical and fluid, and the writing is clear and concise without being superficial.

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Strengths: 
• The page has an excellent structure covering a broad variety of topics regarding the cerebral cortex. It was great to see how you also explored abnormalities associated with the cerebral cortex. Furthermore the use of various subheadings and headings related to cerebral cortex development meets criteria 1 and 2 of the assessment. 
• The presentation of the wiki page was excellent in that a variety of images, videos and tables were utilized. The use of such sources of information helps present information in a much more clear and concise manner, whilst also providing a thorough explanation to visual learners. Hence the wiki page has an element of teaching at a peer level (criteria 4 is satisfied). 
• A large number of references have also been included within the wiki page, a characteristic which helps increase the reliability of information presented. Furthermore, most sources are recent which another great characteristic. Thus, it appears that the group has satisfied criteria 3 for the assessment. 
• Each topic appears to show a significant amount of detail which is excellent. In addition, the use of images alongside the text is a great tool as the audience is able to better visualize the concept being described. 

Areas of improvement: 
• Although you have provided a variety of recent references, to improve you may avoid using sources as old as 1977 as results presented from this study may be outdated. 
• It was excellent that the functional areas of the brain were listed, however to improve you may wish to elaborate on the specific functions of these areas. You may also explore how abnormalities of these areas during development may impact upon the behaviour of the individual following birth 
• Whilst a variety of topics have been covered, you may wish to also describe the importance of signaling throughout the process of cortical development. For example, you may investigate different growth factors and receptors involved in the process. 
• Another possible improvement would be to perhaps include a timeline of different researchers who contributed to the in-depth understanding of the developing cortex that we have today. You may also describe what each researcher discovered. 
• In order to completely satisfy criteria 5, you may wish to conduct further research beyond the scope of formal teaching activities. For example you may explore the contribution of animal models towards our understanding of cortical development. 

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This peer review is based on the relevant dot points of the ‘Group Assessment Criteria’, as well as subheadings suggested by Mark. This information can be found on the student page.

{| border="1" align="left"
|-
|Criteria
|Strengths
|Weaknesses
|-
| 1. The choice of content shows a good understanding of the topic area
| The developmental origin of the cerebral cortex is addressed well under the sub-heading ‘Early development of the brain’.

The development timeline of the cerebral cortex is described clearly and in detail in the table of the ‘Timeline of corticogenesis’.

Abnormal development of the cerebral cortex and the associated conditions are covered in an immense amount of detail. The accompanying images and videos enhance the written information, as well as making it easier for the reader to comprehend. In addition, the sub-headings of this section compartmentalize the congenital diseases in a logical manner that highlights the link between abnormal development and specific diseases.
| There are several key topic areas missing from the page:
*There is no section covering key historical discoveries relevant to the cerebral cortex and its embryological development.
*There is no information relating to developmental signalling processes
*There is no section on current research in fields relevant to the embryological development of the cerebral cortex.
*There is no section on animal models that have been used to advance scientific understanding of the cerebral cortex.
*There is no section on future questions regarding the development of the cerebral cortex.
*A glossary of terms has not been included.

Some sections that have been included are somewhat irrelevant to the subject matter. For example, there is a large (unfinished) section on the anatomy and functions of the cerebral cortex. While it is important to provide a bit of an anatomical background on the subject, it shouldn’t be a major focus of this assignment. Focus more on the sections mentioned above, and keep the project focused on the embryology of the cerebral cortex.
|-
|2. Content is correctly cited and referenced
|There have been attempts at referencing throughout the assignment. A reference list has been produced and appears mostly correct. References have not been repeated throughout the list.

Peer-reviewed primary research articles have been used in this assignment.

The student-drawn image has been cited correctly, as have most of the images used in the ‘abnormal development’ section.
|Overall, referencing in this assignment is very poor. Most of the content is completely devoid of any references (see ‘introduction’, ‘anatomy of the cortex’ and ‘abnormal development), and sections that have been referenced have been referenced “by paragraph” (see ‘timeline of corticogenesis’)

Many of the sources used in this assignment are inappropriate and/or unreliable. Try to rely more on primary research articles and less on textbooks or websites.

Many of the images have been cited incorrectly and used without permission. Remember to include the full reference, the original summary and the copyright license information for each image.
|-
|3. The wiki has an element of teaching at a peer level
|The information presented is mostly at a level appropriate for peers. Images and hand-drawn diagrams have been included to facilitate the readers understanding of the subject matter. Some of the images contain useful descriptions of the subject matter, and aid in understanding of the topic.
|Many of the acronyms and terms used in this assignment are not well explained. Include a glossary of terms to make some of the content easier to follow and understand.
|-
|4. Relates the topic and content of the Wiki entry to learning aims of embryology
|The development of the cerebral cortex was covered extensively, which is a very important learning aim of embryology.
|There are certain learning aims of embryology that have not been included in this assignment, such as developmental signaling processes (see criteria 1 for more information). There has been no discussion of relevant historical or current research (adding in the subheadings “key developments” and “current research” would help rectify this).
|-
|5. The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic
|Certain aspects have been researched and presented well (such as embryological development).

Links to other pages of the UNSW embryology wiki have been included, however they have been used as references rather than just links.
|Information from the UNSW embryology wiki has been used as direct sources of information. Instead they should be included to relate this particular wiki page to other areas of learning.

The small number of sources cited in the reference list demonstrates a poor and narrow approach to researching this topic. A greater library of sources should be used to create this page (mainly primary research articles).
|}

Grade: FAIL

General Comment:
While some aspects of the wiki page have been done well, the page is largely unfinished. Many sections still need to be added, and others are in need of improvement.

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The introduction of this page gives a good general background but could benefit from adding bullet points to describe the six horizontal layers of the cortex and maybe a short summary of its clinical significance. 'Early Development' was well written, easy to follow and well referenced. 'Development of Cerebral Cortex' would benefit from a short introductory statement instead of going straight into the 'Main classes of neurons'. Pictures and tables in this section were informative and engaging to the reader. Hand-drawn picture was well done, colourful and easy to interpret. 'Anatomy of the Cerebral Cortex' looks unfinished and isn't easy to read as it doesn't flow or show a clear structure. No references can be seen and no pictures or tables to make for easier reading or understanding. The different layers of the cortex would greatly benefit from a table with structure/function format or a clear diagram. The same is true for 'Functions of the Cerebral Cortex'. 'Abnormalities associated with Cerebral Cortex Development' I liked the setup of this section because of its clear headings and subheadings as well as its informative pictures. The captions on some of these pictures need to be elaborated on. Also couldn't see any in text referencing which really needs to be present. Content is clear and concise and easy to follow. This section was engaging and well done. 'INFO/Research Links' was not finished yet but shows lots of research articles that could be promising.
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'''Peer review project 1:'''

I have some general comments which applies to almost all of the sections in the project:
* The referencing is not proper. A lot of the sections do not have reference or all of the reference are at the bottom of the section.
* Some of the sections have bullet points instead of text. It feels like you are reading somebodies notes not a project.
* It would be nice with more pictures to get a better understanding. The pictures there are good, but it does not have any caption. The size is to big as well for some of the pictures (the drawing with the mouse and human model)
* The project does not have a current research, future questions section or animal, which is a requirement for the project.
* I think it would be better for the project if the anatomy and function sections stood before the development part. It would give a better understanding or at least I think so.
* In general, I don’t feel like the project is connected, and expressions like cortigenesis and neurogenesis is not defined.
* I really think the timeline is nice. But a lot of the text within the timeline would have been more appropriate to write in the cortex development section. It should contain some key discoveries instead. But the text there is good, makes sense to me and is well written.
* In the early development of the brain section I don’t understand some of the sentence like: “From there three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five. These are fundamental divisions of the adult brain and communicate freely with each other”. Some of it should properly be rephrased.
* There are some repetions during the project. The text could be compromised.
* In general, the language is neutral and written in a good scientific way.

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- Covers only development, anatomy, functions and abnormalities, more subheadings could be better and exploring other areas of the embryology of the cerebral cortex

- Nice introduction that summarises what the cerebral cortex does and some of its structural layers. Would be nice to see a diagram with the layers of the cerebral cortex or a diagram of the cerebral cortex in the introduction.

- Development of the brain was covered really well and was detailed and also proper and good amount of referencing in this section. Good use of lot of pictures in this section, which made it much easier to understand.

- Timeline of corticogenesis was explained very well in a straightforward manner and use of the table helped.

- Anatomy of cerebral cortex as well as functions of the cerebral cortex is still incomplete and is mainly in dot points and no referencing

- Abnormalities was done well and very detailed and covered many types of abnormalities. Disorders were also divided into categories which is good.

- Good use of pictures in the abnormalities of the section for each abnormalities but use of videos were probably not necessary in this section

- Overall, introduction, development and abnormalities were all done well and good grammar and spelling. Other main headings definitely needed more work and referencing was done incorrectly or absent in some parts. There could be more subheadings and there is no glossary.

- References are from proper journal articles/peer reviewed journals which is good.

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- Introduction provides a good summary, however the list of layers is quite long so maybe adding a diagram would make all that information a bit easier to take in? Or perhaps, listing the layers in dot point form rather than a long sentence.
- Early development of the brain is very detailed, well researched as evidenced by the many references. Perhaps a short table summarising all that information could be added. Some formatting issues, but nothing that can't be easily fixed.
- Development of cerebral cortex section very well done. Good use of diagrams and the table; they made the information easier to understand. However maybe the drawn diagram could be smaller (good job though!). Easy to follow.
- Anatomy and functions sections are obviously unfinished, but it is clear that extensive research has been done to produce all that in the first place. So good job, once it is all formatted, I'm sure it will look great. All the dot points were easy to understand anyway.
- Abnormalities section was very well researched. Great use of diagrams. Personally, I found the subheadings easy to grasp in the Contents, however it was a bit overwhelming to scroll through it all.

Overall, a good job. It is clear that some sections are incomplete, but it seems like there is a clear direction of where it is going. I would recommend a glossary of terms, just because the cerebral cortex is so complex and all the terms can become overwhelming. Tables in the development would help with this also just to provide a quick and easily accesible summary of development.

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* Introduction
** Could have been linked together with anatomy and function for better structuring of page
** Simple diagram could have been used to provide context on body location
* Development of the cerebral cortex
** Section should be expanded upon to give context to the content
*** Seemed like a sudden introduction of neuronal classes and key developmental zones without much expansion
** Section seemed to be more about components of the developing cerebral cortex rather than development itself – could update subheading to reflect this or update content to focus more on development
* Timeline of corticogenesis
** Could have been its own subheading
* Anatomy
** Should be moved up towards start of the page with introduction
* Functions
** Should be moved up towards start of page with introduction
** Functional areas should be expanded upon to briefly discuss their different roles
** Should not rely too much on linked video
* Abnormalities
** Diagram “disorders of cortical formation” gave little information relating to section – seemed like illustration related little to the mentioned stages. Instead, could have mentioned that abnormalities arise during proliferation, migration and organisation during cortical development
** Lettering and numbering of subheadings in this section should be switched for clarity
* Overall was well done. However:
** Some diagrams lacked descriptions and figure legends/abbreviation definitions – diagrams should be self-explanatory and be understandable in combination with their descriptions, when taken out of their contexts within the page
** Minor grammatical errors present throughout the page
** Mostly well-structured but some subheadings can be shifted around - see above for specific feedback
** Remember to clear zIDs before final submission

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*Introduction
**References are missing.
**Labeled images could be included to illustrate the relative position of cerebral cortex and cerebrum in the human brain and the organization of cerebral cortex into the six horizontal layers.

*Early development of the brain
**Written expression could be clearer. For example, L1: “The brain begins to develop during the third week (of pregnancy) when the neural plate and (neural) tube (are derived) from the outermost layer of embryonic cells, (that is) the neuroectoderm.”.
**A table listing the major development occurring at each week (i.e. week 3 – start of development of brain, week 4 – fusion of the neural folds) could be included for easier understanding of the developmental timeline
**Labeled images should be included for clear illustration of the relative positions and development of various parts of the cerebral cortex.

*Development of cerebral cortex
**Appropriate inclusion of images that aid in understanding the content. However, there is little reference or explanation to the images in the text. No caption is included for the images. The first image and the second image are redundant to each other as they are both illustrating the key developmental zones in the human cortex. Author may want to consider taking one of them out.
**Good use of a table in summarising the developmental timeline for corticogenesis. Clear explanation of corticogenesis.

*Anatomy of the cerebral cortex
**Content could be better organized in paragraphs instead of point forms.
**Labelled images should be included for clear illustration

*Functions of the cerebral cortex
**More content could be added to each of the functional areas listed.
**Video is appropriate and useful in facilitating understanding.

*Abnormalities associated with cerebral cortex development
**References should be included where appropriate instead of generalizing as “references used to write”.
**The amount of content seems slightly overwhelming as compared to other sections of the page which are equally important as well. Nonetheless, good effort in explaining the abnormalities in great details.
**Some references are missing.

*References
**Good effort in for having both journal and book references. However, it would be good to adhere to either APA or BJP style of referencing.

__

GROUP 1

Early Development of the Brain: Well written, maybe a little concise, there are some great images which could be useful for this section also Development of Cerebral Cortex: Lots of good information, maybe try to make this section a bit more fluid - comes of a little disjointed Anatomy of the Cerebral Cortex/Functions of the Cerebral Cortex: This section does not read well to the eye - that's not to say it is incorrect - I would try putting this into a friendly format Abnormalities associated with Cerebral Cortex Development: This section is huge, but each condition has a fairly concise explanation so well done

Overall: There is lots of sound information on the page - main emphasis would be giving the page a clean up of the format and trying to make the sections flow together a little nicer

Talk:2017 Group Project 1

2017-10-26T04:29:01Z

Z5177691:

{{ANAT2341Project2017discussion}}



==Image Use==
File:Neural- cortex Cajal drawing 01.jpg uploaded by z5177691
File:Stage 22 image 217.jpg uploaded by z5177691

=Cerebral Cortex=
==Introduction==
https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024757/ [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:37, 23 August 2017 (AEST)

==Lobes and Function==
4 Lobes: parietal, temporal, frontal, occipital
Video Overview: [https://www.khanacademy.org/science/health-and-medicine/human-anatomy-and-physiology/nervous-system-introduction/v/cerebral-cortex "Cerebral Histology"]
[[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:32, 23 August 2017 (AEST)

==Neocortical Development==
Nature article: https://www.nature.com/nrn/journal/v9/n2/full/nrn2252.html [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:57, 23 August 2017 (AEST)

===6 Layers===
Layers I, II, III, IV, V, VI (see [http://www.ruf.rice.edu/~lngbrain/Sidhya/ "Cortical Layer Review"] [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:57, 23 August 2017 (AEST)

==Anatomy and Function==

to do:

-change from dot points

-add images

-references

-finish function information

===Cell Types===
http://www.ruf.rice.edu/~lngbrain/Sidhya/ [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:57, 23 August 2017 (AEST)

==Abnormalities==
PubMed Article: [https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024757/ "Developmental Disorders"] [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:41, 23 August 2017 (AEST)

=Peer Reviews=

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This page is very well structured and sequential. It provides a very detailed explanation of development under chronological subheadings. Subpages under images are well informed, but some images lack a proper Copyright phrase and Student Image Template to indicate reproducibility. On the main page, some subheadings need to be capitalised (formatting) and student signatures need to be provided on relevant sections, rather than student numbers . The "Anatomy of the Cerebral Cortex" section is filled with dot points, and could be improved using paragraphs, images and Wiki formatting. The layout of the Abnormalities section could be improved, by changing the headings and subheadings. The images and videos on the page are all very relevant to the topic, but I don't think the screenshots from youtube are appropriate of reputable. The page could benefit from a glossary list and 'Future Research' section. However, the reference list was well constructed. Overall the the page addresses the brief very well.

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Be careful in how the sentences are expressed for example in the introduction ‘the cerebral cortex is actually the outermost layer’; avoid using ‘actually’ in this sentence. Don’t forget to remove the student numbers from the posts. Minor grammatical errors; no use of commas in long sentences. The images do include copyright however the team has forgotten to place the Student Image Template that is required. The team should add a small description of the images that are on their webpage so readers will see immediately what the image is showing. The team could do a further questions subheading or an animal model subheading to explore more on the research of the Cerebral Cortex.

Subheadings and content that have been used show a good understanding of the topic area. The use of dot points where necessary are done well which makes the project easier to understand and read through. The use of tables to demonstrate the ‘Timeline of Corticogenesis’ is done comprehensively; maybe an image for each day that is explained should be added to show consistency (as only the last row has an image). The team has used their own diagrams which shows that the team was innovative in displaying their research. The references used are cited correctly, however, there are links at the bottom where they need to fix up and place it under references.

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Overall, the page is has nice structuring making it relatively easy to follow. But they are missing major topics necessary including historical discoveries, developmental signalling processes, current research and animal models. The introduction was short and concise, which provided a relevant amount of background knowledge. The anatomy and functions of the cerebral cortex could be put before the development so that it ties in with the introduction. The images and videos were relevant to the topic, which aided in understanding the content. However, labelling, adding a description and citing is necessary for images and videos which has not been done. A table would be a great feature for the timeline because right now its annoying to read and has a messy, unfinished look. References need fixing.

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The page has good structure and formatting, however there is a significant unfinished touch. Anatomy of the Cerebral Cortex heading could place all the information in a table to make it easier to read as well as images to help the viewer visualise the process. Maybe remove the student numbers because they are unnecessary and make the page look not as professional. figures and tables need to be labelled as well as referencing and copyright claims. The diagram under the statement "Migration and division of all six layers of the cortex is completed during the third trimester. Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex." needs to be further explained because I had a hard time understanding the image and what each section meant. The video is a nice touch to help understand the function and placement of the cerebral cortex. Developmental abnormalities was well written, easy to understand and flowed nicely.

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Well-structured and provides a vast amount of background information on the functions and structure of the cortex before delving into the details of development. However, the anatomy of the cerebral cortex and the layers are difficult to understand due to heavy use of dot points – perhaps images would be of good use in this section. There is consistently limited evidence of in-text references or citations throughout the information (rather than at the beginning of some of the sections) which makes it harder to link or follow where information was gathered. Headings are concise and easy to follow however the “other info to add” subheading under “Anatomy of the Cerebral Cortex” needs to be reworded for efficiency. Under the subheading “A) Disorders due to …” the disorders are inconsistently numbered – a 2 needs to be placed with “Hemimegalencephaly” as well as 8 with Schizencephaly. Functions of the cerebral cortex is hard to follow as dot points are used with lacking descriptions or expansion. Perhaps further discussing the actions of each functional area would provide more sufficient information in this part.

--

The layout is looking very good, pictures could be a little smaller. I like the choice of headings, they explain well what is going to be talked about. I feel like you need to add headings like animal models and current research needs to be fixed but I’m sure that’s what is intended. I have some minor points for some of the headings:
Early development:
Spelling: Rhomboncephalon, and the instead of three at the beginning of a paragraph. Overall this heading was covered well
Development of cerebral cortex:
With images, you can add figure titles and this could make your page flow better!! Maybe expand a bit more on the key developmental zones in the human cortex, a brief explanation of what happens could help. The table is very well explained, however for E50-55 I can’t see a reference for all the information, also for the picture in the table for E50-55, you haven’t copied the copyright information so you should add that so it can be used in the page and also add the student template. I really like the drawn picture, but again a figure description would be helpful. This section is very well done.
Anatomy of the cerebral cortex
Some great points but needs to be broken up into paragraphs. Your Wikipedia link for the image is a good image however you should find the original, I recognize it from Cajal’s drawings so I think it could be in a paper about the cerebellum with Cajal. You have good ideas for this heading, also maybe add another image.
Functions of the cerebral cortex
For functional areas, I think a 2 sentence description of each area would be good and maybe a picture for reference.
Abnormalities
Intext referencing would be better. For images, add the student template to each!! Im not entirely sure how I feel about the youtube screenshots as images, maybe use one but try and find some in research articles aswell.
Overall, I think you’ve done a really good job at summarizing abnormalities.

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The introduction was a good opening to the Cortex page as it gives a brief overview and understanding of the cortex generally. The next subheading, “Early development of the Brain”, provides of a simple and clear explanation of the early development process however images would be a great addition to help visualise the text. Try having a look at some images that were shown to us in previous lectures on the brain development where it showed the neural plate, neuroectoderm and subsequent developments.
The next subheading, “Development of Cerebral Cortex”, would probably do better to be called “Later Development of Cerebral Cortex” as it would be a seamless flow from the previous subheading of “Early development…”. It was good that a labelled image was used and information was added for explanation. It helped orient me as I was going on to read about the timeline of corticogenesis. The timeline was detailed and the use of bold helped highlight key terms. However, I would suggest making another column for images on each day. Visual reinforcement just makes the information easier to absorb and make more sense.
The subheading, “Anatomy of the Cerebral Cortex”, is clearly in the editing process. I would just once again definitely recommend the use of images in this section, both hand-drawn diagrams and labelled images from the internet. I thought the use of a video was a clever way to cover the cerebral cortex functions. A bit of general text that briefly covers the functions of the main parts would be a good addition in this section, as a segue into the video.
The “Abnormalities” subheading was a good balance of text and images. It was easier to read because it was split into categories. I would only suggest that you mention at the beginning of the section that abnormalities associated with the cerebral cortex development can be divided into the following categories… I can see the references were placed at the beginning of the section and I’m assuming that is temporary. It is better if they are dispersed within the text where appropriate. There are a good bunch of references but you could probably aim for 25-30 for this page.

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This page needs some more information about current research, signaling processes, future questions and references to animal models. It would also be good with a table or quick overview of developmental origin. There has been a good use of pictures and tables. The setup of the section about abnormalities is really good. This page needs to use more references during the sections and not only at the start of a section. A glossary list would also be good for the reader to understand the page.

*'''Introduction''': Gives a quick knowledge of the cerebral cortex. A picture would be good to support this introduction and maybe a bit more description of the different terms. This section also needs references.
*'''Early Development:''' Good setup with bulleting. I find some of the context a bit confusing to read - especially these two sentences "From there three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five" and "During the fifth week, the embryonic brain undergoes rapid growth folding the neural tube and consequently resulting in three brain flexures" Maybe you can rephrase this.
*'''Development of Cerebral Cortex:''' Good section! Good overview.
*'''Timeline of Corticogenesis:''' Please give a short introduction of what Corticogenesis and Neurogenesis means. Good picture supporting the E50-55, maybe you can put this picture already in the section called "Key developmental zones in the human cortex" since this is the first time we get introduced to the different zones and plates and it would give a better basic knowledge before getting into Corticogenesis.
*'''Anatomy and Function of the Cerebral Cortex''': These two sections should maybe be earlier on the project page together with the introduction since it's a basic understanding of the Cerebral Cortex. Both sections look a bit messy, try to work on making it more simple and easier to read - it kind of looks like personal notes and not a proper information site :-) These sections also need some references. The video in this section gives a good understanding. Good idea putting a video on the page.
*'''Abnormalities associated with Cerebral Cortex Development:''' This section is really good. Great overview of the different scenarios and a lot of pictures to support the reading. Instead of mentioning all the references in the start of the section, you should add the specific reference used for each subsection, this will make it easier for the reader to look up references for specific sections.

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In the introduction section, it was not referenced where the information facts are from. This section should introduce a brief information on the topic, what you are going to discuss on the whole wiki page, introduce current researches and animal models to support the new findings and understandings. Also, don't use "actually" in the sentence.
On the page, It is better to write in full sentences instead of dot points as I've seen a lot of them and include any of scientific words in the glossary section at the end of the page. Where you've inserted picture, it will be clearer to also include it within the text in brackets for example (Figure 1).
Any figures or pictures on this page needs references as well.
In the abnormality section, it is well written with supporting pictures, but in my opinion, it is easier to read if the the figures/pictures are on the same side and texts on the other side instead of alternating. This section was very thoroughly referenced too. I think a small paragraph under the heading introducing the different type of disorders before going into greater details.
Don't focus too much on the anatomy as I can see this section is not finished nor written in paragraph and no pictures or figures, would be better to swap anatomy with some other embryology discussion for example, signalling processes.
Touch on current researches, animal model if any and future questions as they were not seen on the page. Also include a glossary table. References section is looking good but more is needed.

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Overall, a really informative and well-written wiki. The information was well presented and was understandable. The abnormalities section of the wiki, was particularly well done, as it was a good idea to group each abnormality with the disruption of the main event that lead to the abnormality, as it informs the reader that different abnormalities arise from a disruption of different processes that occur in the development of the cerebral cortex. The diagrams and pictures were useful as it functions as a reference point.

Overall, the layout was good, however maybe use more of a dot-point layout in the Anatomy section and maybe add some diagrams of pictures to enhance the information given. Also the sub-title "what is it?" is probably not needed as the introduction itself suggests that you will be describing what the cerebral cortex is and what is does. The Functions of Cerebral cortex may also need a bit more text as the video should just be a supplement rather than the main source for information in that section. Overall, well done as it was an informative and well written wiki.

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Overall I find the information provided to be concise and easy to understand. The introduction was great in giving us a brief overview of page. The layout of the early development of the brain and the development of the cerebral cortex was really nice. I like the use of bullet points as this makes it easier to read. Also good amount of referencing is seen in this area. The use of the table is also a nice touch to the page and I like the picture used for E50-55. However, it could help to have another column with pictures for each row. That would help with the understanding of the text. For the anatomy of the cerebral cortex, it seems a little messy and hard to read as it is too point form. Perhaps these could be phrased into proper sentences with certain parts placed into bullet points to make it easier to read. Also, with the anatomy, pictures would be very helpful to aid in the explanation. For the functions of the cerebral cortex, it lists the functional areas but not the functions of those areas. Although it is stated in the video, which is a nice addition to the page, this could be improved by adding short sentences that state these functions that were mentioned as well. For Sections 1.4 and 1.5, references are also needed to state where the information was obtained from. The abnormalities section provides detailed explanations of the various disorders associated with the development of the cerebral cortex. There is also a good amount of pictures used. One thing I noticed was the references which was placed on the top of the section instead of throughout the text.

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Overall, the page has a good structure and flow with good headings and subheadings. The information provided was concise and easy to comprehend. The introduction provides a brief overview and sufficient background knowledge about the cerebral cortex. I like how the team thought of mentioning about the early development of the brain before narrowing it down to the cerebral cortex. However these two sections do not seem to flow well. Maybe you could have 2-3 sentences that could help ease into the development of the cerebral cortex. I really love the timeline of corticogenesis. This part has been done really well. One minor improvement that could be made is to add images under each embryonic stage instead of just the last stage to better aid the reader into understanding the development. Also, a brief description of what corticogenesis is could be included before the table. For these two sections, there were a good amount of references.

For the anatomy of the cerebral cortex, it seems a little messy and hard to understand as its written in point forms. Perhaps, the dot points could be changed to proper sentences with histological images to tie it together. For the functions of the cerebral cortex, I think you could use a table to list down the areas and then provide a brief description of the functions of that particular part. The video is a good addition to the page. These two sections are lacking citations and references.The abnormalities section was well done. However, the citations should be added within the text instead of at the top of the page. Since there are a lot of abnormalities, maybe the team could list in a few sentences about all the abnormalities that they are going to discuss to have a better start to the section. For the images that are used on this page, the images should be labelled as “figure 1” or “table 1”. Maybe, sections on the “animal models” and “current research” could be added to wrap the page up.

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Overall the project was very good and clear. Pictures were well placed and bullet points spaced out information, making the page easy to look at and follow. The layout of the beginning and end sections with the short paragraphs and interspersed bullet points broke up the information and highlighted key facts. The introduction was a good overview of the page, including a quick summary of the anatomy, function, and development of the cerebral cortex.

There were some basic grammatical and spelling errors (e.g. “neurons” is spelled wrong under the subheading “Layer 4”), but for the most part did not take away from the clarity of the page. One sentence, “From there three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five,” seems to be missing something at the beginning that would increase clarity.

Some pictures had a lot of information in the summary when clicking on them while others lacked sufficient information. Some pictures that could benefit from more information are Corticogenesis of mouse and humans.jpeg, SBH.png, Disorders of Cortical Formation2.png, Symptoms of microcephaly.png, Hemimegalencephaly.png, and SchizencephalicBrain.jpg. These pictures are relevant to the topic and are pretty self-explanatory so this does not take away much clarity from the page but for the parameters of the project, additional summary should be added. The picture Stage22 HPA2L.jpg has good information in the summary but it is oddly structured. FASface.jpeg does not have any copyright information included. Having Gray754.png displayed on the page rather than as a link would look better.

The video describing the functions of the cerebral cortex was a good introduction to that topic. The video was easy to watch and understand. The first video about corpus callosum agenesis was a good introduction to the topic, but the second video about corpus callosum agenesis was long and the lecturer was hard to understand. That subheading would benefit from a brief description of that topic rather that a long video explanation.

The switch from a mix of bullets and short paragraphs to all bullet points in Anatomy of the Cerebral Cortex makes the page look less cohesive. The last bullet point in Layer 4 is hard to understand and the last 2 bullet points in Layer 5 would flow better if they were combined. The information in these sections are good and relatively easy to follow.

Overall the project is very good. The table explaining the timetable of cortex development is a clear way to break down the topic. Breaking down the information of abnormal development into what went wrong in the embryology (e.g. migration problems vs. differentiation problems) highlights importance of embryology in congenital disorders. There is a lot of information about the abnormal development of the cortex but could use some information about past and current research and animal studies. Reference list at the end looks good but the in-text citations of abnormal development should be interspersed with the information rather than all at the beginning.

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*Overall, the page is well structured and relatively easy to follow with the headings and subheadings relevant to the topic area (embryology of the cerebral cortex).

*The introduction was short and concise, which provided a relevant amount of background knowledge before delving straight into the development.

*Perhaps the Anatomy and Functions of the cerebral cortex could be put before the development so that it ties in with the introduction.

*The use of dot points under Anatomy and Function of the Cerebral Cortex was excessive and gives off an unfinished feel. Perhaps you could add in a couple of images to make these dot points easier to understand. Also, it might be better to use the * function to create these dot points.

*The use of the table on the "Timeline of Corticogenesis” was quite clever and made it easier to understand, however I suggest that you add photos in E30, E31-32 and E40-45 since there seems to only be one photo in E50-55. The page is lacking a "further questions" section which would be quite informative in understanding the research gap to date.

*I think the Disorders was nicely done and was very informative. The use of images in the left and right side of the page made it aesthetically pleasing to read. However this section lacks references, which I think you should add to avoid plagiarism.

*The images and videos that are on the page are very relevant to the topic, which aided in understanding the content. However perhaps you could label them using "Figure 1", or "Table 1" etc as well as putting an appropriate description under the image/video. Also, the link of an wiki image under Layers was not inserted properly, so be sure to check that for next time.

*References were inconsistent throughout the page, however most were done properly.

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The chosen headings for the development of the cerebral cortex were very suitable to highlight the key topics in providing a page of summarised information. It was then easy to navigate through the page using the shortcuts and finding information. Although, there was one sub sub heading “Timeline of Corticogenesis” that was formatted to be in bold while the rest were not.

The disorders listed seems to be really interesting and it covers the whole spectrum of the case abnormalities. But I suggest to get rid of the letter bullets (e.g. A), B), C) ) for the breakdown of the abnormalities.

The introduction had a quick and concise text, however, an image of the cerebellum would be suitable in this section on the side. While the sub sub heading stated that the introduction section will talk about the features of a cerebellum, a paragraph about the development and its stages were written down in this section as well. This could be moved into the ‘Early Development of the Brain’ subheading underneath. Bullet points of the brain layers as well as a diagram would be helpful for the visualisation of the brain.

For the sections that explain the development in specific weeks, a table would be advisable to make it neater and easier to look at. Also, an image was left inside the table grids and it was confusing whether it was meant to be there or not. Perhaps adding a photo gallery showing the stages at the bottom of the table would be better.

Hand drawn diagrams were really precise, neat and was very visually appealing. It was taking up all the space and unless it is intentional, I suggest to resize the drawing into a smaller one that fits the page as well as the accompanying text and content of the drawing.

The variety of visual aids were really entertaining and were referenced properly.

Finally, the reference list at the bottom of the page did not have a consistent format. It was mostly APA format however the others looked like a different format.

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The most obvious flaw was the lack of polish in formatting of some of the page. Bullet points are only so useful when it comes to writing a wiki page, instead of taking notes. The page is unfinished, but, the content included especially in the "Development of Cerebral Cortex" and "Abnormalities associated with Cerebral Cortex Development" was extensive and well done. The large table that linked the development with the time period was very useful and the choice of bolding key words allowed the main idea in the paragraph to be quickly understood from a glance. The use of images very much enhanced the descriptions and checker-like the layout of the different abnormalities was refreshing. Some subheadings, such as the Anatomy and Function of the cerebral cortex, could be elaborated on but the overall structure of the page is logical and fluid, and the writing is clear and concise without being superficial.

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Strengths: 
• The page has an excellent structure covering a broad variety of topics regarding the cerebral cortex. It was great to see how you also explored abnormalities associated with the cerebral cortex. Furthermore the use of various subheadings and headings related to cerebral cortex development meets criteria 1 and 2 of the assessment. 
• The presentation of the wiki page was excellent in that a variety of images, videos and tables were utilized. The use of such sources of information helps present information in a much more clear and concise manner, whilst also providing a thorough explanation to visual learners. Hence the wiki page has an element of teaching at a peer level (criteria 4 is satisfied). 
• A large number of references have also been included within the wiki page, a characteristic which helps increase the reliability of information presented. Furthermore, most sources are recent which another great characteristic. Thus, it appears that the group has satisfied criteria 3 for the assessment. 
• Each topic appears to show a significant amount of detail which is excellent. In addition, the use of images alongside the text is a great tool as the audience is able to better visualize the concept being described. 

Areas of improvement: 
• Although you have provided a variety of recent references, to improve you may avoid using sources as old as 1977 as results presented from this study may be outdated. 
• It was excellent that the functional areas of the brain were listed, however to improve you may wish to elaborate on the specific functions of these areas. You may also explore how abnormalities of these areas during development may impact upon the behaviour of the individual following birth 
• Whilst a variety of topics have been covered, you may wish to also describe the importance of signaling throughout the process of cortical development. For example, you may investigate different growth factors and receptors involved in the process. 
• Another possible improvement would be to perhaps include a timeline of different researchers who contributed to the in-depth understanding of the developing cortex that we have today. You may also describe what each researcher discovered. 
• In order to completely satisfy criteria 5, you may wish to conduct further research beyond the scope of formal teaching activities. For example you may explore the contribution of animal models towards our understanding of cortical development. 

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This peer review is based on the relevant dot points of the ‘Group Assessment Criteria’, as well as subheadings suggested by Mark. This information can be found on the student page.

{| border="1" align="left"
|-
|Criteria
|Strengths
|Weaknesses
|-
| 1. The choice of content shows a good understanding of the topic area
| The developmental origin of the cerebral cortex is addressed well under the sub-heading ‘Early development of the brain’.

The development timeline of the cerebral cortex is described clearly and in detail in the table of the ‘Timeline of corticogenesis’.

Abnormal development of the cerebral cortex and the associated conditions are covered in an immense amount of detail. The accompanying images and videos enhance the written information, as well as making it easier for the reader to comprehend. In addition, the sub-headings of this section compartmentalize the congenital diseases in a logical manner that highlights the link between abnormal development and specific diseases.
| There are several key topic areas missing from the page:
*There is no section covering key historical discoveries relevant to the cerebral cortex and its embryological development.
*There is no information relating to developmental signalling processes
*There is no section on current research in fields relevant to the embryological development of the cerebral cortex.
*There is no section on animal models that have been used to advance scientific understanding of the cerebral cortex.
*There is no section on future questions regarding the development of the cerebral cortex.
*A glossary of terms has not been included.

Some sections that have been included are somewhat irrelevant to the subject matter. For example, there is a large (unfinished) section on the anatomy and functions of the cerebral cortex. While it is important to provide a bit of an anatomical background on the subject, it shouldn’t be a major focus of this assignment. Focus more on the sections mentioned above, and keep the project focused on the embryology of the cerebral cortex.
|-
|2. Content is correctly cited and referenced
|There have been attempts at referencing throughout the assignment. A reference list has been produced and appears mostly correct. References have not been repeated throughout the list.

Peer-reviewed primary research articles have been used in this assignment.

The student-drawn image has been cited correctly, as have most of the images used in the ‘abnormal development’ section.
|Overall, referencing in this assignment is very poor. Most of the content is completely devoid of any references (see ‘introduction’, ‘anatomy of the cortex’ and ‘abnormal development), and sections that have been referenced have been referenced “by paragraph” (see ‘timeline of corticogenesis’)

Many of the sources used in this assignment are inappropriate and/or unreliable. Try to rely more on primary research articles and less on textbooks or websites.

Many of the images have been cited incorrectly and used without permission. Remember to include the full reference, the original summary and the copyright license information for each image.
|-
|3. The wiki has an element of teaching at a peer level
|The information presented is mostly at a level appropriate for peers. Images and hand-drawn diagrams have been included to facilitate the readers understanding of the subject matter. Some of the images contain useful descriptions of the subject matter, and aid in understanding of the topic.
|Many of the acronyms and terms used in this assignment are not well explained. Include a glossary of terms to make some of the content easier to follow and understand.
|-
|4. Relates the topic and content of the Wiki entry to learning aims of embryology
|The development of the cerebral cortex was covered extensively, which is a very important learning aim of embryology.
|There are certain learning aims of embryology that have not been included in this assignment, such as developmental signaling processes (see criteria 1 for more information). There has been no discussion of relevant historical or current research (adding in the subheadings “key developments” and “current research” would help rectify this).
|-
|5. The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic
|Certain aspects have been researched and presented well (such as embryological development).

Links to other pages of the UNSW embryology wiki have been included, however they have been used as references rather than just links.
|Information from the UNSW embryology wiki has been used as direct sources of information. Instead they should be included to relate this particular wiki page to other areas of learning.

The small number of sources cited in the reference list demonstrates a poor and narrow approach to researching this topic. A greater library of sources should be used to create this page (mainly primary research articles).
|}

Grade: FAIL

General Comment:
While some aspects of the wiki page have been done well, the page is largely unfinished. Many sections still need to be added, and others are in need of improvement.

----
The introduction of this page gives a good general background but could benefit from adding bullet points to describe the six horizontal layers of the cortex and maybe a short summary of its clinical significance. 'Early Development' was well written, easy to follow and well referenced. 'Development of Cerebral Cortex' would benefit from a short introductory statement instead of going straight into the 'Main classes of neurons'. Pictures and tables in this section were informative and engaging to the reader. Hand-drawn picture was well done, colourful and easy to interpret. 'Anatomy of the Cerebral Cortex' looks unfinished and isn't easy to read as it doesn't flow or show a clear structure. No references can be seen and no pictures or tables to make for easier reading or understanding. The different layers of the cortex would greatly benefit from a table with structure/function format or a clear diagram. The same is true for 'Functions of the Cerebral Cortex'. 'Abnormalities associated with Cerebral Cortex Development' I liked the setup of this section because of its clear headings and subheadings as well as its informative pictures. The captions on some of these pictures need to be elaborated on. Also couldn't see any in text referencing which really needs to be present. Content is clear and concise and easy to follow. This section was engaging and well done. 'INFO/Research Links' was not finished yet but shows lots of research articles that could be promising.
----

'''Peer review project 1:'''

I have some general comments which applies to almost all of the sections in the project:
* The referencing is not proper. A lot of the sections do not have reference or all of the reference are at the bottom of the section.
* Some of the sections have bullet points instead of text. It feels like you are reading somebodies notes not a project.
* It would be nice with more pictures to get a better understanding. The pictures there are good, but it does not have any caption. The size is to big as well for some of the pictures (the drawing with the mouse and human model)
* The project does not have a current research, future questions section or animal, which is a requirement for the project.
* I think it would be better for the project if the anatomy and function sections stood before the development part. It would give a better understanding or at least I think so.
* In general, I don’t feel like the project is connected, and expressions like cortigenesis and neurogenesis is not defined.
* I really think the timeline is nice. But a lot of the text within the timeline would have been more appropriate to write in the cortex development section. It should contain some key discoveries instead. But the text there is good, makes sense to me and is well written.
* In the early development of the brain section I don’t understand some of the sentence like: “From there three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five. These are fundamental divisions of the adult brain and communicate freely with each other”. Some of it should properly be rephrased.
* There are some repetions during the project. The text could be compromised.
* In general, the language is neutral and written in a good scientific way.

----
- Covers only development, anatomy, functions and abnormalities, more subheadings could be better and exploring other areas of the embryology of the cerebral cortex

- Nice introduction that summarises what the cerebral cortex does and some of its structural layers. Would be nice to see a diagram with the layers of the cerebral cortex or a diagram of the cerebral cortex in the introduction.

- Development of the brain was covered really well and was detailed and also proper and good amount of referencing in this section. Good use of lot of pictures in this section, which made it much easier to understand.

- Timeline of corticogenesis was explained very well in a straightforward manner and use of the table helped.

- Anatomy of cerebral cortex as well as functions of the cerebral cortex is still incomplete and is mainly in dot points and no referencing

- Abnormalities was done well and very detailed and covered many types of abnormalities. Disorders were also divided into categories which is good.

- Good use of pictures in the abnormalities of the section for each abnormalities but use of videos were probably not necessary in this section

- Overall, introduction, development and abnormalities were all done well and good grammar and spelling. Other main headings definitely needed more work and referencing was done incorrectly or absent in some parts. There could be more subheadings and there is no glossary.

- References are from proper journal articles/peer reviewed journals which is good.

----

- Introduction provides a good summary, however the list of layers is quite long so maybe adding a diagram would make all that information a bit easier to take in? Or perhaps, listing the layers in dot point form rather than a long sentence.
- Early development of the brain is very detailed, well researched as evidenced by the many references. Perhaps a short table summarising all that information could be added. Some formatting issues, but nothing that can't be easily fixed.
- Development of cerebral cortex section very well done. Good use of diagrams and the table; they made the information easier to understand. However maybe the drawn diagram could be smaller (good job though!). Easy to follow.
- Anatomy and functions sections are obviously unfinished, but it is clear that extensive research has been done to produce all that in the first place. So good job, once it is all formatted, I'm sure it will look great. All the dot points were easy to understand anyway.
- Abnormalities section was very well researched. Great use of diagrams. Personally, I found the subheadings easy to grasp in the Contents, however it was a bit overwhelming to scroll through it all.

Overall, a good job. It is clear that some sections are incomplete, but it seems like there is a clear direction of where it is going. I would recommend a glossary of terms, just because the cerebral cortex is so complex and all the terms can become overwhelming. Tables in the development would help with this also just to provide a quick and easily accesible summary of development.

----

* Introduction
** Could have been linked together with anatomy and function for better structuring of page
** Simple diagram could have been used to provide context on body location
* Development of the cerebral cortex
** Section should be expanded upon to give context to the content
*** Seemed like a sudden introduction of neuronal classes and key developmental zones without much expansion
** Section seemed to be more about components of the developing cerebral cortex rather than development itself – could update subheading to reflect this or update content to focus more on development
* Timeline of corticogenesis
** Could have been its own subheading
* Anatomy
** Should be moved up towards start of the page with introduction
* Functions
** Should be moved up towards start of page with introduction
** Functional areas should be expanded upon to briefly discuss their different roles
** Should not rely too much on linked video
* Abnormalities
** Diagram “disorders of cortical formation” gave little information relating to section – seemed like illustration related little to the mentioned stages. Instead, could have mentioned that abnormalities arise during proliferation, migration and organisation during cortical development
** Lettering and numbering of subheadings in this section should be switched for clarity
* Overall was well done. However:
** Some diagrams lacked descriptions and figure legends/abbreviation definitions – diagrams should be self-explanatory and be understandable in combination with their descriptions, when taken out of their contexts within the page
** Minor grammatical errors present throughout the page
** Mostly well-structured but some subheadings can be shifted around - see above for specific feedback
** Remember to clear zIDs before final submission

----
*Introduction
**References are missing.
**Labeled images could be included to illustrate the relative position of cerebral cortex and cerebrum in the human brain and the organization of cerebral cortex into the six horizontal layers.

*Early development of the brain
**Written expression could be clearer. For example, L1: “The brain begins to develop during the third week (of pregnancy) when the neural plate and (neural) tube (are derived) from the outermost layer of embryonic cells, (that is) the neuroectoderm.”.
**A table listing the major development occurring at each week (i.e. week 3 – start of development of brain, week 4 – fusion of the neural folds) could be included for easier understanding of the developmental timeline
**Labeled images should be included for clear illustration of the relative positions and development of various parts of the cerebral cortex.

*Development of cerebral cortex
**Appropriate inclusion of images that aid in understanding the content. However, there is little reference or explanation to the images in the text. No caption is included for the images. The first image and the second image are redundant to each other as they are both illustrating the key developmental zones in the human cortex. Author may want to consider taking one of them out.
**Good use of a table in summarising the developmental timeline for corticogenesis. Clear explanation of corticogenesis.

*Anatomy of the cerebral cortex
**Content could be better organized in paragraphs instead of point forms.
**Labelled images should be included for clear illustration

*Functions of the cerebral cortex
**More content could be added to each of the functional areas listed.
**Video is appropriate and useful in facilitating understanding.

*Abnormalities associated with cerebral cortex development
**References should be included where appropriate instead of generalizing as “references used to write”.
**The amount of content seems slightly overwhelming as compared to other sections of the page which are equally important as well. Nonetheless, good effort in explaining the abnormalities in great details.
**Some references are missing.

*References
**Good effort in for having both journal and book references. However, it would be good to adhere to either APA or BJP style of referencing.

__

GROUP 1

Early Development of the Brain: Well written, maybe a little concise, there are some great images which could be useful for this section also Development of Cerebral Cortex: Lots of good information, maybe try to make this section a bit more fluid - comes of a little disjointed Anatomy of the Cerebral Cortex/Functions of the Cerebral Cortex: This section does not read well to the eye - that's not to say it is incorrect - I would try putting this into a friendly format Abnormalities associated with Cerebral Cortex Development: This section is huge, but each condition has a fairly concise explanation so well done

Overall: There is lots of sound information on the page - main emphasis would be giving the page a clean up of the format and trying to make the sections flow together a little nicer

2017 Group Project 1

2017-10-26T03:04:28Z

Z5177691: /* Glossary */

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Intro section cortex.jpg|thumb|right|350px|'''Figure1. Cerebral cortex is the outermost layer of the cerebrum''' <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex is part of the brain which surrounds the cerebral hemispheres. It has a very large surface area (largest part of human brain). The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres (Figure 1). It is a layer of gray matter around 2-4 mm in thickness, and consists of approximately 10 billion nerve cell bodies and dendrites. It appears gray because of the cell bodies (Figure 2). 
[[File:Brain sectin showing cortex.jpg|thumb|left|300px|'''Figure 2. Section of the human brain''' <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]]

The cerebral cortex is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The development of the cerebral cortex involves 3 main stages:
*Proliferation (or growth or differentiation)
*Migration of neurons
*Maturation (or organisation or folding). 
 
The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. Xxternal pyramidal, IV. Internal granular layer, V. Internal pyramidal layer, VI. Multiform layer. These individual layers organise the capacity for interconnections between both input and output signals. 

This project will explore the various embryologic aspects of the cerebral cortex, including early development of the brain, development of the cerebral cortex, anatomy and functions of the cortex, and abnormalities associated with cortical development. 
<ref>Moore, K., Persaud, T. and Torchia, M. (2011). The Developing Human. London: Elsevier Health Sciences, pp.The Nervous System; 379-414.</ref><ref>Van Essen, D. (2005). A Population-Average, Landmark- and Surface-based (PALS) atlas of human cerebral cortex. NeuroImage, 28(3), pp.635-662.</ref><ref>Differencebetween.com. (2017). Difference Between Cerebrum and Cerebral Cortex. [online] Available at: http://www.differencebetween.com/difference-between-cerebrum-and-vs-cerebral-cortex/ [Accessed 26 Oct. 2017].</ref><ref>Dartmouth.edu. (2006). Chapter 11: The Cerebral Cortex. [online] Available at: http://www.dartmouth.edu/~rswenson/NeuroSci/chapter_11.html.</ref><ref name="first">Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
 

==Early Development of the Brain==

 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
[[File:Brain Development 2.png|thumb|400px|right|'''Figure 3. A longitudinal perspective of the neural tube, showing the primary brain vesicles divided into the five secondary subdivisions'''.]]

*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five, as depicted in Figure 3. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.

'''Brain Flexures'''
[[File:Brain Development.png|thumb|400px|right|'''Figure 4. Lateral perspective of the neural tube, showing the three flexures, and five secondary subdivisions'''.]]
During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures, as depicted in Figure 4, in proximity to the five secondary vesicles. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

Through the foundation of structures and processes in during the early developmental brain, the fetus' brain is able to further develop into a much more complex organ.

[[File:Neural- cortex Cajal drawing 01.jpg |thumb|right|200px|'''Figure 5. Laminar and columnar organization of the cerebral cortex (Historical drawing by Cajal)''']]
 

==Later Development: Development of the Cerebral Cortex==
 
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes. The diversity in neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned in above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contributes to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|400px|super|'''Figure 6. Key developmental zones in the human cortex'''.]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone
**Subplate
*Cortical Plate: establishment of the 6 cortical layers form in this region between the subplate and the marginal zone

===Timeline of Corticogenesis===
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (e.g fate) of the neurons so that specific connections and cortical structure are achieved. "E" relates to embryonic day in relation to corticogenesis.
 

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along in order to expand the neocortex. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area as well as the preplate and many of the cells in the SVZ contribute to the later cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to the target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layers 6 is populated before layer 5; layer 5 is populated before layer 4 and so on <ref name="boulder"/>. Each layer condenses and the neurons are closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex such as sensory and motor function.
[[File:Corticogenesis.png|center|thumb|700px|super|'''Figure 7. Corticogenesis from E30 to adult human brain''']]

===Signalling involved in Cerebral Cortex Development===
 
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 8. Shh signalling increases the number of proliferating cells''']]
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.

[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 9. Cortex development in wild-type and ''reeler'' mice''']]

'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 11) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 12). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|500px|'''Figure 10. Cortical thickness in the absence of Bmp7''']]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers. Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.
 

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref> 
 
[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|'''Figure 11. Anatomy of the human cerebral cortex''' <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]] 

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull (see figure 10). The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri, as shown in figure 10. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri (see figure 10). Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>
 
'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}
 

==Functions of the Cerebral Cortex==
 
[[File:Cortical areas.png|thumb|right|text-top|450px|'''Figure 12. Cortical areas human cortex''' <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]
[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|'''Figure 13. Cortical Homonculus'''<ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]
The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas, as shown in Figure 11. <ref name="overall function"><pubmed>21653723</pubmed></ref>

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body (see figure 12). The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>
 
==Abnormalities associated with Cerebral Cortex Development==
[[File:Stages of development.png|thumb|right|text-top||520px|'''Figure 14. Main stages of cortical development where abnormalities may arise'''.<ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>]]
 

The embryologic development of the cerebral cortex involves highly organised and complex events. As mentioned in the 'Introduction', these events are generally divided by scientists into 3 major stages in cortical formation where crucial changes occur in neuronal cells; these stages include: 
1. Proliferation (or Growth), 
2. Migration, 
3. Organisation (or Maturation or Differentiation).

Disruptions can occur in these stages of cortical development due to multiple causes, and these disruptions give rise to malformations or irregularities in the cerebral cortex (Figure 13). 

Although multitudinous and/or severe effects ensue from such disorders, epilepsy and mental retardation (of varying degrees) are almost always present with these disorders. 

This section will explore some abnormalities that are commonly discussed in scientific literature. <ref name="first"/><ref name="second">Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref><ref name="third">Christopher A, C. (1999). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 
 
===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder that results because neuroblasts are not able to successfully complete the proliferation stage of cortical development. Mechanism of development of this disorder is not well understood and FCD is categorised as due to uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers (lamination disorganisation). Very large dysmorphic cells called 'balloon' cells are also seen due to abnormal regulation of cell growth. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

If symptoms do present, then these are associated with epilepsy ( tonic-clonic, tonic, simple partial and complex partial seizures). In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. <ref name="first"/><ref name="second"/> 
[[File:Hemimegalencephaly2.png|thumb|left|upright=1.42|'''Figure 15. Observable radiographic features in Hemimegalencephaly'''. <ref name="imaging"/> ]]
 
<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form tumour-like, benign malformation(s) ) of one cerebral hemisphere, part of a hemisphere or one hemisphere with partial involvement of the other hemisphere. MRI findings usually show enlargement of one hemisphere or at least one lobe and abnormal white matter (Figure 15).

Clinical symptoms of this disease may include developmental delay, mental retardation, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. 
<ref name="imaging"/><ref name="second"/>
[[File:Image.png|thumb|right|upright=1.45|'''Figure 16. Possible clinical features of Microcephaly in a newborn'''. <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]] 
 
 
 
<big><big>'''3) Microcephaly Vera'''</big></big>

Amongst cortical congenital disorders, Microcephaly Vera is a relatively common disorder. Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs, and can be caused by genetic or non-genetic factors. 

'''Microcephaly Vera or Primary Microcephaly''' is genetic and does not involve other organs. It from abnormal cortical development, specifically cell division or proliferation. In this malformation the circumference of the head (and so the brain) is much less than normal, while the rest of the body is of normal size. Microcephaly Vera clinically most frequently presents with mental retardation and sometimes epilepsy, although some other features can be observed ocassionally (Figure 16). 
<ref name="imaging"/><ref name="second"/><ref name="third"/> 
 

<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms), which can occur in several tissues of the body, including cerebral cortex. In the cortical gray matter, cortical tubers and bizarre cells are seen because laminar disorganisation occurs (like Focal Cortical Dyplasia). TSC is thus called because at the scientists thought that the lesions seen resembled potato tubers. 

No signs or symptoms are known to be observed for TSC, and diagnosis is determined after a brain scan. 
<ref name="imaging"/><ref name="third"/> 

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:Heteroptopia.png|thumb|upright=1.85|right|'''Figure 17. Observable radiographic features of subcortical band heterotopia'''. <ref name="imaging"/> ]]
For neurons to successfully execute the migration stage of development, some steps have to be completed including departure from the ventricular zone, migration to the cortical plate and then arrest of movement at the appropriate layer. 
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex (Figure 17). 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 
<ref name="imaging"/><ref name="second"/><ref name="third"/> 
<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 
Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. Type II Lissencephaly also includes:
#Muscle-Eye-Brain Disease
#Walker-Warburg Syndrome
#Fukuyama Syndrome 
*'''Microlissencephaly''' 
Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly(discussed previously), and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span. 
<ref name="first"/><ref name="imaging"/><ref name="second"/><ref name="third"/> 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Clinical presentation of Kallman Syndrome includes Archinencephaly, which is hypoplasia (underdevelopment or incomplete development) of the olfactory cortex and olfactory bulb, and deficient or absent sense of smell. 
<ref name="imaging"/><ref name="third"/> 

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

Affected patients can have varying degrees of symptoms, including epilepsy and developmental delay. For example, bilateral poylmicrogyria causes developmental delay, hypertonicity, ataxia, and refractory seizures. 
<ref name="first"/><ref name="second"/> 
[[File:SchizencephalicB.jpg|thumb|left|upright=1.45|'''Figure 18. Coronal and axial sections of the brain of a patient with Schizencephaly'''.<ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]
 

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder classified within the same group as Polymicrogyria. It is characterised by a cleft(s) or lesion(s) on the brain surface,extending from the cerebral cortex to the ventricle and is typically filled with CSF (cerebrospinal fluid) and lined by cortex gray matter. These lesions or clefts are thought to be 'destructive'. 

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly. Type I presents with partial seizures or spastic hemiparesis, while Type II presents with epilepsy or seizures, spasticity, severe developmental delay and microcephaly.

Schizencephaly can be bilateral or unilateral; and commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
<ref name="first"/><ref name="imaging"/><ref name="second"/> 
 
 
 
 
 
{| role="presentation" class="wikitable mw-collapsible mw-collapsed"
| <big><big><big>Other disorders of varying etiology</big></big></big>
|-
| <big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right|'''Figure 19. Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD)'''.<ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome. 
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

The corpus callosum is a structure present in the brain which connects both the hemispheres of the brain. The video below briefly describes this:

<html5media height="350" width="550">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref> 
Agenesis of the corpus callosum (ACC) occurs when the corpus callosum is partially or completely absent. It is thought to be due to a disruption of brain cell migration during fetal development.
<ref>Ninds.nih.gov. (2017). Agenesis of the Corpus Callosum Information Page. [online] Available at: https://www.ninds.nih.gov/Disorders/All-Disorders/Agenesis-Corpus-Callosum-Information-Page [Accessed 26 Oct. 2017].</ref> 
Some clinical symptoms include epilepsy or seizures, developmental delay, vision and hearing impairment, trouble in motor coordination and language skills and difficulty in muscle coordination and tone coordination.
<ref>Vasudevan, C., McKechnie, L. and Levene, M. (2012). Long-term outcome of antenatally diagnosed agenesis of corpus callosum and cerebellar malformations. Seminars in Fetal and Neonatal Medicine, 17(5), pp.295-300. </ref>
|}
 

==Models and Research==
===Animal Models===
[[File:Corticogenesis of mouse and humans.jpeg|thumb|right|text-top|590px|'''Figure 20. Mouse vs Human Neurogenesis''']]

====Mice Model====
Mice have often been used to study corticogenesis in mammals. Corticogenesis lasts from E11 to E19 in mice and lasts eight days, which is far shorter than human corticogenesis. While there are many similarities between human corticogenesis, the rodent brain is much smaller than that of a human’s and therefore, there are different types of progenitor cells involved in mice and the cortex does not expand as greatly. <ref name="control">Dehay, C. and Kennedy, H. (2007). Cell-cycle control and cortical development. Nature Reviews Neuroscience, 8(6),438-450.</ref>Humans have greater numbers of intermediate precursor cells (to aid in further differentiation) and outer radial glial cells compared those of mice. <ref name="cerebral"/> In addition, the SVZ does not split into the inner and outer subventricular zone, but stays intact as one. <ref name="control"/> The importance of reelin has also been greatly studied in mice. Studies showed that mutant mice have disruptions in the migration of neurons into their subsequent layers. By injecting thymidine at various time points of gestation into the female mice, researchers were able to track the development of various populations of neurons. Later developing neurons were unable to ascend past the already early formed neurons due to disruptions in reelin signaling (in the marginal zone). Instead, superficial layer neurons resided below the older, deep layer neurons. This inverted lamination comprises sensory and motor function.<ref> Caviness, V. (1982). Neocortical histogenesis in normal and reeler mice: A developmental study based upon [3H]thymidine autoradiography. Developmental Brain Research, 4(3), 293-302.</ref>
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Figure 21. Timeline and protocol of cerebral organoid development''']]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

The development of these brain organoids has allowed more comprehensive understanding of the self-organisational properties of the brain, and is quickly advancing, however the lack of vasculature in cultured organoids restricts their ability to be used for specific neurological disorders. Furthermore there are still challenges associated with the generation of individual, discrete brain regions, which should be addressed in the future. <ref><pubmed>28822354</pubmed></ref>

==Glossary==

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
|'''Sulcus'''|| Sulci (plural) are grooves in the cerebral cortex.
|-bgcolor="FAF5FF"
|'''Gyrus '''|| Gyri (plural) are folds/ridges in the cerebral cortex.
|-bgcolor="FAF5FF"
|'''Fissures'''|| Large sulci.
|-bgcolor="FAF5FF"
|'''Corticogenesis'''|| The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes.
|-bgcolor="FAF5FF"
|'''Cajal-Retzius (CR) cells'''|| Cortical neurons that develop early on, at the same time as the preplate, and express an important glycoprotein known as reelin, which helps with the proper migration of neurons into their respective layers.
|-bgcolor="FAF5FF"
|'''GABAergic Neurons'''|| Generate gamma aminobutyric acid (GABA) as their output, one of the two inhibitory neurotransmitters in the central nervous system (CNS).
|-bgcolor="FAF5FF"
|'''Radial glial cells '''|| A class of distinct nonneuronal cells that are bipolar shaped and span the entire width of the cortex during development.
|-bgcolor="FAF5FF"
|'''Ventricular zone (VZ)'''|| First formed single-celled layer in the cortex, arising from progenitors in the dorsal telencephalon that divide symmetrically. It lies adjacent to the ventricular surface.
|-bgcolor="FAF5FF"
|'''Preplate'''|| First "pioneer neurons" from dividing cells in the ventricular zone for this layer above the ventricular zone
|-bgcolor="FAF5FF"
|'''Subventricular zone (SVZ)'''|| Cells in the VZ continue to divide symmetrically and give rise to another zone above the VZ known as the SVZ. This zone later splits into an inner (ISVZ) and outer ventricular zone (OSVZ)
|-bgcolor="FAF5FF"
|'''Marginal Zone (MZ)'''|| A subsection of the preplate that forms around E50-55. It lies at the uppermost area of the cortex nearest the pial surface.
|-bgcolor="FAF5FF"
|'''Subplate'''|| A subsection of the preplate that forms around E50-55.
|-bgcolor="FAF5FF"
|'''Cortical Plate'''|| Forms in between the marginal zone and subplate and gives rise to the 6 layers of the cortex involved in sensory and motor function.
|-bgcolor="FAF5FF"
|'''Intermediate zone'''|| Forms below the subplate between E50-55 and contains only migrating cells and no intermediate precursor cells.
|-bgcolor="FAF5FF"
|'''Total agyria'''||gyri and sulci absent resulting in 'smooth brain'
|-bgcolor="FAF5FF"
|'''Pachygyria'''|| gyri can be seen but are very few compared to normal brain
|-bgcolor="FAF5FF"
|'''Hypoplasia'''|| underdevelopment or incomplete development of a tissue or organ
|-bgcolor="FAF5FF"
|'''Agenesis'''|| total absence of something
|-bgcolor="FAF5FF"
|}

==References==

2017 Group Project 1

2017-10-26T03:01:27Z

Z5177691: /* Glossary */

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Intro section cortex.jpg|thumb|right|350px|'''Figure1. Cerebral cortex is the outermost layer of the cerebrum''' <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex is part of the brain which surrounds the cerebral hemispheres. It has a very large surface area (largest part of human brain). The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres (Figure 1). It is a layer of gray matter around 2-4 mm in thickness, and consists of approximately 10 billion nerve cell bodies and dendrites. It appears gray because of the cell bodies (Figure 2). 
[[File:Brain sectin showing cortex.jpg|thumb|left|300px|'''Figure 2. Section of the human brain''' <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]]

The cerebral cortex is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The development of the cerebral cortex involves 3 main stages:
*Proliferation (or growth or differentiation)
*Migration of neurons
*Maturation (or organisation or folding). 
 
The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. Xxternal pyramidal, IV. Internal granular layer, V. Internal pyramidal layer, VI. Multiform layer. These individual layers organise the capacity for interconnections between both input and output signals. 

This project will explore the various embryologic aspects of the cerebral cortex, including early development of the brain, development of the cerebral cortex, anatomy and functions of the cortex, and abnormalities associated with cortical development. 
<ref>Moore, K., Persaud, T. and Torchia, M. (2011). The Developing Human. London: Elsevier Health Sciences, pp.The Nervous System; 379-414.</ref><ref>Van Essen, D. (2005). A Population-Average, Landmark- and Surface-based (PALS) atlas of human cerebral cortex. NeuroImage, 28(3), pp.635-662.</ref><ref>Differencebetween.com. (2017). Difference Between Cerebrum and Cerebral Cortex. [online] Available at: http://www.differencebetween.com/difference-between-cerebrum-and-vs-cerebral-cortex/ [Accessed 26 Oct. 2017].</ref><ref>Dartmouth.edu. (2006). Chapter 11: The Cerebral Cortex. [online] Available at: http://www.dartmouth.edu/~rswenson/NeuroSci/chapter_11.html.</ref><ref name="first">Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
 

==Early Development of the Brain==

 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
[[File:Brain Development 2.png|thumb|400px|right|'''Figure 3. A longitudinal perspective of the neural tube, showing the primary brain vesicles divided into the five secondary subdivisions'''.]]

*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five, as depicted in Figure 3. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.

'''Brain Flexures'''
[[File:Brain Development.png|thumb|400px|right|'''Figure 4. Lateral perspective of the neural tube, showing the three flexures, and five secondary subdivisions'''.]]
During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures, as depicted in Figure 4, in proximity to the five secondary vesicles. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

Through the foundation of structures and processes in during the early developmental brain, the fetus' brain is able to further develop into a much more complex organ.

[[File:Neural- cortex Cajal drawing 01.jpg |thumb|right|200px|'''Figure 5. Laminar and columnar organization of the cerebral cortex (Historical drawing by Cajal)''']]
 

==Later Development: Development of the Cerebral Cortex==
 
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes. The diversity in neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned in above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contributes to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|400px|super|'''Figure 6. Key developmental zones in the human cortex'''.]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone
**Subplate
*Cortical Plate: establishment of the 6 cortical layers form in this region between the subplate and the marginal zone

===Timeline of Corticogenesis===
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (e.g fate) of the neurons so that specific connections and cortical structure are achieved. "E" relates to embryonic day in relation to corticogenesis.
 

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along in order to expand the neocortex. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area as well as the preplate and many of the cells in the SVZ contribute to the later cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to the target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layers 6 is populated before layer 5; layer 5 is populated before layer 4 and so on <ref name="boulder"/>. Each layer condenses and the neurons are closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex such as sensory and motor function.
[[File:Corticogenesis.png|center|thumb|700px|super|'''Figure 7. Corticogenesis from E30 to adult human brain''']]

===Signalling involved in Cerebral Cortex Development===
 
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 8. Shh signalling increases the number of proliferating cells''']]
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.

[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 9. Cortex development in wild-type and ''reeler'' mice''']]

'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 11) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 12). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|500px|'''Figure 10. Cortical thickness in the absence of Bmp7''']]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers. Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.
 

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref> 
 
[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|'''Figure 11. Anatomy of the human cerebral cortex''' <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]] 

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull (see figure 10). The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri, as shown in figure 10. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri (see figure 10). Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>
 
'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}
 

==Functions of the Cerebral Cortex==
 
[[File:Cortical areas.png|thumb|right|text-top|450px|'''Figure 12. Cortical areas human cortex''' <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]
[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|'''Figure 13. Cortical Homonculus'''<ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]
The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas, as shown in Figure 11. <ref name="overall function"><pubmed>21653723</pubmed></ref>

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body (see figure 12). The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>
 
==Abnormalities associated with Cerebral Cortex Development==
[[File:Stages of development.png|thumb|right|text-top||520px|'''Figure 14. Main stages of cortical development where abnormalities may arise'''.<ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>]]
 

The embryologic development of the cerebral cortex involves highly organised and complex events. As mentioned in the 'Introduction', these events are generally divided by scientists into 3 major stages in cortical formation where crucial changes occur in neuronal cells; these stages include: 
1. Proliferation (or Growth), 
2. Migration, 
3. Organisation (or Maturation or Differentiation).

Disruptions can occur in these stages of cortical development due to multiple causes, and these disruptions give rise to malformations or irregularities in the cerebral cortex (Figure 13). 

Although multitudinous and/or severe effects ensue from such disorders, epilepsy and mental retardation (of varying degrees) are almost always present with these disorders. 

This section will explore some abnormalities that are commonly discussed in scientific literature. <ref name="first"/><ref name="second">Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref><ref name="third">Christopher A, C. (1999). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 
 
===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder that results because neuroblasts are not able to successfully complete the proliferation stage of cortical development. Mechanism of development of this disorder is not well understood and FCD is categorised as due to uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers (lamination disorganisation). Very large dysmorphic cells called 'balloon' cells are also seen due to abnormal regulation of cell growth. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

If symptoms do present, then these are associated with epilepsy ( tonic-clonic, tonic, simple partial and complex partial seizures). In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. <ref name="first"/><ref name="second"/> 
[[File:Hemimegalencephaly2.png|thumb|left|upright=1.42|'''Figure 15. Observable radiographic features in Hemimegalencephaly'''. <ref name="imaging"/> ]]
 
<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form tumour-like, benign malformation(s) ) of one cerebral hemisphere, part of a hemisphere or one hemisphere with partial involvement of the other hemisphere. MRI findings usually show enlargement of one hemisphere or at least one lobe and abnormal white matter (Figure 15).

Clinical symptoms of this disease may include developmental delay, mental retardation, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. 
<ref name="imaging"/><ref name="second"/>
[[File:Image.png|thumb|right|upright=1.45|'''Figure 16. Possible clinical features of Microcephaly in a newborn'''. <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]] 
 
 
 
<big><big>'''3) Microcephaly Vera'''</big></big>

Amongst cortical congenital disorders, Microcephaly Vera is a relatively common disorder. Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs, and can be caused by genetic or non-genetic factors. 

'''Microcephaly Vera or Primary Microcephaly''' is genetic and does not involve other organs. It from abnormal cortical development, specifically cell division or proliferation. In this malformation the circumference of the head (and so the brain) is much less than normal, while the rest of the body is of normal size. Microcephaly Vera clinically most frequently presents with mental retardation and sometimes epilepsy, although some other features can be observed ocassionally (Figure 16). 
<ref name="imaging"/><ref name="second"/><ref name="third"/> 
 

<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms), which can occur in several tissues of the body, including cerebral cortex. In the cortical gray matter, cortical tubers and bizarre cells are seen because laminar disorganisation occurs (like Focal Cortical Dyplasia). TSC is thus called because at the scientists thought that the lesions seen resembled potato tubers. 

No signs or symptoms are known to be observed for TSC, and diagnosis is determined after a brain scan. 
<ref name="imaging"/><ref name="third"/> 

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:Heteroptopia.png|thumb|upright=1.85|right|'''Figure 17. Observable radiographic features of subcortical band heterotopia'''. <ref name="imaging"/> ]]
For neurons to successfully execute the migration stage of development, some steps have to be completed including departure from the ventricular zone, migration to the cortical plate and then arrest of movement at the appropriate layer. 
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex (Figure 17). 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 
<ref name="imaging"/><ref name="second"/><ref name="third"/> 
<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 
Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. Type II Lissencephaly also includes:
#Muscle-Eye-Brain Disease
#Walker-Warburg Syndrome
#Fukuyama Syndrome 
*'''Microlissencephaly''' 
Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly(discussed previously), and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span. 
<ref name="first"/><ref name="imaging"/><ref name="second"/><ref name="third"/> 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Clinical presentation of Kallman Syndrome includes Archinencephaly, which is hypoplasia (underdevelopment or incomplete development) of the olfactory cortex and olfactory bulb, and deficient or absent sense of smell. 
<ref name="imaging"/><ref name="third"/> 

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

Affected patients can have varying degrees of symptoms, including epilepsy and developmental delay. For example, bilateral poylmicrogyria causes developmental delay, hypertonicity, ataxia, and refractory seizures. 
<ref name="first"/><ref name="second"/> 
[[File:SchizencephalicB.jpg|thumb|left|upright=1.45|'''Figure 18. Coronal and axial sections of the brain of a patient with Schizencephaly'''.<ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]
 

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder classified within the same group as Polymicrogyria. It is characterised by a cleft(s) or lesion(s) on the brain surface,extending from the cerebral cortex to the ventricle and is typically filled with CSF (cerebrospinal fluid) and lined by cortex gray matter. These lesions or clefts are thought to be 'destructive'. 

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly. Type I presents with partial seizures or spastic hemiparesis, while Type II presents with epilepsy or seizures, spasticity, severe developmental delay and microcephaly.

Schizencephaly can be bilateral or unilateral; and commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
<ref name="first"/><ref name="imaging"/><ref name="second"/> 
 
 
 
 
 
{| role="presentation" class="wikitable mw-collapsible mw-collapsed"
| <big><big><big>Other disorders of varying etiology</big></big></big>
|-
| <big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right|'''Figure 19. Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD)'''.<ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome. 
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

The corpus callosum is a structure present in the brain which connects both the hemispheres of the brain. The video below briefly describes this:

<html5media height="350" width="550">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref> 
Agenesis of the corpus callosum (ACC) occurs when the corpus callosum is partially or completely absent. It is thought to be due to a disruption of brain cell migration during fetal development.
<ref>Ninds.nih.gov. (2017). Agenesis of the Corpus Callosum Information Page. [online] Available at: https://www.ninds.nih.gov/Disorders/All-Disorders/Agenesis-Corpus-Callosum-Information-Page [Accessed 26 Oct. 2017].</ref> 
Some clinical symptoms include epilepsy or seizures, developmental delay, vision and hearing impairment, trouble in motor coordination and language skills and difficulty in muscle coordination and tone coordination.
<ref>Vasudevan, C., McKechnie, L. and Levene, M. (2012). Long-term outcome of antenatally diagnosed agenesis of corpus callosum and cerebellar malformations. Seminars in Fetal and Neonatal Medicine, 17(5), pp.295-300. </ref>
|}
 

==Models and Research==
===Animal Models===
[[File:Corticogenesis of mouse and humans.jpeg|thumb|right|text-top|590px|'''Figure 20. Mouse vs Human Neurogenesis''']]

====Mice Model====
Mice have often been used to study corticogenesis in mammals. Corticogenesis lasts from E11 to E19 in mice and lasts eight days, which is far shorter than human corticogenesis. While there are many similarities between human corticogenesis, the rodent brain is much smaller than that of a human’s and therefore, there are different types of progenitor cells involved in mice and the cortex does not expand as greatly. <ref name="control">Dehay, C. and Kennedy, H. (2007). Cell-cycle control and cortical development. Nature Reviews Neuroscience, 8(6),438-450.</ref>Humans have greater numbers of intermediate precursor cells (to aid in further differentiation) and outer radial glial cells compared those of mice. <ref name="cerebral"/> In addition, the SVZ does not split into the inner and outer subventricular zone, but stays intact as one. <ref name="control"/> The importance of reelin has also been greatly studied in mice. Studies showed that mutant mice have disruptions in the migration of neurons into their subsequent layers. By injecting thymidine at various time points of gestation into the female mice, researchers were able to track the development of various populations of neurons. Later developing neurons were unable to ascend past the already early formed neurons due to disruptions in reelin signaling (in the marginal zone). Instead, superficial layer neurons resided below the older, deep layer neurons. This inverted lamination comprises sensory and motor function.<ref> Caviness, V. (1982). Neocortical histogenesis in normal and reeler mice: A developmental study based upon [3H]thymidine autoradiography. Developmental Brain Research, 4(3), 293-302.</ref>
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Figure 21. Timeline and protocol of cerebral organoid development''']]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

The development of these brain organoids has allowed more comprehensive understanding of the self-organisational properties of the brain, and is quickly advancing, however the lack of vasculature in cultured organoids restricts their ability to be used for specific neurological disorders. Furthermore there are still challenges associated with the generation of individual, discrete brain regions, which should be addressed in the future. <ref><pubmed>28822354</pubmed></ref>

==Glossary==

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
|'''Sulcus'''|| Sulci (plural) are grooves in the cerebral cortex.
|-bgcolor="FAF5FF"
|'''Gyrus '''|| Gyri (plural) are folds/ridges in the cerebral cortex.
|-bgcolor="FAF5FF"
|'''Fissures'''|| Large sulci.
|-bgcolor="FAF5FF"
|'''Corticogenesis'''|| The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes.
|-bgcolor="FAF5FF"
|'''Cajal-Retzius (CR) cells'''|| Cortical neurons that develop early on, at the same time as the preplate, and express an important glycoprotein known as reelin, which helps with the proper migration of neurons into their respective layers.
|-bgcolor="FAF5FF"
|'''GABAergic Neurons'''|| Generate gamma aminobutyric acid (GABA) as their output, one of the two inhibitory neurotransmitters in the central nervous system (CNS).
|-bgcolor="FAF5FF"
|'''Radial glial cells '''|| A class of distinct nonneuronal cells that are bipolar shaped and span the entire width of the cortex during development.
|-bgcolor="FAF5FF"
|'''Ventricular zone (VZ)'''|| First formed single-celled layer in the cortex, arising from progenitors in the dorsal telencephalon that divide symmetrically. It lies adjacent to the ventricular surface.
|-bgcolor="FAF5FF"
|'''Preplate'''|| First "pioneer neurons" from dividing cells in the ventricular zone for this layer above the ventricular zone
|-bgcolor="FAF5FF"
|'''Subventricular zone (SVZ)'''|| Cells in the VZ continue to divide symmetrically and give rise to another zone above the VZ known as the SVZ. This zone later splits into an inner (ISVZ) and outer ventricular zone (OSVZ)
|-bgcolor="FAF5FF"
|'''Marginal Zone (MZ)'''|| A subsection of the preplate that forms around E50-55. It lies at the uppermost area of the cortex nearest the pial surface.
|-bgcolor="FAF5FF"
|'''Subplate'''|| A subsection of the preplate that forms around E50-55.
|-bgcolor="FAF5FF"
|'''Cortical Plate'''|| Forms in between the marginal zone and subplate and gives rise to the 6 layers of the cortex involved in sensory and motor function.
|-bgcolor="FAF5FF"
|'''Intermediate zone'''|| Forms below the subplate between E50-55 and contains only migrating cells and no intermediate precursor cells.
|-bgcolor="FAF5FF"
|Total agyria||gyri and sulci absent resulting in 'smooth brain'
|-
|Pachygyria|| gyri can be seen but are very few compared to normal brain
|-
|Hypoplasia|| underdevelopment or incomplete development of a tissue or organ
|-
|Agenesis|| total absence of something
|-
|}

==References==

2017 Group Project 1

2017-10-26T02:42:42Z

Z5177691: /* Glossary */

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Intro section cortex.jpg|thumb|right|350px|'''Figure1. Cerebral cortex is the outermost layer of the cerebrum''' <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex is part of the brain which surrounds the cerebral hemispheres. It has a very large surface area (largest part of human brain). The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres (Figure 1). It is a layer of gray matter around 2-4 mm in thickness, and consists of approximately 10 billion nerve cell bodies and dendrites. It appears gray because of the cell bodies (Figure 2). 
[[File:Brain sectin showing cortex.jpg|thumb|left|300px|'''Figure 2. Section of the human brain''' <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]]

The cerebral cortex is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The development of the cerebral cortex involves 3 main stages:
*Proliferation (or growth or differentiation)
*Migration of neurons
*Maturation (or organisation or folding). 
 
The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. Xxternal pyramidal, IV. Internal granular layer, V. Internal pyramidal layer, VI. Multiform layer. These individual layers organise the capacity for interconnections between both input and output signals. 

This project will explore the various embryologic aspects of the cerebral cortex, including early development of the brain, development of the cerebral cortex, anatomy and functions of the cortex, and abnormalities associated with cortical development. 
<ref>Moore, K., Persaud, T. and Torchia, M. (2011). The Developing Human. London: Elsevier Health Sciences, pp.The Nervous System; 379-414.</ref><ref>Van Essen, D. (2005). A Population-Average, Landmark- and Surface-based (PALS) atlas of human cerebral cortex. NeuroImage, 28(3), pp.635-662.</ref><ref>Differencebetween.com. (2017). Difference Between Cerebrum and Cerebral Cortex. [online] Available at: http://www.differencebetween.com/difference-between-cerebrum-and-vs-cerebral-cortex/ [Accessed 26 Oct. 2017].</ref> <ref>Dartmouth.edu. (2006). Chapter 11: The Cerebral Cortex. [online] Available at: http://www.dartmouth.edu/~rswenson/NeuroSci/chapter_11.html.</ref><ref name="first">Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
 

==Early Development of the Brain==

 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
[[File:Brain Development 2.png|thumb|400px|right|'''Figure 3. A longitudinal perspective of the neural tube, showing the primary brain vesicles divided into the five secondary subdivisions'''.]]

*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five, as depicted in Figure 3. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.

'''Brain Flexures'''
[[File:Brain Development.png|thumb|400px|right|'''Figure 4. Lateral perspective of the neural tube, showing the three flexures, and five secondary subdivisions'''.]]
During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures, as depicted in Figure 4, in proximity to the five secondary vesicles. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

Through the foundation of structures and processes in during the early developmental brain, the fetus' brain is able to further develop into a much more complex organ.

[[File:Neural- cortex Cajal drawing 01.jpg |thumb|right|200px|'''Figure 5. Laminar and columnar organization of the cerebral cortex (Historical drawing by Cajal)''']]
 

==Later Development: Development of the Cerebral Cortex==
 
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes. The diversity in neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned in above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contributes to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|400px|super|'''Figure 6. Key developmental zones in the human cortex'''.]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone
**Subplate
*Cortical Plate: establishment of the 6 cortical layers form in this region between the subplate and the marginal zone

===Timeline of Corticogenesis===
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (e.g fate) of the neurons so that specific connections and cortical structure are achieved. "E" relates to embryonic day in relation to corticogenesis.
 

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along in order to expand the neocortex. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area as well as the preplate and many of the cells in the SVZ contribute to the later cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to the target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layers 6 is populated before layer 5; layer 5 is populated before layer 4 and so on <ref name="boulder"/>. Each layer condenses and the neurons are closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex such as sensory and motor function.
[[File:Corticogenesis.png|center|thumb|700px|super|'''Figure 7. Corticogenesis from E30 to adult human brain''']]

===Signalling involved in Cerebral Cortex Development===
 
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 8. Shh signalling increases the number of proliferating cells''']]
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.

[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 9. Cortex development in wild-type and ''reeler'' mice''']]

'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 11) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 12). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|500px|'''Figure 10. Cortical thickness in the absence of Bmp7''']]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers. Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.
 

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref> 
 
[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|'''Figure 11. Anatomy of the human cerebral cortex''' <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]] 

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull (see figure 10). The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri, as shown in figure 10. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri (see figure 10). Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>
 
'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}
 

==Functions of the Cerebral Cortex==
 
[[File:Cortical areas.png|thumb|right|text-top|450px|'''Figure 12. Cortical areas human cortex''' <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]
[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|'''Figure 13. Cortical Homonculus'''<ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]
The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas, as shown in Figure 11. <ref name="overall function"><pubmed>21653723</pubmed></ref>

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body (see figure 12). The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>
 
==Abnormalities associated with Cerebral Cortex Development==
[[File:Stages of development.png|thumb|right|text-top||520px|'''Figure 14. Main stages of cortical development where abnormalities may arise'''.<ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>]]
 

The embryologic development of the cerebral cortex involves highly organised and complex events. As mentioned in the 'Introduction', these events are generally divided by scientists into 3 major stages in cortical formation where crucial changes occur in neuronal cells; these stages include: 
1. Proliferation (or Growth), 
2. Migration, 
3. Organisation (or Maturation or Differentiation).

Disruptions can occur in these stages of cortical development due to multiple causes, and these disruptions give rise to malformations or irregularities in the cerebral cortex (Figure 13). 

Although multitudinous and/or severe effects ensue from such disorders, epilepsy and mental retardation (of varying degrees) are almost always present with these disorders. 

This section will explore some abnormalities that are commonly discussed in scientific literature. <ref name="first"/><ref name="second">Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref><ref name="third">Christopher A, C. (1999). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 
 
===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder that results because neuroblasts are not able to successfully complete the proliferation stage of cortical development. Mechanism of development of this disorder is not well understood and FCD is categorised as due to uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers (lamination disorganisation). Very large dysmorphic cells called 'balloon' cells are also seen due to abnormal regulation of cell growth. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

If symptoms do present, then these are associated with epilepsy ( tonic-clonic, tonic, simple partial and complex partial seizures). In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. <ref name="first"/><ref name="second"/> 
[[File:Hemimegalencephaly2.png|thumb|left|upright=1.42|'''Figure 15. Observable radiographic features in Hemimegalencephaly'''. <ref name="imaging"/> ]]
 
<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form tumour-like, benign malformation(s) ) of one cerebral hemisphere, part of a hemisphere or one hemisphere with partial involvement of the other hemisphere. MRI findings usually show enlargement of one hemisphere or at least one lobe and abnormal white matter (Figure 15).

Clinical symptoms of this disease may include developmental delay, mental retardation, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. 
<ref name="imaging"/><ref name="second"/>
[[File:Symptoms of microcephaly.png|thumb|right|upright=1.45|'''Figure 16. Possible clinical features of Microcephaly in a newborn'''. <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]] 
 
 
 
<big><big>'''3) Microcephaly Vera'''</big></big>

Amongst cortical congenital disorders, Microcephaly Vera is a relatively common disorder. Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs, and can be caused by genetic or non-genetic factors. 

'''Microcephaly Vera or Primary Microcephaly''' is genetic and does not involve other organs. It from abnormal cortical development, specifically cell division or proliferation. In this malformation the circumference of the head (and so the brain) is much less than normal, while the rest of the body is of normal size. Microcephaly Vera clinically most frequently presents with mental retardation and sometimes epilepsy, although some other features can be observed ocassionally (Figure 16). 
<ref name="imaging"/><ref name="second"/><ref name="third"/> 
 

<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms), which can occur in several tissues of the body, including cerebral cortex. In the cortical gray matter, cortical tubers and bizarre cells are seen because laminar disorganisation occurs (like Focal Cortical Dyplasia). TSC is thus called because at the scientists thought that the lesions seen resembled potato tubers. 

No signs or symptoms are known to be observed for TSC, and diagnosis is determined after a brain scan. 
<ref name="imaging"/><ref name="third"/> 

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:SBH.png|thumb|upright=1.85|right|'''Figure 17. Observable radiographic features of subcortical band heterotopia'''. <ref name="imaging"/> ]]
For neurons to successfully execute the migration stage of development, some steps have to be completed including departure from the ventricular zone, migration to the cortical plate and then arrest of movement at the appropriate layer. 
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex (Figure 17). 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 
<ref name="imaging"/><ref name="second"/><ref name="third"/> 
<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 
Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. Type II Lissencephaly also includes:
#Muscle-Eye-Brain Disease
#Walker-Warburg Syndrome
#Fukuyama Syndrome 
*'''Microlissencephaly''' 
Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly(discussed previously), and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span. 
<ref name="first"/><ref name="imaging"/><ref name="second"/><ref name="third"/> 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Clinical presentation of Kallman Syndrome includes Archinencephaly, which is hypoplasia (underdevelopment or incomplete development) of the olfactory cortex and olfactory bulb, and deficient or absent sense of smell. 
<ref name="imaging"/><ref name="third"/> 

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

Affected patients can have varying degrees of symptoms, including epilepsy and developmental delay. For example, bilateral poylmicrogyria causes developmental delay, hypertonicity, ataxia, and refractory seizures. 
<ref name="first"/><ref name="second"/> 
[[File:SchizencephalicBrain.jpg|thumb|left|upright=1.45|'''Figure 18. Coronal and axial sections of the brain of a patient with Schizencephaly'''.<ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]
 

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder classified within the same group as Polymicrogyria. It is characterised by a cleft(s) or lesion(s) on the brain surface,extending from the cerebral cortex to the ventricle and is typically filled with CSF (cerebrospinal fluid) and lined by cortex gray matter. These lesions or clefts are thought to be 'destructive'. 

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly. Type I presents with partial seizures or spastic hemiparesis, while Type II presents with epilepsy or seizures, spasticity, severe developmental delay and microcephaly.

Schizencephaly can be bilateral or unilateral; and commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
<ref name="first"/><ref name="imaging"/><ref name="second"/> 
 
 
 
 
 
{| role="presentation" class="wikitable mw-collapsible mw-collapsed"
| <big><big><big>Other disorders of varying etiology</big></big></big>
|-
| <big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right|'''Figure 19. Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD)'''.<ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome. 
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

The corpus callosum is a structure present in the brain which connects both the hemispheres of the brain. The video below briefly describes this:

<html5media height="350" width="550">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref> 
Agenesis of the corpus callosum (ACC) occurs when the corpus callosum is partially or completely absent. It is thought to be due to a disruption of brain cell migration during fetal development.
<ref>Ninds.nih.gov. (2017). Agenesis of the Corpus Callosum Information Page. [online] Available at: https://www.ninds.nih.gov/Disorders/All-Disorders/Agenesis-Corpus-Callosum-Information-Page [Accessed 26 Oct. 2017].</ref> 
Some clinical symptoms include epilepsy or seizures, developmental delay, vision and hearing impairment, trouble in motor coordination and language skills and difficulty in muscle coordination and tone coordination.
<ref>Vasudevan, C., McKechnie, L. and Levene, M. (2012). Long-term outcome of antenatally diagnosed agenesis of corpus callosum and cerebellar malformations. Seminars in Fetal and Neonatal Medicine, 17(5), pp.295-300. </ref>
|}
 

==Models and Research==
===Animal Models===
[[File:Corticogenesis of mouse and humans.jpeg|thumb|right|text-top|590px|'''Figure 20. Mouse vs Human Neurogenesis''']]

====Mice Model====
Mice have often been used to study corticogenesis in mammals. Corticogenesis lasts from E11 to E19 in mice and lasts eight days, which is far shorter than human corticogenesis. While there are many similarities between human corticogenesis, the rodent brain is much smaller than that of a human’s and therefore, there are different types of progenitor cells involved in mice and the cortex does not expand as greatly. <ref name="control">Dehay, C. and Kennedy, H. (2007). Cell-cycle control and cortical development. Nature Reviews Neuroscience, 8(6),438-450.</ref>Humans have greater numbers of intermediate precursor cells (to aid in further differentiation) and outer radial glial cells compared those of mice. <ref name="cerebral"/> In addition, the SVZ does not split into the inner and outer subventricular zone, but stays intact as one. <ref name="control"/> The importance of reelin has also been greatly studied in mice. Studies showed that mutant mice have disruptions in the migration of neurons into their subsequent layers. By injecting thymidine at various time points of gestation into the female mice, researchers were able to track the development of various populations of neurons. Later developing neurons were unable to ascend past the already early formed neurons due to disruptions in reelin signaling (in the marginal zone). Instead, superficial layer neurons resided below the older, deep layer neurons. This inverted lamination comprises sensory and motor function.<ref> Caviness, V. (1982). Neocortical histogenesis in normal and reeler mice: A developmental study based upon [3H]thymidine autoradiography. Developmental Brain Research, 4(3), 293-302.</ref>
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Figure 21. Timeline and protocol of cerebral organoid development''']]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

The development of these brain organoids has allowed more comprehensive understanding of the self-organisational properties of the brain, and is quickly advancing, however the lack of vasculature in cultured organoids restricts their ability to be used for specific neurological disorders. Furthermore there are still challenges associated with the generation of individual, discrete brain regions, which should be addressed in the future. <ref><pubmed>28822354</pubmed></ref>

==Glossary==

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
|'''Sulcus'''|| Sulci (plural) are grooves in the cerebral cortex.
|-bgcolor="FAF5FF"
|'''Gyrus '''|| Gyri (plural) are folds/ridges in the cerebral cortex.
|-bgcolor="FAF5FF"
|'''Fissures'''|| Large sulci.
|-bgcolor="FAF5FF"
|'''Corticogenesis'''|| The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes.
|-bgcolor="FAF5FF"
|'''Cajal-Retzius (CR) cells'''|| Cortical neurons that develop early on, at the same time as the preplate, and express an important glycoprotein known as reelin, which helps with the proper migration of neurons into their respective layers.
|-bgcolor="FAF5FF"
|'''GABAergic Neurons'''|| Generate gamma aminobutyric acid (GABA) as their output, one of the two inhibitory neurotransmitters in the central nervous system (CNS).
|-bgcolor="FAF5FF"
|'''Radial glial cells '''|| A class of distinct nonneuronal cells that are bipolar shaped and span the entire width of the cortex during development.
|-bgcolor="FAF5FF"
|'''Ventricular zone (VZ)'''|| First formed single-celled layer in the cortex, arising from progenitors in the dorsal telencephalon that divide symmetrically. It lies adjacent to the ventricular surface.
|-bgcolor="FAF5FF"
|'''Preplate'''|| First "pioneer neurons" from dividing cells in the ventricular zone for this layer above the ventricular zone
|-bgcolor="FAF5FF"
|'''Subventricular zone (SVZ)'''|| Cells in the VZ continue to divide symmetrically and give rise to another zone above the VZ known as the SVZ. This zone later splits into an inner (ISVZ) and outer ventricular zone (OSVZ)
|-bgcolor="FAF5FF"
|'''Marginal Zone (MZ)'''|| A subsection of the preplate that forms around E50-55. It lies at the uppermost area of the cortex nearest the pial surface.
|-bgcolor="FAF5FF"
|'''Subplate'''|| A subsection of the preplate that forms around E50-55.
|-bgcolor="FAF5FF"
|'''Cortical Plate'''|| Forms in between the marginal zone and subplate and gives rise to the 6 layers of the cortex involved in sensory and motor function.
|-bgcolor="FAF5FF"
|'''Intermediate zone'''|| Forms below the subplate between E50-55 and contains only migrating cells and no intermediate precursor cells.
|-bgcolor="FAF5FF"
|'''Epilepsy
Mental retardation
Heterogeneous
Etiology
Neuroblasts
Developmental delay
Benign
Neoplasms
Total agyria - gyri and sulci absent resulting in 'smooth brain'
Pachygyria - gyri can be seen but are very few compared to normal brain
Hypoplasia- is underdevelopment or incomplete development of a tissue or organ
Olfactory
Agenesis- total absence of something
|-
|}

==References==

2017 Group Project 1

2017-10-26T02:39:08Z

Z5177691: /* Timeline of Corticogenesis */

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Intro section cortex.jpg|thumb|right|350px|'''Figure1. Cerebral cortex is the outermost layer of the cerebrum''' <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex is part of the brain which surrounds the cerebral hemispheres. It has a very large surface area (largest part of human brain). The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres (Figure 1). It is a layer of gray matter around 2-4 mm in thickness, and consists of approximately 10 billion nerve cell bodies and dendrites. It appears gray because of the cell bodies (Figure 2). 
[[File:Brain sectin showing cortex.jpg|thumb|left|300px|'''Figure 2. Section of the human brain''' <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]]

The cerebral cortex is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The development of the cerebral cortex involves 3 main stages:
*Proliferation (or growth or differentiation)
*Migration of neurons
*Maturation (or organisation or folding). 
 
The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. Xxternal pyramidal, IV. Internal granular layer, V. Internal pyramidal layer, VI. Multiform layer. These individual layers organise the capacity for interconnections between both input and output signals. 

This project will explore the various embryologic aspects of the cerebral cortex, including early development of the brain, development of the cerebral cortex, anatomy and functions of the cortex, and abnormalities associated with cortical development. 
<ref>Moore, K., Persaud, T. and Torchia, M. (2011). The Developing Human. London: Elsevier Health Sciences, pp.The Nervous System; 379-414.</ref><ref>Van Essen, D. (2005). A Population-Average, Landmark- and Surface-based (PALS) atlas of human cerebral cortex. NeuroImage, 28(3), pp.635-662.</ref><ref>Differencebetween.com. (2017). Difference Between Cerebrum and Cerebral Cortex. [online] Available at: http://www.differencebetween.com/difference-between-cerebrum-and-vs-cerebral-cortex/ [Accessed 26 Oct. 2017].</ref> <ref>Dartmouth.edu. (2006). Chapter 11: The Cerebral Cortex. [online] Available at: http://www.dartmouth.edu/~rswenson/NeuroSci/chapter_11.html.</ref><ref name="first">Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
 

==Early Development of the Brain==

 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
[[File:Brain Development 2.png|thumb|400px|right|'''Figure 3. A longitudinal perspective of the neural tube, showing the primary brain vesicles divided into the five secondary subdivisions'''.]]

*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five, as depicted in Figure 3. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.

'''Brain Flexures'''
[[File:Brain Development.png|thumb|400px|right|'''Figure 4. Lateral perspective of the neural tube, showing the three flexures, and five secondary subdivisions'''.]]
During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures, as depicted in Figure 4, in proximity to the five secondary vesicles. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

Through the foundation of structures and processes in during the early developmental brain, the fetus' brain is able to further develop into a much more complex organ.

[[File:Neural- cortex Cajal drawing 01.jpg |thumb|right|200px|'''Figure 5. Laminar and columnar organization of the cerebral cortex (Historical drawing by Cajal)''']]
 

==Later Development: Development of the Cerebral Cortex==
 
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes. The diversity in neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned in above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contributes to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|400px|super|'''Figure 6. Key developmental zones in the human cortex'''.]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone
**Subplate
*Cortical Plate: establishment of the 6 cortical layers form in this region between the subplate and the marginal zone

===Timeline of Corticogenesis===
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (e.g fate) of the neurons so that specific connections and cortical structure are achieved. "E" relates to embryonic day in relation to corticogenesis.
 

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along in order to expand the neocortex. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area as well as the preplate and many of the cells in the SVZ contribute to the later cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to the target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layers 6 is populated before layer 5; layer 5 is populated before layer 4 and so on <ref name="boulder"/>. Each layer condenses and the neurons are closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex such as sensory and motor function.
[[File:Corticogenesis.png|center|thumb|700px|super|'''Figure 7. Corticogenesis from E30 to adult human brain''']]

===Signalling involved in Cerebral Cortex Development===
 
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 8. Shh signalling increases the number of proliferating cells''']]
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.

[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 9. Cortex development in wild-type and ''reeler'' mice''']]

'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 11) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 12). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|500px|'''Figure 10. Cortical thickness in the absence of Bmp7''']]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers. Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.
 

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref> 
 
[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|'''Figure 11. Anatomy of the human cerebral cortex''' <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]] 

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull (see figure 10). The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri, as shown in figure 10. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri (see figure 10). Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>
 
'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}
 

==Functions of the Cerebral Cortex==
 
[[File:Cortical areas.png|thumb|right|text-top|450px|'''Figure 12. Cortical areas human cortex''' <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]
[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|'''Figure 13. Cortical Homonculus'''<ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]
The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas, as shown in Figure 11. <ref name="overall function"><pubmed>21653723</pubmed></ref>

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body (see figure 12). The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>
 
==Abnormalities associated with Cerebral Cortex Development==
[[File:Stages of development.png|thumb|right|text-top||520px|'''Figure 14. Main stages of cortical development where abnormalities may arise'''.<ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>]]
 

The embryologic development of the cerebral cortex involves highly organised and complex events. As mentioned in the 'Introduction', these events are generally divided by scientists into 3 major stages in cortical formation where crucial changes occur in neuronal cells; these stages include: 
1. Proliferation (or Growth), 
2. Migration, 
3. Organisation (or Maturation or Differentiation).

Disruptions can occur in these stages of cortical development due to multiple causes, and these disruptions give rise to malformations or irregularities in the cerebral cortex (Figure 13). 

Although multitudinous and/or severe effects ensue from such disorders, epilepsy and mental retardation (of varying degrees) are almost always present with these disorders. 

This section will explore some abnormalities that are commonly discussed in scientific literature. <ref name="first"/><ref name="second">Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref><ref name="third">Christopher A, C. (1999). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 
 
===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder that results because neuroblasts are not able to successfully complete the proliferation stage of cortical development. Mechanism of development of this disorder is not well understood and FCD is categorised as due to uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers (lamination disorganisation). Very large dysmorphic cells called 'balloon' cells are also seen due to abnormal regulation of cell growth. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

If symptoms do present, then these are associated with epilepsy ( tonic-clonic, tonic, simple partial and complex partial seizures). In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. <ref name="first"/><ref name="second"/> 
[[File:Hemimegalencephaly.png|thumb|left|upright=1.42|'''Figure 15. Observable radiographic features in Hemimegalencephaly'''. <ref name="imaging"/> ]]
 
<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form tumour-like, benign malformation(s) ) of one cerebral hemisphere, part of a hemisphere or one hemisphere with partial involvement of the other hemisphere. MRI findings usually show enlargement of one hemisphere or at least one lobe and abnormal white matter (Figure 15).

Clinical symptoms of this disease may include developmental delay, mental retardation, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. 
<ref name="imaging"/><ref name="second"/>
[[File:Symptoms of microcephaly.png|thumb|right|upright=1.45|'''Figure 16. Possible clinical features of Microcephaly in a newborn'''. <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]] 
 
 
 
<big><big>'''3) Microcephaly Vera'''</big></big>

Amongst cortical congenital disorders, Microcephaly Vera is a relatively common disorder. Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs, and can be caused by genetic or non-genetic factors. 

'''Microcephaly Vera or Primary Microcephaly''' is genetic and does not involve other organs. It from abnormal cortical development, specifically cell division or proliferation. In this malformation the circumference of the head (and so the brain) is much less than normal, while the rest of the body is of normal size. Microcephaly Vera clinically most frequently presents with mental retardation and sometimes epilepsy, although some other features can be observed ocassionally (Figure 16). 
<ref name="imaging"/><ref name="second"/><ref name="third"/> 
 

<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms), which can occur in several tissues of the body, including cerebral cortex. In the cortical gray matter, cortical tubers and bizarre cells are seen because laminar disorganisation occurs (like Focal Cortical Dyplasia). TSC is thus called because at the scientists thought that the lesions seen resembled potato tubers. 

No signs or symptoms are known to be observed for TSC, and diagnosis is determined after a brain scan. 
<ref name="imaging"/><ref name="third"/> 

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:SBH.png|thumb|upright=1.85|right|'''Figure 17. Observable radiographic features of subcortical band heterotopia'''. <ref name="imaging"/> ]]
For neurons to successfully execute the migration stage of development, some steps have to be completed including departure from the ventricular zone, migration to the cortical plate and then arrest of movement at the appropriate layer. 
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex (Figure 17). 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 
<ref name="imaging"/><ref name="second"/><ref name="third"/> 
<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 
Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. Type II Lissencephaly also includes:
#Muscle-Eye-Brain Disease
#Walker-Warburg Syndrome
#Fukuyama Syndrome 
*'''Microlissencephaly''' 
Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly(discussed previously), and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span. 
<ref name="first"/><ref name="imaging"/><ref name="second"/><ref name="third"/> 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Clinical presentation of Kallman Syndrome includes Archinencephaly, which is hypoplasia (underdevelopment or incomplete development) of the olfactory cortex and olfactory bulb, and deficient or absent sense of smell. 
<ref name="imaging"/><ref name="third"/> 

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

Affected patients can have varying degrees of symptoms, including epilepsy and developmental delay. For example, bilateral poylmicrogyria causes developmental delay, hypertonicity, ataxia, and refractory seizures. 
<ref name="first"/><ref name="second"/> 
[[File:SchizencephalicBrain.jpg|thumb|left|upright=1.45|'''Figure 18. Coronal and axial sections of the brain of a patient with Schizencephaly'''.<ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]
 

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder classified within the same group as Polymicrogyria. It is characterised by a cleft(s) or lesion(s) on the brain surface,extending from the cerebral cortex to the ventricle and is typically filled with CSF (cerebrospinal fluid) and lined by cortex gray matter. These lesions or clefts are thought to be 'destructive'. 

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly. Type I presents with partial seizures or spastic hemiparesis, while Type II presents with epilepsy or seizures, spasticity, severe developmental delay and microcephaly.

Schizencephaly can be bilateral or unilateral; and commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
<ref name="first"/><ref name="imaging"/><ref name="second"/> 
 
 
 
 
 
{| role="presentation" class="wikitable mw-collapsible mw-collapsed"
| <big><big><big>Other disorders of varying etiology</big></big></big>
|-
| <big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right|'''Figure 19. Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD)'''.<ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome. 
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

The corpus callosum is a structure present in the brain which connects both the hemispheres of the brain. The video below briefly describes this:

<html5media height="350" width="550">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref> 
Agenesis of the corpus callosum (ACC) occurs when the corpus callosum is partially or completely absent. It is thought to be due to a disruption of brain cell migration during fetal development.
<ref>Ninds.nih.gov. (2017). Agenesis of the Corpus Callosum Information Page. [online] Available at: https://www.ninds.nih.gov/Disorders/All-Disorders/Agenesis-Corpus-Callosum-Information-Page [Accessed 26 Oct. 2017].</ref> 
Some clinical symptoms include epilepsy or seizures, developmental delay, vision and hearing impairment, trouble in motor coordination and language skills and difficulty in muscle coordination and tone coordination.
<ref>Vasudevan, C., McKechnie, L. and Levene, M. (2012). Long-term outcome of antenatally diagnosed agenesis of corpus callosum and cerebellar malformations. Seminars in Fetal and Neonatal Medicine, 17(5), pp.295-300. </ref>
|}
 

==Models and Research==
===Animal Models===
[[File:Corticogenesis of mouse and humans.jpeg|thumb|right|text-top|590px|'''Figure 20. Mouse vs Human Neurogenesis''']]

====Mice Model====
Mice have often been used to study corticogenesis in mammals. Corticogenesis lasts from E11 to E19 in mice and lasts eight days, which is far shorter than human corticogenesis. While there are many similarities between human corticogenesis, the rodent brain is much smaller than that of a human’s and therefore, there are different types of progenitor cells involved in mice and the cortex does not expand as greatly. <ref name="control">Dehay, C. and Kennedy, H. (2007). Cell-cycle control and cortical development. Nature Reviews Neuroscience, 8(6),438-450.</ref>Humans have greater numbers of intermediate precursor cells (to aid in further differentiation) and outer radial glial cells compared those of mice. <ref name="cerebral"/> In addition, the SVZ does not split into the inner and outer subventricular zone, but stays intact as one. <ref name="control"/> The importance of reelin has also been greatly studied in mice. Studies showed that mutant mice have disruptions in the migration of neurons into their subsequent layers. By injecting thymidine at various time points of gestation into the female mice, researchers were able to track the development of various populations of neurons. Later developing neurons were unable to ascend past the already early formed neurons due to disruptions in reelin signaling (in the marginal zone). Instead, superficial layer neurons resided below the older, deep layer neurons. This inverted lamination comprises sensory and motor function.<ref> Caviness, V. (1982). Neocortical histogenesis in normal and reeler mice: A developmental study based upon [3H]thymidine autoradiography. Developmental Brain Research, 4(3), 293-302.</ref>
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Figure 21. Timeline and protocol of cerebral organoid development''']]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

The development of these brain organoids has allowed more comprehensive understanding of the self-organisational properties of the brain, and is quickly advancing, however the lack of vasculature in cultured organoids restricts their ability to be used for specific neurological disorders. Furthermore there are still challenges associated with the generation of individual, discrete brain regions, which should be addressed in the future. <ref><pubmed>28822354</pubmed></ref>

==Glossary==

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
|'''Sulcus'''|| Sulci (plural) are grooves in the cerebral cortex.
|-
|'''Gyrus '''|| Gyri (plural) are folds/ridges in the cerebral cortex.
|-
|'''Fissures'''|| Large sulci.
|-
|'''Corticogenesis'''|| The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes.
|-
|'''Cajal-Retzius (CR) cells'''|| Cortical neurons that develop early on, at the same time as the preplate, and express an important glycoprotein known as reelin, which helps with the proper migration of neurons into their respective layers.
|-
|'''GABAergic Neurons'''|| Generate gamma aminobutyric acid (GABA) as their output, one of the two inhibitory neurotransmitters in the central nervous system (CNS).
|-
|'''Radial glial cells '''|| A class of distinct nonneuronal cells that are bipolar shaped and span the entire width of the cortex during development.
|-
|'''Ventricular zone (VZ)'''|| First formed single-celled layer in the cortex, arising from progenitors in the dorsal telencephalon that divide symmetrically. It lies adjacent to the ventricular surface.
|-
|'''Preplate'''|| First "pioneer neurons" from dividing cells in the ventricular zone for this layer above the ventricular zone
|-
|'''Subventricular zone (SVZ)'''|| Cells in the VZ continue to divide symmetrically and give rise to another zone above the VZ known as the SVZ. This zone later splits into an inner (ISVZ) and outer ventricular zone (OSVZ)
|-
|'''Marginal Zone (MZ)'''|| A subsection of the preplate that forms around E50-55. It lies at the uppermost area of the cortex nearest the pial surface.
|-
|'''Subplate'''|| A subsection of the preplate that forms around E50-55.
|-
|'''Cortical Plate'''|| Forms in between the marginal zone and subplate and gives rise to the 6 layers of the cortex involved in sensory and motor function.
|-
|'''Intermediate zone'''|| Forms below the subplate between E50-55 and contains only migrating cells and no intermediate precursor cells.
|-
|'''Epilepsy
Mental retardation
Heterogeneous
Etiology
Neuroblasts
Developmental delay
Benign
Neoplasms
Total agyria - gyri and sulci absent resulting in 'smooth brain'
Pachygyria - gyri can be seen but are very few compared to normal brain
Hypoplasia- is underdevelopment or incomplete development of a tissue or organ
Olfactory
Agenesis- total absence of something
|-
|}

==References==

2017 Group Project 1

2017-10-25T12:10:50Z

Z5177691: /* Timeline of Corticogenesis */

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Intro section cortex.jpg|thumb|right|350px| Fig.1. Cerebral cortex is the outermost layer of the cerebrum <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex surrounds the cerebrum, and is the largest part of the human brain. It is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres; it is around 2-4 mm in thickness, consists of the layer of grey matter and has ~ 10 billion nerve cell bodies and dendrites. 
[[File:Brain sectin showing cortex.jpg|thumb|left|300px| Fig 2. Section of the human brain <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]] 

The development of the cerebral cortex involves 3 main stages: proliferation/growth/differentiation, migration of neurons, and maturation/organisation/folding. The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. external pyramidal, IV. internal granular layer, V. internal pyramidal layer, VI. multiform layer. These individual layers organise the capacity for interconnections between both input and output signals. 
 
 
 
 
 
 

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref> 
 
[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|Figure 3: Anatomy of the human cerebral cortex <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]] 

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull (see figure 10). The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri, as shown in figure 10. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri (see figure 10). Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>
 
'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}
 

==Functions of the Cerebral Cortex==
 
[[File:Cortical areas.png|thumb|right|text-top|450px|Figure 11: Cortical areas human cortex <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]
[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|Figure 12: Cortical Homonculus <ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]
The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas, as shown in Figure 11. <ref name="overall function"><pubmed>21653723</pubmed></ref>

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body (see figure 12). The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>
 
==Early Development of the Brain==

 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
[[File:Brain Development 2.png|400px|right|A longitudinal perspective of the neural tube, showing the primary brain vesicles divided into the five secondary subdivisions.|]]
*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five, as depicted in the image on the right. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.

'''Brain Flexures'''
[[File:Brain Development.png|400px|right|Lateral perspective of the neural tube, showing the three flexures, and five secondary subdivisions.|]]
During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures, as seen in the image to the right in proximity to the five secondary vesicles. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

[[File:Neural- cortex Cajal drawing 01.jpg |thumb|right|200px|Laminar and columnar organization of the cerebral cortex (Historical drawing by Cajal)]]
 
==Later Development: Development of the Cerebral Cortex==
 
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure containing various neuronal subtypes. The diverse set of neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contribute to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' These are excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' These are inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|400px|super|Key developmental zones in the human cortex]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone
**Subplate
*Cortical Plate: establishment of the 6 cortical layers form in this region between the subplate and the marginal zone

===Timeline of Corticogenesis===
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (fate) of the neurons so that correct connections and cortical structure are achieved. "E" relates to embryonic day.
 

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along as the neocortex expands. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area, in addition to the preplate, and many of the cells in the SVZ contribute to the later forming cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to their target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layer 6 is populated before layer 5; layer 5 is populated before layer 4, and so on <ref name="boulder"/>. Each layer condenses and the neurons become closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex such as sensory and motor function.
[[File:Corticogenesis.png|center| 700px|super|Corticogenesis from E30 to adult human brain]]

===Signalling involved in Cerebral Cortex Development===
 
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 1: Shh signalling increases the number of proliferating cells''']]
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.

[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 2: Cortex development in wild-type and ''reeler'' mice''' <ref>Gilmore, E. and Herrup, K. (1997). Cortical development: Layers of complexity. Current Biology, 7(4), pp.R231-R234. http://www.sciencedirect.com/science/article/pii/S0960982206001084 </ref>]]

'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 1) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 2). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|500px|'''Figure 3: Cortical thickness in the absence of Bmp7'''<ref><pubmed>22461901</pubmed></ref>]]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers. Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.
 

==Abnormalities associated with Cerebral Cortex Development==
[[File:Stages of development.png|thumb|right|text-top||520px|Main stages of cortical development where abnormalities may arise <ref name="imaging"/> ]]
 

The embryologic development of the cerebral cortex involves highly organised and complex events (as has been seen in the section 'Development of the cerebral cortex'). 

These events are generally divided by scientists into 3 major stages in cortical formation where crucial changes occur in neuronal cells; these stages include: 
1. Proliferation (or Growth), 
2. Migration, 
3. Organisation (or Maturation or Differentiation). 
 

Disruptions in these stages of cortical development, are the precedent that give rise to malformations or irregularities in the cerebral cortex (Fig. ). This section will explore some abnormalities that are commonly discussed in scientific literature.
 
 

===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder of uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers and very large cells called 'balloon' cells. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. 
[[File:Hemimegalencephaly.png|thumb|left|upright=1.42|Hemimegalencephaly <ref name="imaging"/> ]]
 
 
<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of a 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form a tumour-like, benign malformation) on part or all of the cerebral hemisphere.

Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. Clinical symptoms of this disease may include developmental delay, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.
[[File:Symptoms of microcephaly.png|thumb|right|upright=1.45|Microcephaly <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]]
 
 
 
 
 
<big><big>'''3) Microcephaly Vera'''</big></big>

Microcephaly Vera is relatively common cortical congenital disorder. Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs. 

'''Microcephaly Vera or Primary Microcephaly''' results only due to abnormal cortical development, specifically cell division or proliferation. It is a congenital malformation in which the circumference of the head is quite less than normal and is accompanied by mental retardation and sometimes epilepsy. 

References used to write: <ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>
<ref>Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
<ref>Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref>
<ref>Christopher A, C. (2017). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 
 
<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is thus called due to lesions seen that resembled potato tubers; and is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms) in the cortex. 

" Beneath the cortex, the brain in tuberous sclerosis also shows nodular collections of small cells along the surface of the lateral ventricle that resemble ventricular cells and are called subependymal nodules...or, more descriptively, “candle drippings.” These nodules often contain numerous balloon cells and can in some cases become transformed into glial tumors referred to as subependymal giant cell astrocytomas..."

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:SBH.png|thumb|upright=2.0|right| Heterotopia <ref name="imaging"/> ]]
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex. 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 
 

<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. 
Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 
Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. Type II Lissencephaly also includes: #Muscle-Eye-Brain Disease #Walker-Warburg Syndrome #Fukuyama Syndrome 
*'''Microlissencephaly''' 
Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly, and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span.
 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Kallman Syndrome is associated with hypoplasia of the olfactory bulbs and olfactory cortex, called arhinencephaly, and lack of the sense of smell. [not yet changed into own words]

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

[[File:SchizencephalicBrain.jpg|thumb|left|upright=1.3| Schizencephaly <ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]
 

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder characterised by a cleft(s) or lesion(s) on the brain surface, which is filled with CSF and lined by gray matter.
Schizencephaly can be bilateral or unilateral.

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly.

Schizencephaly commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
 
 
 
 
 
===Other Disorders===
<big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right| Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD) <ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome.
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

<html5media height="350" width="550">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref>
 

<ref> dimedcom (2013).Corpus callosum agenesis. [video] Available at: https://www.youtube.com/watch?v=M7e9JXGOWD4 [Accessed 6 Oct. 2017].</ref>

==Models and Research==
===Animal Models===
[[File:Corticogenesis of mouse and humans.jpeg|thumb|right|text-top|590px|'''Mouse vs Human Neurogenesis''']]

====Mice Model====
Mice have often been used to study corticogenesis in mammals. Corticogenesis lasts from E11 to E19 in mice and lasts eight days, which is far shorter than human corticogenesis. While there are many similarities between human corticogenesis, the rodent brain is much smaller than that of a human’s and therefore, there are different types of progenitor cells involved in mice and the cortex does not expand as greatly. <ref name="control">Dehay, C. and Kennedy, H. (2007). Cell-cycle control and cortical development. Nature Reviews Neuroscience, 8(6),438-450.</ref>Humans have greater numbers of intermediate precursor cells (to aid in further differentiation) and outer radial glial cells compared those of mice. <ref name="cerebral"/> In addition, the SVZ does not split into the inner and outer subventricular zone, but stays intact as one. <ref name="control"/> The importance of reelin has also been greatly studied in mice. Studies showed that mutant mice have disruptions in the migration of neurons into their subsequent layers. By injecting thymidine at various time points of gestation into the female mice, researchers were able to track the development of various populations of neurons. Later developing neurons were unable to ascend past the already early formed neurons due to disruptions in reelin signaling (in the marginal zone). Instead, superficial layer neurons resided below the older, deep layer neurons. This inverted lamination comprises sensory and motor function.<ref> Caviness, V. (1982). Neocortical histogenesis in normal and reeler mice: A developmental study based upon [3H]thymidine autoradiography. Developmental Brain Research, 4(3), 293-302.</ref>
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Timeline and protocol of cerebral organoid development'''<ref><pubmed>25188634</pubmed></ref>]]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

==Glossary==

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
|'''Sulcus'''|| Sulci (plural) are grooves in the cerebral cortex.
|-
|'''Gyrus '''|| Gyri (plural) are folds/ridges in the cerebral cortex.
|-
|'''Fissures'''|| Large sulci.
|-
|'''Corticogenesis'''|| The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes.
|-
|'''Cajal-Retzius (CR) cells'''|| Cortical neurons that develop early on, at the same time as the preplate, and express an important glycoprotein known as reelin, which helps with the proper migration of neurons into their respective layers.
|-
|'''GABAergic Neurons'''|| Generate gamma aminobutyric acid (GABA) as their output, one of the two inhibitory neurotransmitters in the central nervous system (CNS).
|-
|'''Radial glial cells '''|| A class of distinct nonneuronal cells that are bipolar shaped and span the entire width of the cortex during development.
|-
|'''Ventricular zone (VZ)'''|| First formed single-celled layer in the cortex, arising from progenitors in the dorsal telencephalon that divide symmetrically. It lies adjacent to the ventricular surface.
|-
|'''Preplate'''|| First "pioneer neurons" from dividing cells in the ventricular zone for this layer above the ventricular zone
|-
|'''Subventricular zone (SVZ)'''|| Cells in the VZ continue to divide symmetrically and give rise to another zone above the VZ known as the SVZ. This zone later splits into an inner (ISVZ) and outer ventricular zone (OSVZ)
|-
|'''Marginal Zone (MZ)'''|| A subsection of the preplate that forms around E50-55. It lies at the uppermost area of the cortex nearest the pial surface.
|-
|'''Subplate'''|| A subsection of the preplate that forms around E50-55.
|-
|'''Cortical Plate'''|| Forms in between the marginal zone and subplate and gives rise to the 6 layers of the cortex involved in sensory and motor function.
|-
|'''Intermediate zone'''|| Forms below the subplate between E50-55 and contains only migrating cells and no intermediate precursor cells.

|}

==References==

2017 Group Project 1

2017-10-25T12:05:38Z

Z5177691: /* Timeline of Corticogenesis */

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Intro section cortex.jpg|thumb|right|350px| Fig.1. Cerebral cortex is the outermost layer of the cerebrum <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex surrounds the cerebrum, and is the largest part of the human brain. It is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres; it is around 2-4 mm in thickness, consists of the layer of grey matter and has ~ 10 billion nerve cell bodies and dendrites. 
[[File:Brain sectin showing cortex.jpg|thumb|left|300px| Fig 2. Section of the human brain <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]] 

The development of the cerebral cortex involves 3 main stages: proliferation/growth/differentiation, migration of neurons, and maturation/organisation/folding. The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. external pyramidal, IV. internal granular layer, V. internal pyramidal layer, VI. multiform layer. These individual layers organise the capacity for interconnections between both input and output signals. 
 
 
 
 
 
 

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref> 
 
[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|Figure 3: Anatomy of the human cerebral cortex <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]] 

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull (see figure 10). The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri, as shown in figure 10. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri (see figure 10). Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>
 
'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}
 

==Functions of the Cerebral Cortex==
 
[[File:Cortical areas.png|thumb|right|text-top|450px|Figure 11: Cortical areas human cortex <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]
[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|Figure 12: Cortical Homonculus <ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]
The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas, as shown in Figure 11. <ref name="overall function"><pubmed>21653723</pubmed></ref>

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body (see figure 12). The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>
 
==Early Development of the Brain==

 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
[[File:Brain Development 2.png|400px|right|A longitudinal perspective of the neural tube, showing the primary brain vesicles divided into the five secondary subdivisions.|]]
*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five, as depicted in the image on the right. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.

'''Brain Flexures'''
[[File:Brain Development.png|400px|right|Lateral perspective of the neural tube, showing the three flexures, and five secondary subdivisions.|]]
During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures, as seen in the image to the right in proximity to the five secondary vesicles. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

[[File:Neural- cortex Cajal drawing 01.jpg |thumb|right|200px|Laminar and columnar organization of the cerebral cortex (Historical drawing by Cajal)]]
 
==Later Development: Development of the Cerebral Cortex==
 
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure containing various neuronal subtypes. The diverse set of neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contribute to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' These are excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' These are inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|400px|super|Key developmental zones in the human cortex]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone
**Subplate
*Cortical Plate: establishment of the 6 cortical layers form in this region between the subplate and the marginal zone

===Timeline of Corticogenesis===
 
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (fate) of the neurons so that correct connections and cortical structure are achieved. "E" relates to embryonic day.
 

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along in order to expand the neocortex. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area as well as the preplate and many of the cells in the SVZ contribute to the later cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to the target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layers 6 is populated before layer 5; layer 5 is populated before layer 4 and so on <ref name="boulder"/>. Each layer condenses and the neurons are closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex such as sensory and motor function.
[[File:Corticogenesis.png|center| 700px|super|Corticogenesis from E30 to adult human brain]]

===Signalling involved in Cerebral Cortex Development===
 
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 1: Shh signalling increases the number of proliferating cells''']]
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.

[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 2: Cortex development in wild-type and ''reeler'' mice''' <ref>Gilmore, E. and Herrup, K. (1997). Cortical development: Layers of complexity. Current Biology, 7(4), pp.R231-R234. http://www.sciencedirect.com/science/article/pii/S0960982206001084 </ref>]]

'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 1) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 2). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|500px|'''Figure 3: Cortical thickness in the absence of Bmp7'''<ref><pubmed>22461901</pubmed></ref>]]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers. Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.
 

==Abnormalities associated with Cerebral Cortex Development==
[[File:Stages of development.png|thumb|right|text-top||520px|Main stages of cortical development where abnormalities may arise <ref name="imaging"/> ]]
 

The embryologic development of the cerebral cortex involves highly organised and complex events (as has been seen in the section 'Development of the cerebral cortex'). 

These events are generally divided by scientists into 3 major stages in cortical formation where crucial changes occur in neuronal cells; these stages include: 
1. Proliferation (or Growth), 
2. Migration, 
3. Organisation (or Maturation or Differentiation). 
 

Disruptions in these stages of cortical development, are the precedent that give rise to malformations or irregularities in the cerebral cortex (Fig. ). This section will explore some abnormalities that are commonly discussed in scientific literature.
 
 

===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder of uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers and very large cells called 'balloon' cells. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. 
[[File:Hemimegalencephaly.png|thumb|left|upright=1.42|Hemimegalencephaly <ref name="imaging"/> ]]
 
 
<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of a 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form a tumour-like, benign malformation) on part or all of the cerebral hemisphere.

Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. Clinical symptoms of this disease may include developmental delay, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.
[[File:Symptoms of microcephaly.png|thumb|right|upright=1.45|Microcephaly <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]]
 
 
 
 
 
<big><big>'''3) Microcephaly Vera'''</big></big>

Microcephaly Vera is relatively common cortical congenital disorder. Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs. 

'''Microcephaly Vera or Primary Microcephaly''' results only due to abnormal cortical development, specifically cell division or proliferation. It is a congenital malformation in which the circumference of the head is quite less than normal and is accompanied by mental retardation and sometimes epilepsy. 

References used to write: <ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>
<ref>Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
<ref>Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref>
<ref>Christopher A, C. (2017). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 
 
<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is thus called due to lesions seen that resembled potato tubers; and is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms) in the cortex. 

" Beneath the cortex, the brain in tuberous sclerosis also shows nodular collections of small cells along the surface of the lateral ventricle that resemble ventricular cells and are called subependymal nodules...or, more descriptively, “candle drippings.” These nodules often contain numerous balloon cells and can in some cases become transformed into glial tumors referred to as subependymal giant cell astrocytomas..."

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:SBH.png|thumb|upright=2.0|right| Heterotopia <ref name="imaging"/> ]]
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex. 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 
 

<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. 
Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 
Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. Type II Lissencephaly also includes: #Muscle-Eye-Brain Disease #Walker-Warburg Syndrome #Fukuyama Syndrome 
*'''Microlissencephaly''' 
Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly, and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span.
 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Kallman Syndrome is associated with hypoplasia of the olfactory bulbs and olfactory cortex, called arhinencephaly, and lack of the sense of smell. [not yet changed into own words]

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

[[File:SchizencephalicBrain.jpg|thumb|left|upright=1.3| Schizencephaly <ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]
 

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder characterised by a cleft(s) or lesion(s) on the brain surface, which is filled with CSF and lined by gray matter.
Schizencephaly can be bilateral or unilateral.

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly.

Schizencephaly commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
 
 
 
 
 
===Other Disorders===
<big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right| Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD) <ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome.
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

<html5media height="350" width="550">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref>
 

<ref> dimedcom (2013).Corpus callosum agenesis. [video] Available at: https://www.youtube.com/watch?v=M7e9JXGOWD4 [Accessed 6 Oct. 2017].</ref>

==Models and Research==
===Animal Models===
[[File:Corticogenesis of mouse and humans.jpeg|thumb|right|text-top|590px|'''Mouse vs Human Neurogenesis''']]

====Mice Model====
Mice have often been used to study corticogenesis in mammals. Corticogenesis lasts from E11 to E19 in mice and lasts eight days, which is far shorter than human corticogenesis. While there are many similarities between human corticogenesis, the rodent brain is much smaller than that of a human’s and therefore, there are different types of progenitor cells involved in mice and the cortex does not expand as greatly. <ref name="control">Dehay, C. and Kennedy, H. (2007). Cell-cycle control and cortical development. Nature Reviews Neuroscience, 8(6),438-450.</ref>Humans have greater numbers of intermediate precursor cells (to aid in further differentiation) and outer radial glial cells compared those of mice. <ref name="cerebral"/> In addition, the SVZ does not split into the inner and outer subventricular zone, but stays intact as one. <ref name="control"/> The importance of reelin has also been greatly studied in mice. Studies showed that mutant mice have disruptions in the migration of neurons into their subsequent layers. By injecting thymidine at various time points of gestation into the female mice, researchers were able to track the development of various populations of neurons. Later developing neurons were unable to ascend past the already early formed neurons due to disruptions in reelin signaling (in the marginal zone). Instead, superficial layer neurons resided below the older, deep layer neurons. This inverted lamination comprises sensory and motor function.<ref> Caviness, V. (1982). Neocortical histogenesis in normal and reeler mice: A developmental study based upon [3H]thymidine autoradiography. Developmental Brain Research, 4(3), 293-302.</ref>
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Timeline and protocol of cerebral organoid development'''<ref><pubmed>25188634</pubmed></ref>]]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

==Glossary==

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
|'''Sulcus'''|| Sulci (plural) are grooves in the cerebral cortex.
|-
|'''Gyrus '''|| Gyri (plural) are folds/ridges in the cerebral cortex.
|-
|'''Fissures'''|| Large sulci.
|-
|'''Corticogenesis'''|| The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes.
|-
|'''Cajal-Retzius (CR) cells'''|| Cortical neurons that develop early on, at the same time as the preplate, and express an important glycoprotein known as reelin, which helps with the proper migration of neurons into their respective layers.
|-
|'''GABAergic Neurons'''|| Generate gamma aminobutyric acid (GABA) as their output, one of the two inhibitory neurotransmitters in the central nervous system (CNS).
|-
|'''Radial glial cells '''|| A class of distinct nonneuronal cells that are bipolar shaped and span the entire width of the cortex during development.
|-
|'''Ventricular zone (VZ)'''|| First formed single-celled layer in the cortex, arising from progenitors in the dorsal telencephalon that divide symmetrically. It lies adjacent to the ventricular surface.
|-
|'''Preplate'''|| First "pioneer neurons" from dividing cells in the ventricular zone for this layer above the ventricular zone
|-
|'''Subventricular zone (SVZ)'''|| Cells in the VZ continue to divide symmetrically and give rise to another zone above the VZ known as the SVZ. This zone later splits into an inner (ISVZ) and outer ventricular zone (OSVZ)
|-
|'''Marginal Zone (MZ)'''|| A subsection of the preplate that forms around E50-55. It lies at the uppermost area of the cortex nearest the pial surface.
|-
|'''Subplate'''|| A subsection of the preplate that forms around E50-55.
|-
|'''Cortical Plate'''|| Forms in between the marginal zone and subplate and gives rise to the 6 layers of the cortex involved in sensory and motor function.
|-
|'''Intermediate zone'''|| Forms below the subplate between E50-55 and contains only migrating cells and no intermediate precursor cells.

|}

==References==

2017 Group Project 1

2017-10-25T12:03:18Z

Z5177691: /* Later Development: Development of the Cerebral Cortex */

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Intro section cortex.jpg|thumb|right|350px| Fig.1. Cerebral cortex is the outermost layer of the cerebrum <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex surrounds the cerebrum, and is the largest part of the human brain. It is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres; it is around 2-4 mm in thickness, consists of the layer of grey matter and has ~ 10 billion nerve cell bodies and dendrites. 
[[File:Brain sectin showing cortex.jpg|thumb|left|300px| Fig 2. Section of the human brain <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]] 

The development of the cerebral cortex involves 3 main stages: proliferation/growth/differentiation, migration of neurons, and maturation/organisation/folding. The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. external pyramidal, IV. internal granular layer, V. internal pyramidal layer, VI. multiform layer. These individual layers organise the capacity for interconnections between both input and output signals. 
 
 
 
 
 
 

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref> 
 
[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|Figure 3: Anatomy of the human cerebral cortex <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]] 

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull (see figure 10). The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri, as shown in figure 10. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri (see figure 10). Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>
 
'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}
 

==Functions of the Cerebral Cortex==
 
[[File:Cortical areas.png|thumb|right|text-top|450px|Figure 11: Cortical areas human cortex <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]
[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|Figure 12: Cortical Homonculus <ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]
The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas, as shown in Figure 11. <ref name="overall function"><pubmed>21653723</pubmed></ref>

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body (see figure 12). The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>
 
==Early Development of the Brain==

 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
[[File:Brain Development 2.png|400px|right|A longitudinal perspective of the neural tube, showing the primary brain vesicles divided into the five secondary subdivisions.|]]
*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five, as depicted in the image on the right. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.

'''Brain Flexures'''
[[File:Brain Development.png|400px|right|Lateral perspective of the neural tube, showing the three flexures, and five secondary subdivisions.|]]
During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures, as seen in the image to the right in proximity to the five secondary vesicles. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

[[File:Neural- cortex Cajal drawing 01.jpg |thumb|right|200px|Laminar and columnar organization of the cerebral cortex (Historical drawing by Cajal)]]
 
==Later Development: Development of the Cerebral Cortex==
 
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure containing various neuronal subtypes. The diverse set of neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contribute to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' These are excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' These are inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|400px|super|Key developmental zones in the human cortex]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone
**Subplate
*Cortical Plate: establishment of the 6 cortical layers form in this region between the subplate and the marginal zone

===Timeline of Corticogenesis===
 
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (e.g fate) of the neurons so that specific connections and cortical structure are achieved. "E" relates to embryonic day in relation to corticogenesis.
 

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along in order to expand the neocortex. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area as well as the preplate and many of the cells in the SVZ contribute to the later cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to the target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layers 6 is populated before layer 5; layer 5 is populated before layer 4 and so on <ref name="boulder"/>. Each layer condenses and the neurons are closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex such as sensory and motor function.
[[File:Corticogenesis.png|center| 700px|super|Corticogenesis from E30 to adult human brain]]

===Signalling involved in Cerebral Cortex Development===
 
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 1: Shh signalling increases the number of proliferating cells''']]
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.

[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 2: Cortex development in wild-type and ''reeler'' mice''' <ref>Gilmore, E. and Herrup, K. (1997). Cortical development: Layers of complexity. Current Biology, 7(4), pp.R231-R234. http://www.sciencedirect.com/science/article/pii/S0960982206001084 </ref>]]

'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 1) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 2). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|500px|'''Figure 3: Cortical thickness in the absence of Bmp7'''<ref><pubmed>22461901</pubmed></ref>]]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers. Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.
 

==Abnormalities associated with Cerebral Cortex Development==
[[File:Stages of development.png|thumb|right|text-top||520px|Main stages of cortical development where abnormalities may arise <ref name="imaging"/> ]]
 

The embryologic development of the cerebral cortex involves highly organised and complex events (as has been seen in the section 'Development of the cerebral cortex'). 

These events are generally divided by scientists into 3 major stages in cortical formation where crucial changes occur in neuronal cells; these stages include: 
1. Proliferation (or Growth), 
2. Migration, 
3. Organisation (or Maturation or Differentiation). 
 

Disruptions in these stages of cortical development, are the precedent that give rise to malformations or irregularities in the cerebral cortex (Fig. ). This section will explore some abnormalities that are commonly discussed in scientific literature.
 
 

===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder of uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers and very large cells called 'balloon' cells. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. 
[[File:Hemimegalencephaly.png|thumb|left|upright=1.42|Hemimegalencephaly <ref name="imaging"/> ]]
 
 
<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of a 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form a tumour-like, benign malformation) on part or all of the cerebral hemisphere.

Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. Clinical symptoms of this disease may include developmental delay, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.
[[File:Symptoms of microcephaly.png|thumb|right|upright=1.45|Microcephaly <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]]
 
 
 
 
 
<big><big>'''3) Microcephaly Vera'''</big></big>

Microcephaly Vera is relatively common cortical congenital disorder. Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs. 

'''Microcephaly Vera or Primary Microcephaly''' results only due to abnormal cortical development, specifically cell division or proliferation. It is a congenital malformation in which the circumference of the head is quite less than normal and is accompanied by mental retardation and sometimes epilepsy. 

References used to write: <ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>
<ref>Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
<ref>Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref>
<ref>Christopher A, C. (2017). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 
 
<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is thus called due to lesions seen that resembled potato tubers; and is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms) in the cortex. 

" Beneath the cortex, the brain in tuberous sclerosis also shows nodular collections of small cells along the surface of the lateral ventricle that resemble ventricular cells and are called subependymal nodules...or, more descriptively, “candle drippings.” These nodules often contain numerous balloon cells and can in some cases become transformed into glial tumors referred to as subependymal giant cell astrocytomas..."

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:SBH.png|thumb|upright=2.0|right| Heterotopia <ref name="imaging"/> ]]
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex. 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 
 

<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. 
Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 
Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. Type II Lissencephaly also includes: #Muscle-Eye-Brain Disease #Walker-Warburg Syndrome #Fukuyama Syndrome 
*'''Microlissencephaly''' 
Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly, and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span.
 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Kallman Syndrome is associated with hypoplasia of the olfactory bulbs and olfactory cortex, called arhinencephaly, and lack of the sense of smell. [not yet changed into own words]

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

[[File:SchizencephalicBrain.jpg|thumb|left|upright=1.3| Schizencephaly <ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]
 

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder characterised by a cleft(s) or lesion(s) on the brain surface, which is filled with CSF and lined by gray matter.
Schizencephaly can be bilateral or unilateral.

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly.

Schizencephaly commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
 
 
 
 
 
===Other Disorders===
<big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right| Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD) <ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome.
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

<html5media height="350" width="550">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref>
 

<ref> dimedcom (2013).Corpus callosum agenesis. [video] Available at: https://www.youtube.com/watch?v=M7e9JXGOWD4 [Accessed 6 Oct. 2017].</ref>

==Models and Research==
===Animal Models===
[[File:Corticogenesis of mouse and humans.jpeg|thumb|right|text-top|590px|'''Mouse vs Human Neurogenesis''']]

====Mice Model====
Mice have often been used to study corticogenesis in mammals. Corticogenesis lasts from E11 to E19 in mice and lasts eight days, which is far shorter than human corticogenesis. While there are many similarities between human corticogenesis, the rodent brain is much smaller than that of a human’s and therefore, there are different types of progenitor cells involved in mice and the cortex does not expand as greatly. <ref name="control">Dehay, C. and Kennedy, H. (2007). Cell-cycle control and cortical development. Nature Reviews Neuroscience, 8(6),438-450.</ref>Humans have greater numbers of intermediate precursor cells (to aid in further differentiation) and outer radial glial cells compared those of mice. <ref name="cerebral"/> In addition, the SVZ does not split into the inner and outer subventricular zone, but stays intact as one. <ref name="control"/> The importance of reelin has also been greatly studied in mice. Studies showed that mutant mice have disruptions in the migration of neurons into their subsequent layers. By injecting thymidine at various time points of gestation into the female mice, researchers were able to track the development of various populations of neurons. Later developing neurons were unable to ascend past the already early formed neurons due to disruptions in reelin signaling (in the marginal zone). Instead, superficial layer neurons resided below the older, deep layer neurons. This inverted lamination comprises sensory and motor function.<ref> Caviness, V. (1982). Neocortical histogenesis in normal and reeler mice: A developmental study based upon [3H]thymidine autoradiography. Developmental Brain Research, 4(3), 293-302.</ref>
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Timeline and protocol of cerebral organoid development'''<ref><pubmed>25188634</pubmed></ref>]]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

==Glossary==

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
|'''Sulcus'''|| Sulci (plural) are grooves in the cerebral cortex.
|-
|'''Gyrus '''|| Gyri (plural) are folds/ridges in the cerebral cortex.
|-
|'''Fissures'''|| Large sulci.
|-
|'''Corticogenesis'''|| The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes.
|-
|'''Cajal-Retzius (CR) cells'''|| Cortical neurons that develop early on, at the same time as the preplate, and express an important glycoprotein known as reelin, which helps with the proper migration of neurons into their respective layers.
|-
|'''GABAergic Neurons'''|| Generate gamma aminobutyric acid (GABA) as their output, one of the two inhibitory neurotransmitters in the central nervous system (CNS).
|-
|'''Radial glial cells '''|| A class of distinct nonneuronal cells that are bipolar shaped and span the entire width of the cortex during development.
|-
|'''Ventricular zone (VZ)'''|| First formed single-celled layer in the cortex, arising from progenitors in the dorsal telencephalon that divide symmetrically. It lies adjacent to the ventricular surface.
|-
|'''Preplate'''|| First "pioneer neurons" from dividing cells in the ventricular zone for this layer above the ventricular zone
|-
|'''Subventricular zone (SVZ)'''|| Cells in the VZ continue to divide symmetrically and give rise to another zone above the VZ known as the SVZ. This zone later splits into an inner (ISVZ) and outer ventricular zone (OSVZ)
|-
|'''Marginal Zone (MZ)'''|| A subsection of the preplate that forms around E50-55. It lies at the uppermost area of the cortex nearest the pial surface.
|-
|'''Subplate'''|| A subsection of the preplate that forms around E50-55.
|-
|'''Cortical Plate'''|| Forms in between the marginal zone and subplate and gives rise to the 6 layers of the cortex involved in sensory and motor function.
|-
|'''Intermediate zone'''|| Forms below the subplate between E50-55 and contains only migrating cells and no intermediate precursor cells.

|}

==References==

2017 Group Project 1

2017-10-25T12:01:45Z

Z5177691: /* Later Development: Development of the Cerebral Cortex */

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Intro section cortex.jpg|thumb|right|350px| Fig.1. Cerebral cortex is the outermost layer of the cerebrum <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex surrounds the cerebrum, and is the largest part of the human brain. It is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres; it is around 2-4 mm in thickness, consists of the layer of grey matter and has ~ 10 billion nerve cell bodies and dendrites. 
[[File:Brain sectin showing cortex.jpg|thumb|left|300px| Fig 2. Section of the human brain <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]] 

The development of the cerebral cortex involves 3 main stages: proliferation/growth/differentiation, migration of neurons, and maturation/organisation/folding. The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. external pyramidal, IV. internal granular layer, V. internal pyramidal layer, VI. multiform layer. These individual layers organise the capacity for interconnections between both input and output signals. 
 
 
 
 
 
 

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref> 
 
[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|Figure 3: Anatomy of the human cerebral cortex <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]] 

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull (see figure 10). The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri, as shown in figure 10. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri (see figure 10). Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>
 
'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}
 

==Functions of the Cerebral Cortex==
 
[[File:Cortical areas.png|thumb|right|text-top|450px|Figure 11: Cortical areas human cortex <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]
[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|Figure 12: Cortical Homonculus <ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]
The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas, as shown in Figure 11. <ref name="overall function"><pubmed>21653723</pubmed></ref>

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body (see figure 12). The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>
 
==Early Development of the Brain==

 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
[[File:Brain Development 2.png|400px|right|A longitudinal perspective of the neural tube, showing the primary brain vesicles divided into the five secondary subdivisions.|]]
*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five, as depicted in the image on the right. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.

'''Brain Flexures'''
[[File:Brain Development.png|400px|right|Lateral perspective of the neural tube, showing the three flexures, and five secondary subdivisions.|]]
During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures, as seen in the image to the right in proximity to the five secondary vesicles. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

[[File:Neural- cortex Cajal drawing 01.jpg |thumb|right|200px|Laminar and columnar organization of the cerebral cortex (Historical drawing by Cajal)]]
 
==Later Development: Development of the Cerebral Cortex==
 
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure containing various neuronal subtypes. The diverse set of neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contribute to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|400px|super|Key developmental zones in the human cortex]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone
**Subplate
*Cortical Plate: establishment of the 6 cortical layers form in this region between the subplate and the marginal zone

===Timeline of Corticogenesis===
 
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (e.g fate) of the neurons so that specific connections and cortical structure are achieved. "E" relates to embryonic day in relation to corticogenesis.
 

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along in order to expand the neocortex. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area as well as the preplate and many of the cells in the SVZ contribute to the later cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to the target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layers 6 is populated before layer 5; layer 5 is populated before layer 4 and so on <ref name="boulder"/>. Each layer condenses and the neurons are closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex such as sensory and motor function.
[[File:Corticogenesis.png|center| 700px|super|Corticogenesis from E30 to adult human brain]]

===Signalling involved in Cerebral Cortex Development===
 
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 1: Shh signalling increases the number of proliferating cells''']]
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.

[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 2: Cortex development in wild-type and ''reeler'' mice''' <ref>Gilmore, E. and Herrup, K. (1997). Cortical development: Layers of complexity. Current Biology, 7(4), pp.R231-R234. http://www.sciencedirect.com/science/article/pii/S0960982206001084 </ref>]]

'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 1) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 2). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|500px|'''Figure 3: Cortical thickness in the absence of Bmp7'''<ref><pubmed>22461901</pubmed></ref>]]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers. Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.
 

==Abnormalities associated with Cerebral Cortex Development==
[[File:Stages of development.png|thumb|right|text-top||520px|Main stages of cortical development where abnormalities may arise <ref name="imaging"/> ]]
 

The embryologic development of the cerebral cortex involves highly organised and complex events (as has been seen in the section 'Development of the cerebral cortex'). 

These events are generally divided by scientists into 3 major stages in cortical formation where crucial changes occur in neuronal cells; these stages include: 
1. Proliferation (or Growth), 
2. Migration, 
3. Organisation (or Maturation or Differentiation). 
 

Disruptions in these stages of cortical development, are the precedent that give rise to malformations or irregularities in the cerebral cortex (Fig. ). This section will explore some abnormalities that are commonly discussed in scientific literature.
 
 

===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder of uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers and very large cells called 'balloon' cells. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. 
[[File:Hemimegalencephaly.png|thumb|left|upright=1.42|Hemimegalencephaly <ref name="imaging"/> ]]
 
 
<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of a 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form a tumour-like, benign malformation) on part or all of the cerebral hemisphere.

Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. Clinical symptoms of this disease may include developmental delay, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.
[[File:Symptoms of microcephaly.png|thumb|right|upright=1.45|Microcephaly <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]]
 
 
 
 
 
<big><big>'''3) Microcephaly Vera'''</big></big>

Microcephaly Vera is relatively common cortical congenital disorder. Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs. 

'''Microcephaly Vera or Primary Microcephaly''' results only due to abnormal cortical development, specifically cell division or proliferation. It is a congenital malformation in which the circumference of the head is quite less than normal and is accompanied by mental retardation and sometimes epilepsy. 

References used to write: <ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>
<ref>Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
<ref>Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref>
<ref>Christopher A, C. (2017). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 
 
<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is thus called due to lesions seen that resembled potato tubers; and is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms) in the cortex. 

" Beneath the cortex, the brain in tuberous sclerosis also shows nodular collections of small cells along the surface of the lateral ventricle that resemble ventricular cells and are called subependymal nodules...or, more descriptively, “candle drippings.” These nodules often contain numerous balloon cells and can in some cases become transformed into glial tumors referred to as subependymal giant cell astrocytomas..."

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:SBH.png|thumb|upright=2.0|right| Heterotopia <ref name="imaging"/> ]]
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex. 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 
 

<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. 
Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 
Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. Type II Lissencephaly also includes: #Muscle-Eye-Brain Disease #Walker-Warburg Syndrome #Fukuyama Syndrome 
*'''Microlissencephaly''' 
Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly, and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span.
 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Kallman Syndrome is associated with hypoplasia of the olfactory bulbs and olfactory cortex, called arhinencephaly, and lack of the sense of smell. [not yet changed into own words]

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

[[File:SchizencephalicBrain.jpg|thumb|left|upright=1.3| Schizencephaly <ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]
 

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder characterised by a cleft(s) or lesion(s) on the brain surface, which is filled with CSF and lined by gray matter.
Schizencephaly can be bilateral or unilateral.

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly.

Schizencephaly commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
 
 
 
 
 
===Other Disorders===
<big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right| Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD) <ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome.
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

<html5media height="350" width="550">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref>
 

<ref> dimedcom (2013).Corpus callosum agenesis. [video] Available at: https://www.youtube.com/watch?v=M7e9JXGOWD4 [Accessed 6 Oct. 2017].</ref>

==Models and Research==
===Animal Models===
[[File:Corticogenesis of mouse and humans.jpeg|thumb|right|text-top|590px|'''Mouse vs Human Neurogenesis''']]

====Mice Model====
Mice have often been used to study corticogenesis in mammals. Corticogenesis lasts from E11 to E19 in mice and lasts eight days, which is far shorter than human corticogenesis. While there are many similarities between human corticogenesis, the rodent brain is much smaller than that of a human’s and therefore, there are different types of progenitor cells involved in mice and the cortex does not expand as greatly. <ref name="control">Dehay, C. and Kennedy, H. (2007). Cell-cycle control and cortical development. Nature Reviews Neuroscience, 8(6),438-450.</ref>Humans have greater numbers of intermediate precursor cells (to aid in further differentiation) and outer radial glial cells compared those of mice. <ref name="cerebral"/> In addition, the SVZ does not split into the inner and outer subventricular zone, but stays intact as one. <ref name="control"/> The importance of reelin has also been greatly studied in mice. Studies showed that mutant mice have disruptions in the migration of neurons into their subsequent layers. By injecting thymidine at various time points of gestation into the female mice, researchers were able to track the development of various populations of neurons. Later developing neurons were unable to ascend past the already early formed neurons due to disruptions in reelin signaling (in the marginal zone). Instead, superficial layer neurons resided below the older, deep layer neurons. This inverted lamination comprises sensory and motor function.<ref> Caviness, V. (1982). Neocortical histogenesis in normal and reeler mice: A developmental study based upon [3H]thymidine autoradiography. Developmental Brain Research, 4(3), 293-302.</ref>
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Timeline and protocol of cerebral organoid development'''<ref><pubmed>25188634</pubmed></ref>]]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

==Glossary==

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
|'''Sulcus'''|| Sulci (plural) are grooves in the cerebral cortex.
|-
|'''Gyrus '''|| Gyri (plural) are folds/ridges in the cerebral cortex.
|-
|'''Fissures'''|| Large sulci.
|-
|'''Corticogenesis'''|| The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes.
|-
|'''Cajal-Retzius (CR) cells'''|| Cortical neurons that develop early on, at the same time as the preplate, and express an important glycoprotein known as reelin, which helps with the proper migration of neurons into their respective layers.
|-
|'''GABAergic Neurons'''|| Generate gamma aminobutyric acid (GABA) as their output, one of the two inhibitory neurotransmitters in the central nervous system (CNS).
|-
|'''Radial glial cells '''|| A class of distinct nonneuronal cells that are bipolar shaped and span the entire width of the cortex during development.
|-
|'''Ventricular zone (VZ)'''|| First formed single-celled layer in the cortex, arising from progenitors in the dorsal telencephalon that divide symmetrically. It lies adjacent to the ventricular surface.
|-
|'''Preplate'''|| First "pioneer neurons" from dividing cells in the ventricular zone for this layer above the ventricular zone
|-
|'''Subventricular zone (SVZ)'''|| Cells in the VZ continue to divide symmetrically and give rise to another zone above the VZ known as the SVZ. This zone later splits into an inner (ISVZ) and outer ventricular zone (OSVZ)
|-
|'''Marginal Zone (MZ)'''|| A subsection of the preplate that forms around E50-55. It lies at the uppermost area of the cortex nearest the pial surface.
|-
|'''Subplate'''|| A subsection of the preplate that forms around E50-55.
|-
|'''Cortical Plate'''|| Forms in between the marginal zone and subplate and gives rise to the 6 layers of the cortex involved in sensory and motor function.
|-
|'''Intermediate zone'''|| Forms below the subplate between E50-55 and contains only migrating cells and no intermediate precursor cells.

|}

==References==

2017 Group Project 1

2017-10-25T11:59:31Z

Z5177691: /* Later Development: Development of the Cerebral Cortex */

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Intro section cortex.jpg|thumb|right|350px| Fig.1. Cerebral cortex is the outermost layer of the cerebrum <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex surrounds the cerebrum, and is the largest part of the human brain. It is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres; it is around 2-4 mm in thickness, consists of the layer of grey matter and has ~ 10 billion nerve cell bodies and dendrites. 
[[File:Brain sectin showing cortex.jpg|thumb|left|300px| Fig 2. Section of the human brain <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]] 

The development of the cerebral cortex involves 3 main stages: proliferation/growth/differentiation, migration of neurons, and maturation/organisation/folding. The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. external pyramidal, IV. internal granular layer, V. internal pyramidal layer, VI. multiform layer. These individual layers organise the capacity for interconnections between both input and output signals. 
 
 
 
 
 
 

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref> 
 
[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|Figure 3: Anatomy of the human cerebral cortex <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]] 

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull (see figure 10). The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri, as shown in figure 10. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri (see figure 10). Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>
 
'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}
 

==Functions of the Cerebral Cortex==
 
[[File:Cortical areas.png|thumb|right|text-top|450px|Figure 11: Cortical areas human cortex <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]
[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|Figure 12: Cortical Homonculus <ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]
The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas, as shown in Figure 11. <ref name="overall function"><pubmed>21653723</pubmed></ref>

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body (see figure 12). The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>
 
==Early Development of the Brain==

 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
[[File:Brain Development 2.png|400px|right|A longitudinal perspective of the neural tube, showing the primary brain vesicles divided into the five secondary subdivisions.|]]
*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five, as depicted in the image on the right. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.

'''Brain Flexures'''
[[File:Brain Development.png|400px|right|Lateral perspective of the neural tube, showing the three flexures, and five secondary subdivisions.|]]
During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures, as seen in the image to the right in proximity to the five secondary vesicles. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

[[File:Neural- cortex Cajal drawing 01.jpg |thumb|right|200px|Laminar and columnar organization of the cerebral cortex (Historical drawing by Cajal)]]
 
==Later Development: Development of the Cerebral Cortex==
 
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure containing various neuronal subtypes. The diversity in neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned in above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contributes to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|400px|super|Key developmental zones in the human cortex]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone
**Subplate
*Cortical Plate: establishment of the 6 cortical layers form in this region between the subplate and the marginal zone

===Timeline of Corticogenesis===
 
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (e.g fate) of the neurons so that specific connections and cortical structure are achieved. "E" relates to embryonic day in relation to corticogenesis.
 

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along in order to expand the neocortex. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area as well as the preplate and many of the cells in the SVZ contribute to the later cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to the target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layers 6 is populated before layer 5; layer 5 is populated before layer 4 and so on <ref name="boulder"/>. Each layer condenses and the neurons are closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex such as sensory and motor function.
[[File:Corticogenesis.png|center| 700px|super|Corticogenesis from E30 to adult human brain]]

===Signalling involved in Cerebral Cortex Development===
 
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 1: Shh signalling increases the number of proliferating cells''']]
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.

[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 2: Cortex development in wild-type and ''reeler'' mice''' <ref>Gilmore, E. and Herrup, K. (1997). Cortical development: Layers of complexity. Current Biology, 7(4), pp.R231-R234. http://www.sciencedirect.com/science/article/pii/S0960982206001084 </ref>]]

'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 1) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 2). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|500px|'''Figure 3: Cortical thickness in the absence of Bmp7'''<ref><pubmed>22461901</pubmed></ref>]]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers. Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.
 

==Abnormalities associated with Cerebral Cortex Development==
[[File:Stages of development.png|thumb|right|text-top||520px|Main stages of cortical development where abnormalities may arise <ref name="imaging"/> ]]
 

The embryologic development of the cerebral cortex involves highly organised and complex events (as has been seen in the section 'Development of the cerebral cortex'). 

These events are generally divided by scientists into 3 major stages in cortical formation where crucial changes occur in neuronal cells; these stages include: 
1. Proliferation (or Growth), 
2. Migration, 
3. Organisation (or Maturation or Differentiation). 
 

Disruptions in these stages of cortical development, are the precedent that give rise to malformations or irregularities in the cerebral cortex (Fig. ). This section will explore some abnormalities that are commonly discussed in scientific literature.
 
 

===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder of uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers and very large cells called 'balloon' cells. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. 
[[File:Hemimegalencephaly.png|thumb|left|upright=1.42|Hemimegalencephaly <ref name="imaging"/> ]]
 
 
<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of a 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form a tumour-like, benign malformation) on part or all of the cerebral hemisphere.

Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. Clinical symptoms of this disease may include developmental delay, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.
[[File:Symptoms of microcephaly.png|thumb|right|upright=1.45|Microcephaly <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]]
 
 
 
 
 
<big><big>'''3) Microcephaly Vera'''</big></big>

Microcephaly Vera is relatively common cortical congenital disorder. Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs. 

'''Microcephaly Vera or Primary Microcephaly''' results only due to abnormal cortical development, specifically cell division or proliferation. It is a congenital malformation in which the circumference of the head is quite less than normal and is accompanied by mental retardation and sometimes epilepsy. 

References used to write: <ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>
<ref>Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
<ref>Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref>
<ref>Christopher A, C. (2017). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 
 
<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is thus called due to lesions seen that resembled potato tubers; and is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms) in the cortex. 

" Beneath the cortex, the brain in tuberous sclerosis also shows nodular collections of small cells along the surface of the lateral ventricle that resemble ventricular cells and are called subependymal nodules...or, more descriptively, “candle drippings.” These nodules often contain numerous balloon cells and can in some cases become transformed into glial tumors referred to as subependymal giant cell astrocytomas..."

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:SBH.png|thumb|upright=2.0|right| Heterotopia <ref name="imaging"/> ]]
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex. 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 
 

<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. 
Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 
Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. Type II Lissencephaly also includes: #Muscle-Eye-Brain Disease #Walker-Warburg Syndrome #Fukuyama Syndrome 
*'''Microlissencephaly''' 
Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly, and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span.
 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Kallman Syndrome is associated with hypoplasia of the olfactory bulbs and olfactory cortex, called arhinencephaly, and lack of the sense of smell. [not yet changed into own words]

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

[[File:SchizencephalicBrain.jpg|thumb|left|upright=1.3| Schizencephaly <ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]
 

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder characterised by a cleft(s) or lesion(s) on the brain surface, which is filled with CSF and lined by gray matter.
Schizencephaly can be bilateral or unilateral.

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly.

Schizencephaly commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
 
 
 
 
 
===Other Disorders===
<big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right| Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD) <ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome.
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

<html5media height="350" width="550">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref>
 

<ref> dimedcom (2013).Corpus callosum agenesis. [video] Available at: https://www.youtube.com/watch?v=M7e9JXGOWD4 [Accessed 6 Oct. 2017].</ref>

==Models and Research==
===Animal Models===
[[File:Corticogenesis of mouse and humans.jpeg|thumb|right|text-top|590px|'''Mouse vs Human Neurogenesis''']]

====Mice Model====
Mice have often been used to study corticogenesis in mammals. Corticogenesis lasts from E11 to E19 in mice and lasts eight days, which is far shorter than human corticogenesis. While there are many similarities between human corticogenesis, the rodent brain is much smaller than that of a human’s and therefore, there are different types of progenitor cells involved in mice and the cortex does not expand as greatly. <ref name="control">Dehay, C. and Kennedy, H. (2007). Cell-cycle control and cortical development. Nature Reviews Neuroscience, 8(6),438-450.</ref>Humans have greater numbers of intermediate precursor cells (to aid in further differentiation) and outer radial glial cells compared those of mice. <ref name="cerebral"/> In addition, the SVZ does not split into the inner and outer subventricular zone, but stays intact as one. <ref name="control"/> The importance of reelin has also been greatly studied in mice. Studies showed that mutant mice have disruptions in the migration of neurons into their subsequent layers. By injecting thymidine at various time points of gestation into the female mice, researchers were able to track the development of various populations of neurons. Later developing neurons were unable to ascend past the already early formed neurons due to disruptions in reelin signaling (in the marginal zone). Instead, superficial layer neurons resided below the older, deep layer neurons. This inverted lamination comprises sensory and motor function.<ref> Caviness, V. (1982). Neocortical histogenesis in normal and reeler mice: A developmental study based upon [3H]thymidine autoradiography. Developmental Brain Research, 4(3), 293-302.</ref>
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Timeline and protocol of cerebral organoid development'''<ref><pubmed>25188634</pubmed></ref>]]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

==Glossary==

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
|'''Sulcus'''|| Sulci (plural) are grooves in the cerebral cortex.
|-
|'''Gyrus '''|| Gyri (plural) are folds/ridges in the cerebral cortex.
|-
|'''Fissures'''|| Large sulci.
|-
|'''Corticogenesis'''|| The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes.
|-
|'''Cajal-Retzius (CR) cells'''|| Cortical neurons that develop early on, at the same time as the preplate, and express an important glycoprotein known as reelin, which helps with the proper migration of neurons into their respective layers.
|-
|'''GABAergic Neurons'''|| Generate gamma aminobutyric acid (GABA) as their output, one of the two inhibitory neurotransmitters in the central nervous system (CNS).
|-
|'''Radial glial cells '''|| A class of distinct nonneuronal cells that are bipolar shaped and span the entire width of the cortex during development.
|-
|'''Ventricular zone (VZ)'''|| First formed single-celled layer in the cortex, arising from progenitors in the dorsal telencephalon that divide symmetrically. It lies adjacent to the ventricular surface.
|-
|'''Preplate'''|| First "pioneer neurons" from dividing cells in the ventricular zone for this layer above the ventricular zone
|-
|'''Subventricular zone (SVZ)'''|| Cells in the VZ continue to divide symmetrically and give rise to another zone above the VZ known as the SVZ. This zone later splits into an inner (ISVZ) and outer ventricular zone (OSVZ)
|-
|'''Marginal Zone (MZ)'''|| A subsection of the preplate that forms around E50-55. It lies at the uppermost area of the cortex nearest the pial surface.
|-
|'''Subplate'''|| A subsection of the preplate that forms around E50-55.
|-
|'''Cortical Plate'''|| Forms in between the marginal zone and subplate and gives rise to the 6 layers of the cortex involved in sensory and motor function.
|-
|'''Intermediate zone'''|| Forms below the subplate between E50-55 and contains only migrating cells and no intermediate precursor cells.

|}

==References==

2017 Group Project 1

2017-10-25T11:39:03Z

Z5177691: /* Mice Model */

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Intro section cortex.jpg|thumb|right|350px| Fig.1. Cerebral cortex is the outermost layer of the cerebrum <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex surrounds the cerebrum, and is the largest part of the human brain. It is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres; it is around 2-4 mm in thickness, consists of the layer of grey matter and has ~ 10 billion nerve cell bodies and dendrites. 
[[File:Brain sectin showing cortex.jpg|thumb|left|300px| Fig 2. Section of the human brain <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]] 

The development of the cerebral cortex involves 3 main stages: proliferation/growth/differentiation, migration of neurons, and maturation/organisation/folding. The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. external pyramidal, IV. internal granular layer, V. internal pyramidal layer, VI. multiform layer. These individual layers organise the capacity for interconnections between both input and output signals. 
 
 
 
 
 
 

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref> 
 
[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|Figure 10: Anatomy of the human cerebral cortex <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]] 

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull (see figure 10). The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri, as shown in figure 10. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri (see figure 10). Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>
 
'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}
 
==Functions of the Cerebral Cortex==
 
[[File:Cortical areas.png|thumb|right|text-top|450px|Figure 11: Cortical areas human cortex <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]
[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|Figure 12: Cortical Homonculus <ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]
The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas, as shown in Figure 11. <ref name="overall function"><pubmed>21653723</pubmed></ref>

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body (see figure 12). The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>
 
==Early Development of the Brain==

 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
[[File:Brain Development 2.png|400px|right|A longitudinal perspective of the neural tube, showing the primary brain vesicles divided into the five secondary subdivisions.|]]
*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five, as depicted in the image on the right. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.

'''Brain Flexures'''
[[File:Brain Development.png|400px|right|Lateral perspective of the neural tube, showing the three flexures, and five secondary subdivisions.|]]
During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures, as seen in the image to the right in proximity to the five secondary vesicles. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

[[File:Neural- cortex Cajal drawing 01.jpg |thumb|right|200px|Laminar and columnar organization of the cerebral cortex (Historical drawing by Cajal)]]
 
==Later Development: Development of the Cerebral Cortex==
 
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes. The diversity in neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned in above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contributes to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|400px|super|Key developmental zones in the human cortex]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone
**Subplate
*Cortical Plate: establishment of the 6 cortical layers form in this region between the subplate and the marginal zone

===Timeline of Corticogenesis===
 
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (e.g fate) of the neurons so that specific connections and cortical structure are achieved. "E" relates to embryonic day in relation to corticogenesis.
 

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along in order to expand the neocortex. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area as well as the preplate and many of the cells in the SVZ contribute to the later cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to the target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layers 6 is populated before layer 5; layer 5 is populated before layer 4 and so on <ref name="boulder"/>. Each layer condenses and the neurons are closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex such as sensory and motor function.
[[File:Corticogenesis.png|center| 700px|super|Corticogenesis from E30 to adult human brain]]

===Signalling involved in Cerebral Cortex Development===
 
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 1: Shh signalling increases the number of proliferating cells''']]
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.

[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 2: Cortex development in wild-type and ''reeler'' mice''' <ref>Gilmore, E. and Herrup, K. (1997). Cortical development: Layers of complexity. Current Biology, 7(4), pp.R231-R234. http://www.sciencedirect.com/science/article/pii/S0960982206001084 </ref>]]

'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 1) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 2). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|500px|'''Figure 3: Cortical thickness in the absence of Bmp7'''<ref><pubmed>22461901</pubmed></ref>]]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers. Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.
 
==Abnormalities associated with Cerebral Cortex Development==
[[File:Stages of development.png|thumb|right|text-top||520px|Main stages of cortical development where abnormalities may arise <ref name="imaging"/> ]]
 

The embryologic development of the cerebral cortex involves highly organised and complex events (as has been seen in the section 'Development of the cerebral cortex'). 

These events are generally divided by scientists into 3 major stages in cortical formation where crucial changes occur in neuronal cells; these stages include: 
1. Proliferation (or Growth), 
2. Migration, 
3. Organisation (or Maturation or Differentiation). 
 

Disruptions in these stages of cortical development, are the precedent that give rise to malformations or irregularities in the cerebral cortex (Fig. ). This section will explore some abnormalities that are commonly discussed in scientific literature.
 
 

===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder of uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers and very large cells called 'balloon' cells. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. 
[[File:Hemimegalencephaly.png|thumb|left|upright=1.42|Hemimegalencephaly <ref name="imaging"/> ]]
 
 
<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of a 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form a tumour-like, benign malformation) on part or all of the cerebral hemisphere.

Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. Clinical symptoms of this disease may include developmental delay, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.
[[File:Symptoms of microcephaly.png|thumb|right|upright=1.45|Microcephaly <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]]
 
 
 
 
 
<big><big>'''3) Microcephaly Vera'''</big></big>

Microcephaly Vera is relatively common cortical congenital disorder. Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs. 

'''Microcephaly Vera or Primary Microcephaly''' results only due to abnormal cortical development, specifically cell division or proliferation. It is a congenital malformation in which the circumference of the head is quite less than normal and is accompanied by mental retardation and sometimes epilepsy. 

References used to write: <ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>
<ref>Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
<ref>Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref>
<ref>Christopher A, C. (2017). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 
 
<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is thus called due to lesions seen that resembled potato tubers; and is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms) in the cortex. 

" Beneath the cortex, the brain in tuberous sclerosis also shows nodular collections of small cells along the surface of the lateral ventricle that resemble ventricular cells and are called subependymal nodules...or, more descriptively, “candle drippings.” These nodules often contain numerous balloon cells and can in some cases become transformed into glial tumors referred to as subependymal giant cell astrocytomas..."

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:SBH.png|thumb|upright=2.0|right| Heterotopia <ref name="imaging"/> ]]
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex. 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 
 

<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. 
Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 
Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. Type II Lissencephaly also includes: #Muscle-Eye-Brain Disease #Walker-Warburg Syndrome #Fukuyama Syndrome 
*'''Microlissencephaly''' 
Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly, and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span.
 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Kallman Syndrome is associated with hypoplasia of the olfactory bulbs and olfactory cortex, called arhinencephaly, and lack of the sense of smell. [not yet changed into own words]

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

[[File:SchizencephalicBrain.jpg|thumb|left|upright=1.3| Schizencephaly <ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]
 

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder characterised by a cleft(s) or lesion(s) on the brain surface, which is filled with CSF and lined by gray matter.
Schizencephaly can be bilateral or unilateral.

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly.

Schizencephaly commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
 
 
 
 
 
===Other Disorders===
<big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right| Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD) <ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome.
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

<html5media height="350" width="550">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref>
 

<ref> dimedcom (2013).Corpus callosum agenesis. [video] Available at: https://www.youtube.com/watch?v=M7e9JXGOWD4 [Accessed 6 Oct. 2017].</ref>

==Models and Research==
===Animal Models===
[[File:Corticogenesis of mouse and humans.jpeg|thumb|right|text-top|590px|'''Mouse vs Human Neurogenesis''']]

====Mice Model====
Mice have often been used to study corticogenesis in mammals. Corticogenesis lasts from E11 to E19 in mice and lasts eight days, which is far shorter than human corticogenesis. While there are many similarities between human corticogenesis, the rodent brain is much smaller than that of a human’s and therefore, there are different types of progenitor cells involved in mice and the cortex does not expand as greatly. <ref name="control">Dehay, C. and Kennedy, H. (2007). Cell-cycle control and cortical development. Nature Reviews Neuroscience, 8(6),438-450.</ref>Humans have greater numbers of intermediate precursor cells (to aid in further differentiation) and outer radial glial cells compared those of mice. <ref name="cerebral"/> In addition, the SVZ does not split into the inner and outer subventricular zone, but stays intact as one. <ref name="control"/> The importance of reelin has also been greatly studied in mice. Studies showed that mutant mice have disruptions in the migration of neurons into their subsequent layers. By injecting thymidine at various time points of gestation into the female mice, researchers were able to track the development of various populations of neurons. Later developing neurons were unable to ascend past the already early formed neurons due to disruptions in reelin signaling (in the marginal zone). Instead, superficial layer neurons resided below the older, deep layer neurons. This inverted lamination comprises sensory and motor function.<ref> Caviness, V. (1982). Neocortical histogenesis in normal and reeler mice: A developmental study based upon [3H]thymidine autoradiography. Developmental Brain Research, 4(3), 293-302.</ref>
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Timeline and protocol of cerebral organoid development'''<ref><pubmed>25188634</pubmed></ref>]]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

==Glossary==

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
|'''Sulcus'''|| Sulci (plural) are grooves in the cerebral cortex.
|-
|'''Gyrus '''|| Gyri (plural) are folds/ridges in the cerebral cortex.
|-
|'''Fissures'''|| Large sulci.
|-
|'''Corticogenesis'''|| The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes.
|-
|'''Cajal-Retzius (CR) cells'''|| Cortical neurons that develop early on, at the same time as the preplate, and express an important glycoprotein known as reelin, which helps with the proper migration of neurons into their respective layers.
|-
|'''GABAergic Neurons'''|| Generate gamma aminobutyric acid (GABA) as their output, one of the two inhibitory neurotransmitters in the central nervous system (CNS).
|-
|'''Radial glial cells '''|| A class of distinct nonneuronal cells that are bipolar shaped and span the entire width of the cortex during development.
|-
|'''Ventricular zone (VZ)'''|| First formed single-celled layer in the cortex, arising from progenitors in the dorsal telencephalon that divide symmetrically. It lies adjacent to the ventricular surface.
|-
|'''Preplate'''|| First "pioneer neurons" from dividing cells in the ventricular zone for this layer above the ventricular zone
|-
|'''Subventricular zone (SVZ)'''|| Cells in the VZ continue to divide symmetrically and give rise to another zone above the VZ known as the SVZ. This zone later splits into an inner (ISVZ) and outer ventricular zone (OSVZ)
|-
|'''Marginal Zone (MZ)'''|| A subsection of the preplate that forms around E50-55. It lies at the uppermost area of the cortex nearest the pial surface.
|-
|'''Subplate'''|| A subsection of the preplate that forms around E50-55.
|-
|'''Cortical Plate'''|| Forms in between the marginal zone and subplate and gives rise to the 6 layers of the cortex involved in sensory and motor function.
|-
|'''Intermediate zone'''|| Forms below the subplate between E50-55 and contains only migrating cells and no intermediate precursor cells.

|}

==References==

2017 Group Project 1

2017-10-25T11:34:52Z

Z5177691: /* Animal Models */

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Intro section cortex.jpg|thumb|right|350px| Fig.1. Cerebral cortex is the outermost layer of the cerebrum <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex surrounds the cerebrum, and is the largest part of the human brain. It is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres; it is around 2-4 mm in thickness, consists of the layer of grey matter and has ~ 10 billion nerve cell bodies and dendrites. 
[[File:Brain sectin showing cortex.jpg|thumb|left|300px| Fig 2. Section of the human brain <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]] 

The development of the cerebral cortex involves 3 main stages: proliferation/growth/differentiation, migration of neurons, and maturation/organisation/folding. The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. external pyramidal, IV. internal granular layer, V. internal pyramidal layer, VI. multiform layer. These individual layers organise the capacity for interconnections between both input and output signals. 
 
 
 
 
 
 

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref> 
 
[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|Figure 10: Anatomy of the human cerebral cortex <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]] 

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull (see figure 10). The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri, as shown in figure 10. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri (see figure 10). Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>
 
'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}
 
==Functions of the Cerebral Cortex==
 
[[File:Cortical areas.png|thumb|right|text-top|450px|Figure 11: Cortical areas human cortex <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]
[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|Figure 12: Cortical Homonculus <ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]
The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas, as shown in Figure 11. <ref name="overall function"><pubmed>21653723</pubmed></ref>

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body (see figure 12). The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>
 
==Early Development of the Brain==

 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
[[File:Brain Development 2.png|400px|right|A longitudinal perspective of the neural tube, showing the primary brain vesicles divided into the five secondary subdivisions.|]]
*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five, as depicted in the image on the right. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.

'''Brain Flexures'''
[[File:Brain Development.png|400px|right|Lateral perspective of the neural tube, showing the three flexures, and five secondary subdivisions.|]]
During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures, as seen in the image to the right in proximity to the five secondary vesicles. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

[[File:Neural- cortex Cajal drawing 01.jpg |thumb|right|200px|Laminar and columnar organization of the cerebral cortex (Historical drawing by Cajal)]]
 
==Later Development: Development of the Cerebral Cortex==
 
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes. The diversity in neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned in above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contributes to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|400px|super|Key developmental zones in the human cortex]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone
**Subplate
*Cortical Plate: establishment of the 6 cortical layers form in this region between the subplate and the marginal zone

===Timeline of Corticogenesis===
 
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (e.g fate) of the neurons so that specific connections and cortical structure are achieved. "E" relates to embryonic day in relation to corticogenesis.
 

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along in order to expand the neocortex. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area as well as the preplate and many of the cells in the SVZ contribute to the later cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to the target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layers 6 is populated before layer 5; layer 5 is populated before layer 4 and so on <ref name="boulder"/>. Each layer condenses and the neurons are closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex such as sensory and motor function.
[[File:Corticogenesis.png|center| 700px|super|Corticogenesis from E30 to adult human brain]]

===Signalling involved in Cerebral Cortex Development===
 
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 1: Shh signalling increases the number of proliferating cells''']]
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.

[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 2: Cortex development in wild-type and ''reeler'' mice''' <ref>Gilmore, E. and Herrup, K. (1997). Cortical development: Layers of complexity. Current Biology, 7(4), pp.R231-R234. http://www.sciencedirect.com/science/article/pii/S0960982206001084 </ref>]]

'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 1) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 2). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|500px|'''Figure 3: Cortical thickness in the absence of Bmp7'''<ref><pubmed>22461901</pubmed></ref>]]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers. Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.
 
==Abnormalities associated with Cerebral Cortex Development==
[[File:Stages of development.png|thumb|right|text-top||520px|Main stages of cortical development where abnormalities may arise <ref name="imaging"/> ]]
 

The embryologic development of the cerebral cortex involves highly organised and complex events (as has been seen in the section 'Development of the cerebral cortex'). 

These events are generally divided by scientists into 3 major stages in cortical formation where crucial changes occur in neuronal cells; these stages include: 
1. Proliferation (or Growth), 
2. Migration, 
3. Organisation (or Maturation or Differentiation). 
 

Disruptions in these stages of cortical development, are the precedent that give rise to malformations or irregularities in the cerebral cortex (Fig. ). This section will explore some abnormalities that are commonly discussed in scientific literature.
 
 

===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder of uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers and very large cells called 'balloon' cells. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. 
[[File:Hemimegalencephaly.png|thumb|left|upright=1.42|Hemimegalencephaly <ref name="imaging"/> ]]
 
 
<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of a 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form a tumour-like, benign malformation) on part or all of the cerebral hemisphere.

Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. Clinical symptoms of this disease may include developmental delay, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.
[[File:Symptoms of microcephaly.png|thumb|right|upright=1.45|Microcephaly <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]]
 
 
 
 
 
<big><big>'''3) Microcephaly Vera'''</big></big>

Microcephaly Vera is relatively common cortical congenital disorder. Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs. 

'''Microcephaly Vera or Primary Microcephaly''' results only due to abnormal cortical development, specifically cell division or proliferation. It is a congenital malformation in which the circumference of the head is quite less than normal and is accompanied by mental retardation and sometimes epilepsy. 

References used to write: <ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>
<ref>Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
<ref>Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref>
<ref>Christopher A, C. (2017). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 
 
<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is thus called due to lesions seen that resembled potato tubers; and is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms) in the cortex. 

" Beneath the cortex, the brain in tuberous sclerosis also shows nodular collections of small cells along the surface of the lateral ventricle that resemble ventricular cells and are called subependymal nodules...or, more descriptively, “candle drippings.” These nodules often contain numerous balloon cells and can in some cases become transformed into glial tumors referred to as subependymal giant cell astrocytomas..."

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:SBH.png|thumb|upright=2.0|right| Heterotopia <ref name="imaging"/> ]]
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex. 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 
 

<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. 
Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 
Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. Type II Lissencephaly also includes: #Muscle-Eye-Brain Disease #Walker-Warburg Syndrome #Fukuyama Syndrome 
*'''Microlissencephaly''' 
Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly, and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span.
 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Kallman Syndrome is associated with hypoplasia of the olfactory bulbs and olfactory cortex, called arhinencephaly, and lack of the sense of smell. [not yet changed into own words]

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

[[File:SchizencephalicBrain.jpg|thumb|left|upright=1.3| Schizencephaly <ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]
 

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder characterised by a cleft(s) or lesion(s) on the brain surface, which is filled with CSF and lined by gray matter.
Schizencephaly can be bilateral or unilateral.

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly.

Schizencephaly commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
 
 
 
 
 
===Other Disorders===
<big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right| Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD) <ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome.
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

<html5media height="350" width="550">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref>
 

<ref> dimedcom (2013).Corpus callosum agenesis. [video] Available at: https://www.youtube.com/watch?v=M7e9JXGOWD4 [Accessed 6 Oct. 2017].</ref>

==Models and Research==
===Animal Models===
[[File:Corticogenesis of mouse and humans.jpeg|thumb|right|text-top|590px|'''Mouse vs Human Neurogenesis''']]

==Mice Model==
Mice have often been used to study corticogenesis in mammals. Corticogenesis lasts from E11 to E19 in mice and lasts eight days, which is far shorter than human corticogenesis. While there are many similarities between human corticogenesis, the rodent brain is much smaller than that of a human’s and therefore, there are different types of progenitor cells involved in mice and the cortex does not expand as greatly. <ref name="control">Dehay, C. and Kennedy, H. (2007). Cell-cycle control and cortical development. Nature Reviews Neuroscience, 8(6),438-450.</ref>Humans have greater numbers of intermediate precursor cells (to aid in further differentiation) and outer radial glial cells compared those of mice. <ref name="cerebral"/> In addition, the SVZ does not split into the inner and outer subventricular zone, but stays intact as one. <ref name="control"/> The importance of reelin has also been greatly studied in mice. Studies showed that mutant mice have disruptions in the migration of neurons into their subsequent layers. By injecting thymidine at various time points of gestation into the female mice, researchers were able to track the development of various populations of neurons. Later developing neurons were unable to ascend past the already early formed neurons due to disruptions in reelin signaling (in the marginal zone). Instead, superficial layer neurons resided below the older, deep layer neurons. This inverted lamination comprises sensory and motor function.<ref> Caviness, V. (1982). Neocortical histogenesis in normal and reeler mice: A developmental study based upon [3H]thymidine autoradiography. Developmental Brain Research, 4(3), 293-302.</ref>
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Timeline and protocol of cerebral organoid development'''<ref><pubmed>25188634</pubmed></ref>]]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

==Glossary==

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
|'''Sulcus'''|| Sulci (plural) are grooves in the cerebral cortex.
|-
|'''Gyrus '''|| Gyri (plural) are folds/ridges in the cerebral cortex.
|-
|'''Fissures'''|| Large sulci.
|-
|'''Corticogenesis'''|| The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes.
|-
|'''Cajal-Retzius (CR) cells'''|| Cortical neurons that develop early on, at the same time as the preplate, and express an important glycoprotein known as reelin, which helps with the proper migration of neurons into their respective layers.
|-
|'''GABAergic Neurons'''|| Generate gamma aminobutyric acid (GABA) as their output, one of the two inhibitory neurotransmitters in the central nervous system (CNS).
|-
|'''Radial glial cells '''|| A class of distinct nonneuronal cells that are bipolar shaped and span the entire width of the cortex during development.
|-
|'''Ventricular zone (VZ)'''|| First formed single-celled layer in the cortex, arising from progenitors in the dorsal telencephalon that divide symmetrically. It lies adjacent to the ventricular surface.
|-
|'''Preplate'''|| First "pioneer neurons" from dividing cells in the ventricular zone for this layer above the ventricular zone
|-
|'''Subventricular zone (SVZ)'''|| Cells in the VZ continue to divide symmetrically and give rise to another zone above the VZ known as the SVZ. This zone later splits into an inner (ISVZ) and outer ventricular zone (OSVZ)
|-
|'''Marginal Zone (MZ)'''|| A subsection of the preplate that forms around E50-55. It lies at the uppermost area of the cortex nearest the pial surface.
|-
|'''Subplate'''|| A subsection of the preplate that forms around E50-55.
|-
|'''Cortical Plate'''|| Forms in between the marginal zone and subplate and gives rise to the 6 layers of the cortex involved in sensory and motor function.
|-
|'''Intermediate zone'''|| Forms below the subplate between E50-55 and contains only migrating cells and no intermediate precursor cells.

|}

==References==

2017 Group Project 1

2017-10-25T11:13:34Z

Z5177691: /* Glossary */

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Intro section cortex.jpg|thumb|right|350px| Fig.1. Cerebral cortex is the outermost layer of the cerebrum <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex surrounds the cerebrum, and is the largest part of the human brain. It is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres; it is around 2-4 mm in thickness, consists of the layer of grey matter and has ~ 10 billion nerve cell bodies and dendrites. 
[[File:Brain sectin showing cortex.jpg|thumb|left|300px| Fig 2. Section of the human brain <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]] 

The development of the cerebral cortex involves 3 main stages: proliferation/growth/differentiation, migration of neurons, and maturation/organisation/folding. The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. external pyramidal, IV. internal granular layer, V. internal pyramidal layer, VI. multiform layer. These individual layers organise the capacity for interconnections between both input and output signals. 
 
 
 
 
 
 

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref> 
[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|Figure 10: Anatomy of the human cerebral cortex <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]]

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull (see figure 10). The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri, as shown in figure 10. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri (see figure 10). Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>
 
'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}

==Functions of the Cerebral Cortex==
 
[[File:Cortical areas.png|thumb|right|text-top|450px|Figure 11: Cortical areas human cortex <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]
[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|Figure 12: Cortical Homonculus <ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]
The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas, as shown in Figure 11. <ref name="overall function"><pubmed>21653723</pubmed></ref>

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body (see figure 12). The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>

==Early Development of the Brain==

 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
[[File:Brain Development 2.png|400px|right|A longitudinal perspective of the neural tube, showing the primary brain vesicles divided into the five secondary subdivisions.|]]
*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five, as depicted in the image on the right. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.

'''Brain Flexures'''
[[File:Brain Development.png|400px|right|Lateral perspective of the neural tube, showing the three flexures, and five secondary subdivisions.|]]
During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures, as seen in the image to the right in proximity to the five secondary vesicles. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

[[File:Neural- cortex Cajal drawing 01.jpg |thumb|right|200px|Laminar and columnar organization of the cerebral cortex (Historical drawing by Cajal)]]

==Later Development: Development of the Cerebral Cortex==
 
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes. The diversity in neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned in above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contributes to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|400px|super|Key developmental zones in the human cortex]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone
**Subplate
*Cortical Plate: establishment of the 6 cortical layers form in this region between the subplate and the marginal zone

===Timeline of Corticogenesis===
 
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (e.g fate) of the neurons so that specific connections and cortical structure are achieved. "E" relates to embryonic day in relation to corticogenesis.
 

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along in order to expand the neocortex. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area as well as the preplate and many of the cells in the SVZ contribute to the later cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to the target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layers 6 is populated before layer 5; layer 5 is populated before layer 4 and so on <ref name="boulder"/>. Each layer condenses and the neurons are closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex such as sensory and motor function.
[[File:Corticogenesis.png|center| 700px|super|Corticogenesis from E30 to adult human brain]]

===Signalling involved in Cerebral Cortex Development===
 
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 1: Shh signalling increases the number of proliferating cells''']]
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.

[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 2: Cortex development in wild-type and ''reeler'' mice''' <ref>Gilmore, E. and Herrup, K. (1997). Cortical development: Layers of complexity. Current Biology, 7(4), pp.R231-R234. http://www.sciencedirect.com/science/article/pii/S0960982206001084 </ref>]]

'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 1) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 2). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|500px|'''Figure 3: Cortical thickness in the absence of Bmp7'''<ref><pubmed>22461901</pubmed></ref>]]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers. Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.
 
==Abnormalities associated with Cerebral Cortex Development==
[[File:Stages of development.png|thumb|right|text-top||520px|Main stages of cortical development where abnormalities may arise <ref name="imaging"/> ]]
 

The embryologic development of the cerebral cortex involves highly organised and complex events (as has been seen in the section 'Development of the cerebral cortex'). 

These events are generally divided by scientists into 3 major stages in cortical formation where crucial changes occur in neuronal cells; these stages include: 
1. Proliferation (or Growth), 
2. Migration, 
3. Organisation (or Maturation or Differentiation). 
 

Disruptions in these stages of cortical development, are the precedent that give rise to malformations or irregularities in the cerebral cortex (Fig. ). This section will explore some abnormalities that are commonly discussed in scientific literature.
 
 
 
 
===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder of uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers and very large cells called 'balloon' cells. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. 
[[File:Hemimegalencephaly.png|thumb|left|upright=1.3|Hemimegalencephaly <ref name="imaging"/> ]]

 
 

<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of a 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form a tumour-like, benign malformation) on part or all of the cerebral hemisphere.

Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. Clinical symptoms of this disease may include developmental delay, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.
[[File:Symptoms of microcephaly.png|thumb|right|upright=1.45|Microcephaly <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]]
 
 
 
<big><big>'''3) Microcephaly Vera'''</big></big>

Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs. 

'''Primary Microcephaly or Microcephaly Vera''' results only due to abnormal cortical development, specifically cell division or proliferation. It is a congenital malformation in which the circumference of the head is quite less than normal and is accompanied by mental retardation and sometimes epilepsy. 

References used to write: <ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>
<ref>Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
<ref>Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref>
<ref>Christopher A, C. (2017). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 
 
<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is thus called due to lesions seen that resembled potato tubers; and is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms) in the cortex. 

" Beneath the cortex, the brain in tuberous sclerosis also shows nodular collections of small cells along the surface of the lateral ventricle that resemble ventricular cells and are called subependymal nodules...or, more descriptively, “candle drippings.” These nodules often contain numerous balloon cells and can in some cases become transformed into glial tumors referred to as subependymal giant cell astrocytomas..."

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:SBH.png|thumb|upright=2.0|right| Heterotopia <ref name="imaging"/> ]]
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex. 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 
 

<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. 
Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 

Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. 
Type II Lissencephaly also includes: 

#Muscle-Eye-Brain Disease 
#Walker-Warburg Syndrome 
#Fukuyama Syndrome 
*'''Microlissencephaly'''

Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly, and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span.
 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Kallman Syndrome is associated with hypoplasia of the olfactory bulbs and olfactory cortex, called arhinencephaly, and lack of the sense of smell. [not yet changed into own words]

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

[[File:SchizencephalicBrain.jpg|thumb|left|upright=1.6| Schizencephaly <ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder characterised by a cleft(s) or lesion(s) on the brain surface, which is filled with CSF and lined by gray matter.
Schizencephaly can be bilateral or unilateral.

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly.

Schizencephaly commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
 
 
 
 
 
 
 
 
 
 
===Other Disorders===
<big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right| Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD) <ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome.
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

<html5media height="380" width="580">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref>
 

<ref> dimedcom (2013).Corpus callosum agenesis. [video] Available at: https://www.youtube.com/watch?v=M7e9JXGOWD4 [Accessed 6 Oct. 2017].</ref>

[[File:Corticogenesis of mouse and humans.jpeg|thumb|right|text-top|590px|'''Mouse vs Human Neurogenesis''']]

==Models and Research==
===Animal Models===

https://bmcneurosci.biomedcentral.com/articles/10.1186/1471-2202-11-75 (reelin in pig model)

Mice have often been used to study corticogenesis in mammals. Corticogenesis lasts from E11 to E19 in mice and lasts eight days, which is far shorter than human corticogenesis. While there are many similarities between human corticogenesis, the rodent brain is much smaller than that of a human’s and therefore, there are different types of progenitor cells involved in mice and the cortex does not expand as greatly. <ref name="control">Dehay, C. and Kennedy, H. (2007). Cell-cycle control and cortical development. Nature Reviews Neuroscience, 8(6),438-450.</ref>Humans have greater numbers of intermediate precursor cells (to aid in further differentiation) and outer radial glial cells compared those of mice. <ref name="cerebral"/> In addition, the SVZ does not split into the inner and outer subventricular zone, but stays intact as one. <ref name="control"/> The importance of reelin has also been greatly studied in mice. Studies showed that mutant mice have disruptions in the migration of neurons into their subsequent layers. By injecting thymidine at various time points of gestation into the female mice, researchers were able to track the development of various populations of neurons. Later developing neurons were unable to ascend past the already early formed neurons due to disruptions in reelin signaling (in the marginal zone). Instead, superficial layer neurons resided below the older, deep layer neurons. This inverted lamination comprises sensory and motor function.<ref> Caviness, V. (1982). Neocortical histogenesis in normal and reeler mice: A developmental study based upon [3H]thymidine autoradiography. Developmental Brain Research, 4(3), 293-302.</ref>
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Timeline and protocol of cerebral organoid development'''<ref><pubmed>25188634</pubmed></ref>]]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

==Glossary==

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
|'''Sulcus'''|| Sulci (plural) are grooves in the cerebral cortex.
|-
|'''Gyrus '''|| Gyri (plural) are folds/ridges in the cerebral cortex.
|-
|'''Fissures'''|| Large sulci.
|-
|'''Corticogenesis'''|| The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes.
|-
|'''Cajal-Retzius (CR) cells'''|| Cortical neurons that develop early on, at the same time as the preplate, and express an important glycoprotein known as reelin, which helps with the proper migration of neurons into their respective layers.
|-
|'''GABAergic Neurons'''|| Generate gamma aminobutyric acid (GABA) as their output, one of the two inhibitory neurotransmitters in the central nervous system (CNS).
|-
|'''Radial glial cells '''|| A class of distinct nonneuronal cells that are bipolar shaped and span the entire width of the cortex during development.
|-
|'''Ventricular zone (VZ)'''|| First formed single-celled layer in the cortex, arising from progenitors in the dorsal telencephalon that divide symmetrically. It lies adjacent to the ventricular surface.
|-
|'''Preplate'''|| First "pioneer neurons" from dividing cells in the ventricular zone for this layer above the ventricular zone
|-
|'''Subventricular zone (SVZ)'''|| Cells in the VZ continue to divide symmetrically and give rise to another zone above the VZ known as the SVZ. This zone later splits into an inner (ISVZ) and outer ventricular zone (OSVZ)
|-
|'''Marginal Zone (MZ)'''|| A subsection of the preplate that forms around E50-55. It lies at the uppermost area of the cortex nearest the pial surface.
|-
|'''Subplate'''|| A subsection of the preplate that forms around E50-55.
|-
|'''Cortical Plate'''|| Forms in between the marginal zone and subplate and gives rise to the 6 layers of the cortex involved in sensory and motor function.
|-
|'''Intermediate zone'''|| Forms below the subplate between E50-55 and contains only migrating cells and no intermediate precursor cells.

|}

==INFO/ Research Links (temporary heading)==
 

https://www.youtube.com/watch?v=n6zQbTT0yoY 
https://www.youtube.com/watch?v=X-m0JDCw6TE 

https://www.youtube.com/watch?v=luXDQrmMoUU 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ 
http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue 

https://academic.oup.com/jnen/article/61/1/1/2916251 
https://pdfs.semanticscholar.org/67ea/2ce13f57f4ddbfb7033b6bb1328a5dff7742.pdf 
https://www.youtube.com/watch?v=l_nTggR7LTE 

For concept:
https://www.youtube.com/watch?v=dNngOlsLuGI

You might find this helpful (although you need to request copyright permission):

"Difference Between Cerebrum and Cerebral Cortex." DifferenceBetween.Com. August 7, 2012. < http://www.differencebetween.com/difference-between-cerebrum-and-vs-cerebral-cortex/ >

PubMed Searches: [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebral+Cortex+Development ''Cerebral Cortex Development''] | [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebrum+Development ''Cerebrum Development'']

BMC Dev Biol Search: [http://www.biomedcentral.com/bmcdevbiol/search/results?terms=Cerebral+Cortex+Development ''Cerebral Cortex Development'']

Recent papers

<pubmed limit=5>Cerebral+Cortex+Development</pubmed>

==References==

2017 Group Project 1

2017-10-25T11:08:59Z

Z5177691: /* Glossary */

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Intro section cortex.jpg|thumb|right|350px| Fig.1. Cerebral cortex is the outermost layer of the cerebrum <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex surrounds the cerebrum, and is the largest part of the human brain. It is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres; it is around 2-4 mm in thickness, consists of the layer of grey matter and has ~ 10 billion nerve cell bodies and dendrites. 
[[File:Brain sectin showing cortex.jpg|thumb|left|300px| Fig 2. Section of the human brain <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]] 

The development of the cerebral cortex involves 3 main stages: proliferation/growth/differentiation, migration of neurons, and maturation/organisation/folding. The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. external pyramidal, IV. internal granular layer, V. internal pyramidal layer, VI. multiform layer. These individual layers organise the capacity for interconnections between both input and output signals. 
 
 
 
 
 
 

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref> 
[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|Figure 10: Anatomy of the human cerebral cortex <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]]

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull (see figure 10). The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri, as shown in figure 10. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri (see figure 10). Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>
 
'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}

==Functions of the Cerebral Cortex==
 
[[File:Cortical areas.png|thumb|right|text-top|450px|Figure 11: Cortical areas human cortex <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]
[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|Figure 12: Cortical Homonculus <ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]
The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas, as shown in Figure 11. <ref name="overall function"><pubmed>21653723</pubmed></ref>

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body (see figure 12). The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>

==Early Development of the Brain==

 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
[[File:Brain Development 2.png|400px|right|A longitudinal perspective of the neural tube, showing the primary brain vesicles divided into the five secondary subdivisions.|]]
*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five, as depicted in the image on the right. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.

'''Brain Flexures'''
[[File:Brain Development.png|400px|right|Lateral perspective of the neural tube, showing the three flexures, and five secondary subdivisions.|]]
During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures, as seen in the image to the right in proximity to the five secondary vesicles. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

[[File:Neural- cortex Cajal drawing 01.jpg |thumb|right|200px|Laminar and columnar organization of the cerebral cortex (Historical drawing by Cajal)]]

==Later Development: Development of the Cerebral Cortex==
 
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes. The diversity in neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned in above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contributes to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|400px|super|Key developmental zones in the human cortex]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone
**Subplate
*Cortical Plate: establishment of the 6 cortical layers form in this region between the subplate and the marginal zone

===Timeline of Corticogenesis===
 
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (e.g fate) of the neurons so that specific connections and cortical structure are achieved. "E" relates to embryonic day in relation to corticogenesis.
 

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along in order to expand the neocortex. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area as well as the preplate and many of the cells in the SVZ contribute to the later cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to the target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layers 6 is populated before layer 5; layer 5 is populated before layer 4 and so on <ref name="boulder"/>. Each layer condenses and the neurons are closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex such as sensory and motor function.
[[File:Corticogenesis.png|center| 700px|super|Corticogenesis from E30 to adult human brain]]

===Signalling involved in Cerebral Cortex Development===
 
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 1: Shh signalling increases the number of proliferating cells''']]
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.

[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 2: Cortex development in wild-type and ''reeler'' mice''' <ref>Gilmore, E. and Herrup, K. (1997). Cortical development: Layers of complexity. Current Biology, 7(4), pp.R231-R234. http://www.sciencedirect.com/science/article/pii/S0960982206001084 </ref>]]

'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 1) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 2). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|500px|'''Figure 3: Cortical thickness in the absence of Bmp7'''<ref><pubmed>22461901</pubmed></ref>]]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers. Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.
 
==Abnormalities associated with Cerebral Cortex Development==
[[File:Stages of development.png|thumb|right|text-top||520px|Main stages of cortical development where abnormalities may arise <ref name="imaging"/> ]]
 

The embryologic development of the cerebral cortex involves highly organised and complex events (as has been seen in the section 'Development of the cerebral cortex'). 

These events are generally divided by scientists into 3 major stages in cortical formation where crucial changes occur in neuronal cells; these stages include: 
1. Proliferation (or Growth), 
2. Migration, 
3. Organisation (or Maturation or Differentiation). 
 

Disruptions in these stages of cortical development, are the precedent that give rise to malformations or irregularities in the cerebral cortex (Fig. ). This section will explore some abnormalities that are commonly discussed in scientific literature.
 
 
 
 
===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder of uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers and very large cells called 'balloon' cells. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. 
[[File:Hemimegalencephaly.png|thumb|left|upright=1.3|Hemimegalencephaly <ref name="imaging"/> ]]

 
 

<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of a 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form a tumour-like, benign malformation) on part or all of the cerebral hemisphere.

Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. Clinical symptoms of this disease may include developmental delay, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.
[[File:Symptoms of microcephaly.png|thumb|right|upright=1.45|Microcephaly <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]]
 
 
 
<big><big>'''3) Microcephaly Vera'''</big></big>

Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs. 

'''Primary Microcephaly or Microcephaly Vera''' results only due to abnormal cortical development, specifically cell division or proliferation. It is a congenital malformation in which the circumference of the head is quite less than normal and is accompanied by mental retardation and sometimes epilepsy. 

References used to write: <ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>
<ref>Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
<ref>Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref>
<ref>Christopher A, C. (2017). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 
 
<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is thus called due to lesions seen that resembled potato tubers; and is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms) in the cortex. 

" Beneath the cortex, the brain in tuberous sclerosis also shows nodular collections of small cells along the surface of the lateral ventricle that resemble ventricular cells and are called subependymal nodules...or, more descriptively, “candle drippings.” These nodules often contain numerous balloon cells and can in some cases become transformed into glial tumors referred to as subependymal giant cell astrocytomas..."

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:SBH.png|thumb|upright=2.0|right| Heterotopia <ref name="imaging"/> ]]
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex. 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 
 

<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. 
Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 

Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. 
Type II Lissencephaly also includes: 

#Muscle-Eye-Brain Disease 
#Walker-Warburg Syndrome 
#Fukuyama Syndrome 
*'''Microlissencephaly'''

Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly, and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span.
 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Kallman Syndrome is associated with hypoplasia of the olfactory bulbs and olfactory cortex, called arhinencephaly, and lack of the sense of smell. [not yet changed into own words]

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

[[File:SchizencephalicBrain.jpg|thumb|left|upright=1.6| Schizencephaly <ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder characterised by a cleft(s) or lesion(s) on the brain surface, which is filled with CSF and lined by gray matter.
Schizencephaly can be bilateral or unilateral.

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly.

Schizencephaly commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
 
 
 
 
 
 
 
 
 
 
===Other Disorders===
<big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right| Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD) <ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome.
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

<html5media height="380" width="580">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref>
 

<ref> dimedcom (2013).Corpus callosum agenesis. [video] Available at: https://www.youtube.com/watch?v=M7e9JXGOWD4 [Accessed 6 Oct. 2017].</ref>

[[File:Corticogenesis of mouse and humans.jpeg|thumb|right|text-top|590px|'''Mouse vs Human Neurogenesis''']]

==Models and Research==
===Animal Models===

https://bmcneurosci.biomedcentral.com/articles/10.1186/1471-2202-11-75 (reelin in pig model)

Mice have often been used to study corticogenesis in mammals. Corticogenesis lasts from E11 to E19 in mice and lasts eight days, which is far shorter than human corticogenesis. While there are many similarities between human corticogenesis, the rodent brain is much smaller than that of a human’s and therefore, there are different types of progenitor cells involved in mice and the cortex does not expand as greatly. <ref name="control">Dehay, C. and Kennedy, H. (2007). Cell-cycle control and cortical development. Nature Reviews Neuroscience, 8(6),438-450.</ref>Humans have greater numbers of intermediate precursor cells (to aid in further differentiation) and outer radial glial cells compared those of mice. <ref name="cerebral"/> In addition, the SVZ does not split into the inner and outer subventricular zone, but stays intact as one. <ref name="control"/> The importance of reelin has also been greatly studied in mice. Studies showed that mutant mice have disruptions in the migration of neurons into their subsequent layers. By injecting thymidine at various time points of gestation into the female mice, researchers were able to track the development of various populations of neurons. Later developing neurons were unable to ascend past the already early formed neurons due to disruptions in reelin signaling (in the marginal zone). Instead, superficial layer neurons resided below the older, deep layer neurons. This inverted lamination comprises sensory and motor function.<ref> Caviness, V. (1982). Neocortical histogenesis in normal and reeler mice: A developmental study based upon [3H]thymidine autoradiography. Developmental Brain Research, 4(3), 293-302.</ref>
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Timeline and protocol of cerebral organoid development'''<ref><pubmed>25188634</pubmed></ref>]]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

==Glossary==

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
|'''Sulcus'''|| Sulci (plural) are grooves in the cerebral cortex.
|-
|'''Gyrus '''|| Gyri (plural) are folds/ridges in the cerebral cortex.
|-
|'''Fissures'''|| Large sulci.
|-
|'''Corticogenesis'''|| The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes.
|-
|'''Cajal-Retzius (CR) cells'''|| Cortical neurons that develop early on, at the same time as the preplate, and express an important glycoprotein known as reelin, which helps with the proper migration of neurons into their respective layers.
|-
|'''GABAergic Neurons'''|| Generate gamma aminobutyric acid (GABA) as their output, one of the two inhibitory neurotransmitters in the central nervous system (CNS).
|-
|'''Radial glial cells '''|| A class of distinct nonneuronal cells that are bipolar shaped and span the entire width of the cortex during development.
|-
|'''Ventricular zone (VZ)'''|| First formed single-celled layer in the cortex, arising from progenitors in the dorsal telencephalon that divide symmetrically. It lies adjacent to the ventricular surface.
|-
|'''Preplate'''|| First "pioneer neurons" from dividing cells in the ventricular zone for this layer above the ventricular zone
|-
|'''Subventricular zone (SVZ)'''|| Cells in the VZ continue to divide symmetrically and give rise to another zone above the VZ known as the SVZ. This zone later splits into an inner (ISVZ) and outer ventricular zone (OSVZ)
|-
|'''Marginal Zone (MZ)'''|| A subsection of the preplate that forms around E50-55. It lies at the uppermost area of the cortex nearest the pial surface.
|-
|'''Subplate'''|| A subsection of the preplate that forms around E50-55.
|-
|'''Cortical Plate'''|| Forms in between the marginal zone and subplate and gives rise to the 6 layers of the cortex involved in sensory and motor function.
|-
|'''

|}

==INFO/ Research Links (temporary heading)==
 

https://www.youtube.com/watch?v=n6zQbTT0yoY 
https://www.youtube.com/watch?v=X-m0JDCw6TE 

https://www.youtube.com/watch?v=luXDQrmMoUU 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ 
http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue 

https://academic.oup.com/jnen/article/61/1/1/2916251 
https://pdfs.semanticscholar.org/67ea/2ce13f57f4ddbfb7033b6bb1328a5dff7742.pdf 
https://www.youtube.com/watch?v=l_nTggR7LTE 

For concept:
https://www.youtube.com/watch?v=dNngOlsLuGI

You might find this helpful (although you need to request copyright permission):

"Difference Between Cerebrum and Cerebral Cortex." DifferenceBetween.Com. August 7, 2012. < http://www.differencebetween.com/difference-between-cerebrum-and-vs-cerebral-cortex/ >

PubMed Searches: [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebral+Cortex+Development ''Cerebral Cortex Development''] | [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebrum+Development ''Cerebrum Development'']

BMC Dev Biol Search: [http://www.biomedcentral.com/bmcdevbiol/search/results?terms=Cerebral+Cortex+Development ''Cerebral Cortex Development'']

Recent papers

<pubmed limit=5>Cerebral+Cortex+Development</pubmed>

==References==

2017 Group Project 1

2017-10-25T11:01:24Z

Z5177691: /* Glossary */

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Intro section cortex.jpg|thumb|right|350px| Fig.1. Cerebral cortex is the outermost layer of the cerebrum <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex surrounds the cerebrum, and is the largest part of the human brain. It is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres; it is around 2-4 mm in thickness, consists of the layer of grey matter and has ~ 10 billion nerve cell bodies and dendrites. 
[[File:Brain sectin showing cortex.jpg|thumb|left|300px| Fig 2. Section of the human brain <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]] 

The development of the cerebral cortex involves 3 main stages: proliferation/growth/differentiation, migration of neurons, and maturation/organisation/folding. The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. external pyramidal, IV. internal granular layer, V. internal pyramidal layer, VI. multiform layer. These individual layers organise the capacity for interconnections between both input and output signals. 
 
 
 
 
 
 

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref> 
[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|Figure 10: Anatomy of the human cerebral cortex <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]]

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull (see figure 10). The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri, as shown in figure 10. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri (see figure 10). Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>
 
'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}

==Functions of the Cerebral Cortex==
 
[[File:Cortical areas.png|thumb|right|text-top|450px|Figure 11: Cortical areas human cortex <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]
[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|Figure 12: Cortical Homonculus <ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]
The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas, as shown in Figure 11. <ref name="overall function"><pubmed>21653723</pubmed></ref>

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body (see figure 12). The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>

==Early Development of the Brain==

 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
[[File:Brain Development 2.png|400px|right|A longitudinal perspective of the neural tube, showing the primary brain vesicles divided into the five secondary subdivisions.|]]
*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five, as depicted in the image on the right. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.

'''Brain Flexures'''
[[File:Brain Development.png|400px|right|Lateral perspective of the neural tube, showing the three flexures, and five secondary subdivisions.|]]
During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures, as seen in the image to the right in proximity to the five secondary vesicles. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

[[File:Neural- cortex Cajal drawing 01.jpg |thumb|right|200px|Laminar and columnar organization of the cerebral cortex (Historical drawing by Cajal)]]

==Later Development: Development of the Cerebral Cortex==
 
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes. The diversity in neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned in above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contributes to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|400px|super|Key developmental zones in the human cortex]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone
**Subplate
*Cortical Plate: establishment of the 6 cortical layers form in this region between the subplate and the marginal zone

===Timeline of Corticogenesis===
 
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (e.g fate) of the neurons so that specific connections and cortical structure are achieved. "E" relates to embryonic day in relation to corticogenesis.
 

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along in order to expand the neocortex. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area as well as the preplate and many of the cells in the SVZ contribute to the later cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to the target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layers 6 is populated before layer 5; layer 5 is populated before layer 4 and so on <ref name="boulder"/>. Each layer condenses and the neurons are closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex such as sensory and motor function.
[[File:Corticogenesis.png|center| 700px|super|Corticogenesis from E30 to adult human brain]]

===Signalling involved in Cerebral Cortex Development===
 
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 1: Shh signalling increases the number of proliferating cells''']]
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.

[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 2: Cortex development in wild-type and ''reeler'' mice''' <ref>Gilmore, E. and Herrup, K. (1997). Cortical development: Layers of complexity. Current Biology, 7(4), pp.R231-R234. http://www.sciencedirect.com/science/article/pii/S0960982206001084 </ref>]]

'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 1) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 2). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|500px|'''Figure 3: Cortical thickness in the absence of Bmp7'''<ref><pubmed>22461901</pubmed></ref>]]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers. Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.
 
==Abnormalities associated with Cerebral Cortex Development==
[[File:Stages of development.png|thumb|right|text-top||520px|Main stages of cortical development where abnormalities may arise <ref name="imaging"/> ]]
 

The embryologic development of the cerebral cortex involves highly organised and complex events (as has been seen in the section 'Development of the cerebral cortex'). 

These events are generally divided by scientists into 3 major stages in cortical formation where crucial changes occur in neuronal cells; these stages include: 
1. Proliferation (or Growth), 
2. Migration, 
3. Organisation (or Maturation or Differentiation). 
 

Disruptions in these stages of cortical development, are the precedent that give rise to malformations or irregularities in the cerebral cortex (Fig. ). This section will explore some abnormalities that are commonly discussed in scientific literature.
 
 
 
 
===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder of uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers and very large cells called 'balloon' cells. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. 
[[File:Hemimegalencephaly.png|thumb|left|upright=1.3|Hemimegalencephaly <ref name="imaging"/> ]]

 
 

<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of a 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form a tumour-like, benign malformation) on part or all of the cerebral hemisphere.

Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. Clinical symptoms of this disease may include developmental delay, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.
[[File:Symptoms of microcephaly.png|thumb|right|upright=1.45|Microcephaly <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]]
 
 
 
<big><big>'''3) Microcephaly Vera'''</big></big>

Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs. 

'''Primary Microcephaly or Microcephaly Vera''' results only due to abnormal cortical development, specifically cell division or proliferation. It is a congenital malformation in which the circumference of the head is quite less than normal and is accompanied by mental retardation and sometimes epilepsy. 

References used to write: <ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>
<ref>Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
<ref>Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref>
<ref>Christopher A, C. (2017). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 
 
<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is thus called due to lesions seen that resembled potato tubers; and is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms) in the cortex. 

" Beneath the cortex, the brain in tuberous sclerosis also shows nodular collections of small cells along the surface of the lateral ventricle that resemble ventricular cells and are called subependymal nodules...or, more descriptively, “candle drippings.” These nodules often contain numerous balloon cells and can in some cases become transformed into glial tumors referred to as subependymal giant cell astrocytomas..."

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:SBH.png|thumb|upright=2.0|right| Heterotopia <ref name="imaging"/> ]]
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex. 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 
 

<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. 
Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 

Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. 
Type II Lissencephaly also includes: 

#Muscle-Eye-Brain Disease 
#Walker-Warburg Syndrome 
#Fukuyama Syndrome 
*'''Microlissencephaly'''

Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly, and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span.
 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Kallman Syndrome is associated with hypoplasia of the olfactory bulbs and olfactory cortex, called arhinencephaly, and lack of the sense of smell. [not yet changed into own words]

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

[[File:SchizencephalicBrain.jpg|thumb|left|upright=1.6| Schizencephaly <ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder characterised by a cleft(s) or lesion(s) on the brain surface, which is filled with CSF and lined by gray matter.
Schizencephaly can be bilateral or unilateral.

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly.

Schizencephaly commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
 
 
 
 
 
 
 
 
 
 
===Other Disorders===
<big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right| Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD) <ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome.
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

<html5media height="380" width="580">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref>
 

<ref> dimedcom (2013).Corpus callosum agenesis. [video] Available at: https://www.youtube.com/watch?v=M7e9JXGOWD4 [Accessed 6 Oct. 2017].</ref>

[[File:Corticogenesis of mouse and humans.jpeg|thumb|right|text-top|590px|'''Mouse vs Human Neurogenesis''']]

==Models and Research==
===Animal Models===

https://bmcneurosci.biomedcentral.com/articles/10.1186/1471-2202-11-75 (reelin in pig model)

Mice have often been used to study corticogenesis in mammals. Corticogenesis lasts from E11 to E19 in mice and lasts eight days, which is far shorter than human corticogenesis. While there are many similarities between human corticogenesis, the rodent brain is much smaller than that of a human’s and therefore, there are different types of progenitor cells involved in mice and the cortex does not expand as greatly. <ref name="control">Dehay, C. and Kennedy, H. (2007). Cell-cycle control and cortical development. Nature Reviews Neuroscience, 8(6),438-450.</ref>Humans have greater numbers of intermediate precursor cells (to aid in further differentiation) and outer radial glial cells compared those of mice. <ref name="cerebral"/> In addition, the SVZ does not split into the inner and outer subventricular zone, but stays intact as one. <ref name="control"/> The importance of reelin has also been greatly studied in mice. Studies showed that mutant mice have disruptions in the migration of neurons into their subsequent layers. By injecting thymidine at various time points of gestation into the female mice, researchers were able to track the development of various populations of neurons. Later developing neurons were unable to ascend past the already early formed neurons due to disruptions in reelin signaling (in the marginal zone). Instead, superficial layer neurons resided below the older, deep layer neurons. This inverted lamination comprises sensory and motor function.<ref> Caviness, V. (1982). Neocortical histogenesis in normal and reeler mice: A developmental study based upon [3H]thymidine autoradiography. Developmental Brain Research, 4(3), 293-302.</ref>
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Timeline and protocol of cerebral organoid development'''<ref><pubmed>25188634</pubmed></ref>]]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

==Glossary==

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
|'''Sulcus'''|| Sulci (plural) are grooves in the cerebral cortex.
|-
|'''Gyrus '''|| Gyri (plural) are folds/ridges in the cerebral cortex.
|-
|'''Fissures'''|| Large sulci.
|-
|'''Corticogenesis'''|| The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes.
|-
|'''Cajal-Retzius (CR) cells'''|| Cortical neurons that develop early on, at the same time as the preplate, and express an important glycoprotein known as reelin, which helps with the proper migration of neurons into their respective layers.
|-
|'''GABAergic Neurons'''|| Generate gamma aminobutyric acid (GABA) as their output, one of the two inhibitory neurotransmitters in the central nervous system (CNS).
|-
|'''Radial glial cells '''|| A class of distinct nonneuronal cells that are bipolar shaped and span the entire width of the cortex during development.
|-
|'''Ventricular zone'''|| First formed single-celled layer in the cortex, arising from progenitors in the dorsal telencephalon that divide symmetrically. It lies adjacent to the ventricular surface.
|-
|''' '''||
|-
|''' '''||
|-
|''' '''||
|-

|}

==INFO/ Research Links (temporary heading)==
 

https://www.youtube.com/watch?v=n6zQbTT0yoY 
https://www.youtube.com/watch?v=X-m0JDCw6TE 

https://www.youtube.com/watch?v=luXDQrmMoUU 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ 
http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue 

https://academic.oup.com/jnen/article/61/1/1/2916251 
https://pdfs.semanticscholar.org/67ea/2ce13f57f4ddbfb7033b6bb1328a5dff7742.pdf 
https://www.youtube.com/watch?v=l_nTggR7LTE 

For concept:
https://www.youtube.com/watch?v=dNngOlsLuGI

You might find this helpful (although you need to request copyright permission):

"Difference Between Cerebrum and Cerebral Cortex." DifferenceBetween.Com. August 7, 2012. < http://www.differencebetween.com/difference-between-cerebrum-and-vs-cerebral-cortex/ >

PubMed Searches: [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebral+Cortex+Development ''Cerebral Cortex Development''] | [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebrum+Development ''Cerebrum Development'']

BMC Dev Biol Search: [http://www.biomedcentral.com/bmcdevbiol/search/results?terms=Cerebral+Cortex+Development ''Cerebral Cortex Development'']

Recent papers

<pubmed limit=5>Cerebral+Cortex+Development</pubmed>

==References==

2017 Group Project 1

2017-10-25T10:56:19Z

Z5177691: /* Animal Models */

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Intro section cortex.jpg|thumb|right|350px| Fig.1. Cerebral cortex is the outermost layer of the cerebrum <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex surrounds the cerebrum, and is the largest part of the human brain. It is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres; it is around 2-4 mm in thickness, consists of the layer of grey matter and has ~ 10 billion nerve cell bodies and dendrites. 
[[File:Brain sectin showing cortex.jpg|thumb|left|300px| Fig 2. Section of the human brain <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]] 

The development of the cerebral cortex involves 3 main stages: proliferation/growth/differentiation, migration of neurons, and maturation/organisation/folding. The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. external pyramidal, IV. internal granular layer, V. internal pyramidal layer, VI. multiform layer. These individual layers organise the capacity for interconnections between both input and output signals. 
 
 
 
 
 
 

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref> 
[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|Figure 10: Anatomy of the human cerebral cortex <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]]

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull (see figure 10). The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri, as shown in figure 10. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri (see figure 10). Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>
 
'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}

==Functions of the Cerebral Cortex==
 
[[File:Cortical areas.png|thumb|right|text-top|450px|Figure 11: Cortical areas human cortex <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]
[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|Figure 12: Cortical Homonculus <ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]
The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas, as shown in Figure 11. <ref name="overall function"><pubmed>21653723</pubmed></ref>

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body (see figure 12). The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>

==Early Development of the Brain==

 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
[[File:Brain Development 2.png|400px|right|A longitudinal perspective of the neural tube, showing the primary brain vesicles divided into the five secondary subdivisions.|]]
*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five, as depicted in the image on the right. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.

'''Brain Flexures'''
[[File:Brain Development.png|400px|right|Lateral perspective of the neural tube, showing the three flexures, and five secondary subdivisions.|]]
During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures, as seen in the image to the right in proximity to the five secondary vesicles. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

[[File:Neural- cortex Cajal drawing 01.jpg |thumb|right|200px|Laminar and columnar organization of the cerebral cortex (Historical drawing by Cajal)]]

==Later Development: Development of the Cerebral Cortex==
 
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes. The diversity in neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned in above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contributes to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|400px|super|Key developmental zones in the human cortex]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone
**Subplate
*Cortical Plate: establishment of the 6 cortical layers form in this region between the subplate and the marginal zone

===Timeline of Corticogenesis===
 
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (e.g fate) of the neurons so that specific connections and cortical structure are achieved. "E" relates to embryonic day in relation to corticogenesis.
 

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along in order to expand the neocortex. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area as well as the preplate and many of the cells in the SVZ contribute to the later cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to the target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layers 6 is populated before layer 5; layer 5 is populated before layer 4 and so on <ref name="boulder"/>. Each layer condenses and the neurons are closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex such as sensory and motor function.
[[File:Corticogenesis.png|center| 700px|super|Corticogenesis from E30 to adult human brain]]

===Signalling involved in Cerebral Cortex Development===
 
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 1: Shh signalling increases the number of proliferating cells''']]
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.

[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 2: Cortex development in wild-type and ''reeler'' mice''' <ref>Gilmore, E. and Herrup, K. (1997). Cortical development: Layers of complexity. Current Biology, 7(4), pp.R231-R234. http://www.sciencedirect.com/science/article/pii/S0960982206001084 </ref>]]

'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 1) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 2). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|500px|'''Figure 3: Cortical thickness in the absence of Bmp7'''<ref><pubmed>22461901</pubmed></ref>]]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers. Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.
 
==Abnormalities associated with Cerebral Cortex Development==
[[File:Stages of development.png|thumb|right|text-top||520px|Main stages of cortical development where abnormalities may arise <ref name="imaging"/> ]]
 

The embryologic development of the cerebral cortex involves highly organised and complex events (as has been seen in the section 'Development of the cerebral cortex'). 

These events are generally divided by scientists into 3 major stages in cortical formation where crucial changes occur in neuronal cells; these stages include: 
1. Proliferation (or Growth), 
2. Migration, 
3. Organisation (or Maturation or Differentiation). 
 

Disruptions in these stages of cortical development, are the precedent that give rise to malformations or irregularities in the cerebral cortex (Fig. ). This section will explore some abnormalities that are commonly discussed in scientific literature.
 
 
 
 
===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder of uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers and very large cells called 'balloon' cells. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. 
[[File:Hemimegalencephaly.png|thumb|left|upright=1.3|Hemimegalencephaly <ref name="imaging"/> ]]

 
 

<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of a 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form a tumour-like, benign malformation) on part or all of the cerebral hemisphere.

Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. Clinical symptoms of this disease may include developmental delay, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.
[[File:Symptoms of microcephaly.png|thumb|right|upright=1.45|Microcephaly <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]]
 
 
 
 
 
 
<big><big>'''3) Microcephaly Vera'''</big></big>

Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs. 

'''Primary Microcephaly or Microcephaly Vera''' results only due to abnormal cortical development, specifically cell division or proliferation. It is a congenital malformation in which the circumference of the head is quite less than normal and is accompanied by mental retardation and sometimes epilepsy. 

References used to write: <ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>
<ref>Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
<ref>Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref>
<ref>Christopher A, C. (2017). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 

<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is thus called due to lesions seen that resembled potato tubers; and is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms) in the cortex. 

" Beneath the cortex, the brain in tuberous sclerosis also shows nodular collections of small cells along the surface of the lateral ventricle that resemble ventricular cells and are called subependymal nodules...or, more descriptively, “candle drippings.” These nodules often contain numerous balloon cells and can in some cases become transformed into glial tumors referred to as subependymal giant cell astrocytomas..."

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:SBH.png|thumb|upright=2.0|right| Heterotopia <ref name="imaging"/> ]]
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex. 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 
 
<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. 
Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 

Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. 
Type II Lissencephaly also includes: 

#Muscle-Eye-Brain Disease 
#Walker-Warburg Syndrome 
#Fukuyama Syndrome 
*'''Microlissencephaly'''

Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly, and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span.
 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Kallman Syndrome is associated with hypoplasia of the olfactory bulbs and olfactory cortex, called arhinencephaly, and lack of the sense of smell. [not yet changed into own words]

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

[[File:SchizencephalicBrain.jpg|thumb|left|upright=1.6| Schizencephaly <ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder characterised by a cleft(s) or lesion(s) on the brain surface, which is filled with CSF and lined by gray matter.
Schizencephaly can be bilateral or unilateral.

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly.

Schizencephaly commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
 
 
 
 
 
 
 
 
===Other Disorders===
<big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right| Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD) <ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome.
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

<html5media height="380" width="580">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref>
 

<ref> dimedcom (2013).Corpus callosum agenesis. [video] Available at: https://www.youtube.com/watch?v=M7e9JXGOWD4 [Accessed 6 Oct. 2017].</ref>

[[File:Corticogenesis of mouse and humans.jpeg|thumb|right|text-top|590px|'''Mouse vs Human Neurogenesis''']]

==Models and Research==
===Animal Models===

https://bmcneurosci.biomedcentral.com/articles/10.1186/1471-2202-11-75 (reelin in pig model)

Mice have often been used to study corticogenesis in mammals. Corticogenesis lasts from E11 to E19 in mice and lasts eight days, which is far shorter than human corticogenesis. While there are many similarities between human corticogenesis, the rodent brain is much smaller than that of a human’s and therefore, there are different types of progenitor cells involved in mice and the cortex does not expand as greatly. <ref name="control">Dehay, C. and Kennedy, H. (2007). Cell-cycle control and cortical development. Nature Reviews Neuroscience, 8(6),438-450.</ref>Humans have greater numbers of intermediate precursor cells (to aid in further differentiation) and outer radial glial cells compared those of mice. <ref name="cerebral"/> In addition, the SVZ does not split into the inner and outer subventricular zone, but stays intact as one. <ref name="control"/> The importance of reelin has also been greatly studied in mice. Studies showed that mutant mice have disruptions in the migration of neurons into their subsequent layers. By injecting thymidine at various time points of gestation into the female mice, researchers were able to track the development of various populations of neurons. Later developing neurons were unable to ascend past the already early formed neurons due to disruptions in reelin signaling (in the marginal zone). Instead, superficial layer neurons resided below the older, deep layer neurons. This inverted lamination comprises sensory and motor function.<ref> Caviness, V. (1982). Neocortical histogenesis in normal and reeler mice: A developmental study based upon [3H]thymidine autoradiography. Developmental Brain Research, 4(3), 293-302.</ref>
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Timeline and protocol of cerebral organoid development'''<ref><pubmed>25188634</pubmed></ref>]]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

==Glossary==

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
|'''Sulcus'''|| Sulci (plural) are grooves in the cerebral cortex.
|-
|'''Gyrus '''|| Gyri (plural) are folds/ridges in the cerebral cortex.
|-
|'''Fissures'''|| Large sulci.
|-
|'''Corticogenesis'''|| The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes.
|-
|'''Cajal-Retzius (CR) cells'''|| Cortical neurons that develop early on, at the same time as the preplate, and express an important glycoprotein known as reelin, which helps with the proper migration of neurons into their respective layers.
|-
|'''GABAergic Neurons'''|| Generate gamma aminobutyric acid (GABA) as their output, one of the two inhibitory neurotransmitters in the central nervous system (CNS).
|-
|'''Radial glial cells '''|| A class of distinct nonneuronal cells that are bipolar shaped and span the entire width of the cortex during development.
|-
|''' '''||
|-
|''' '''||
|-
|''' '''||
|-
|''' '''||
|-

|}

==INFO/ Research Links (temporary heading)==
 

https://www.youtube.com/watch?v=n6zQbTT0yoY 
https://www.youtube.com/watch?v=X-m0JDCw6TE 

https://www.youtube.com/watch?v=luXDQrmMoUU 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ 
http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue 

https://academic.oup.com/jnen/article/61/1/1/2916251 
https://pdfs.semanticscholar.org/67ea/2ce13f57f4ddbfb7033b6bb1328a5dff7742.pdf 
https://www.youtube.com/watch?v=l_nTggR7LTE 

For concept:
https://www.youtube.com/watch?v=dNngOlsLuGI

You might find this helpful (although you need to request copyright permission):

"Difference Between Cerebrum and Cerebral Cortex." DifferenceBetween.Com. August 7, 2012. < http://www.differencebetween.com/difference-between-cerebrum-and-vs-cerebral-cortex/ >

PubMed Searches: [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebral+Cortex+Development ''Cerebral Cortex Development''] | [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebrum+Development ''Cerebrum Development'']

BMC Dev Biol Search: [http://www.biomedcentral.com/bmcdevbiol/search/results?terms=Cerebral+Cortex+Development ''Cerebral Cortex Development'']

Recent papers

<pubmed limit=5>Cerebral+Cortex+Development</pubmed>

==References==

2017 Group Project 1

2017-10-25T10:51:19Z

Z5177691: /* Animal Models */

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Intro section cortex.jpg|thumb|right|350px| Fig.1. Cerebral cortex is the outermost layer of the cerebrum <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex surrounds the cerebrum, and is the largest part of the human brain. It is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres; it is around 2-4 mm in thickness, consists of the layer of grey matter and has ~ 10 billion nerve cell bodies and dendrites. 
[[File:Brain sectin showing cortex.jpg|thumb|left|300px| Fig 2. Section of the human brain <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]] 

The development of the cerebral cortex involves 3 main stages: proliferation/growth/differentiation, migration of neurons, and maturation/organisation/folding. The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. external pyramidal, IV. internal granular layer, V. internal pyramidal layer, VI. multiform layer. These individual layers organise the capacity for interconnections between both input and output signals. 
 
 
 
 
 
 

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref> 
[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|Figure 10: Anatomy of the human cerebral cortex <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]]

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull (see figure 10). The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri, as shown in figure 10. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri (see figure 10). Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>
 
'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}

==Functions of the Cerebral Cortex==
 
[[File:Cortical areas.png|thumb|right|text-top|450px|Figure 11: Cortical areas human cortex <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]
[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|Figure 12: Cortical Homonculus <ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]
The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas, as shown in Figure 11. <ref name="overall function"><pubmed>21653723</pubmed></ref>

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body (see figure 12). The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>

==Early Development of the Brain==

 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
[[File:Brain Development 2.png|400px|right|A longitudinal perspective of the neural tube, showing the primary brain vesicles divided into the five secondary subdivisions.|]]
*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five, as depicted in the image on the right. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.

'''Brain Flexures'''
[[File:Brain Development.png|400px|right|Lateral perspective of the neural tube, showing the three flexures, and five secondary subdivisions.|]]
During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures, as seen in the image to the right in proximity to the five secondary vesicles. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

[[File:Neural- cortex Cajal drawing 01.jpg |thumb|right|200px|Laminar and columnar organization of the cerebral cortex (Historical drawing by Cajal)]]

==Later Development: Development of the Cerebral Cortex==
 
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes. The diversity in neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned in above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contributes to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|400px|super|Key developmental zones in the human cortex]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone
**Subplate
*Cortical Plate: establishment of the 6 cortical layers form in this region between the subplate and the marginal zone

===Timeline of Corticogenesis===
 
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (e.g fate) of the neurons so that specific connections and cortical structure are achieved. "E" relates to embryonic day in relation to corticogenesis.
 

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along in order to expand the neocortex. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area as well as the preplate and many of the cells in the SVZ contribute to the later cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to the target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layers 6 is populated before layer 5; layer 5 is populated before layer 4 and so on <ref name="boulder"/>. Each layer condenses and the neurons are closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex such as sensory and motor function.
[[File:Corticogenesis.png|center| 700px|super|Corticogenesis from E30 to adult human brain]]

===Signalling involved in Cerebral Cortex Development===
 
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 1: Shh signalling increases the number of proliferating cells''']]
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.

[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 2: Cortex development in wild-type and ''reeler'' mice''' <ref>Gilmore, E. and Herrup, K. (1997). Cortical development: Layers of complexity. Current Biology, 7(4), pp.R231-R234. http://www.sciencedirect.com/science/article/pii/S0960982206001084 </ref>]]

'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 1) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 2). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|500px|'''Figure 3: Cortical thickness in the absence of Bmp7'''<ref><pubmed>22461901</pubmed></ref>]]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers. Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.
 
==Abnormalities associated with Cerebral Cortex Development==
[[File:Stages of development.png|thumb|right|text-top||520px|Main stages of cortical development where abnormalities may arise <ref name="imaging"/> ]]
 

The embryologic development of the cerebral cortex involves highly organised and complex events (as has been seen in the section 'Development of the cerebral cortex'). 

These events are generally divided by scientists into 3 major stages in cortical formation where crucial changes occur in neuronal cells; these stages include: 
1. Proliferation (or Growth), 
2. Migration, 
3. Organisation (or Maturation or Differentiation). 
 

Disruptions in these stages of cortical development, are the precedent that give rise to malformations or irregularities in the cerebral cortex (Fig. ). This section will explore some abnormalities that are commonly discussed in scientific literature.
 
 
 
 
===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder of uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers and very large cells called 'balloon' cells. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. 
[[File:Hemimegalencephaly.png|thumb|left|upright=1.3|Hemimegalencephaly <ref name="imaging"/> ]]

 
 

<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of a 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form a tumour-like, benign malformation) on part or all of the cerebral hemisphere.

Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. Clinical symptoms of this disease may include developmental delay, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.
[[File:Symptoms of microcephaly.png|thumb|right|upright=1.45|Microcephaly <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]]
 
 
 
 
 
 
<big><big>'''3) Microcephaly Vera'''</big></big>

Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs. 

'''Primary Microcephaly or Microcephaly Vera''' results only due to abnormal cortical development, specifically cell division or proliferation. It is a congenital malformation in which the circumference of the head is quite less than normal and is accompanied by mental retardation and sometimes epilepsy. 

References used to write: <ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>
<ref>Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
<ref>Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref>
<ref>Christopher A, C. (2017). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 

<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is thus called due to lesions seen that resembled potato tubers; and is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms) in the cortex. 

" Beneath the cortex, the brain in tuberous sclerosis also shows nodular collections of small cells along the surface of the lateral ventricle that resemble ventricular cells and are called subependymal nodules...or, more descriptively, “candle drippings.” These nodules often contain numerous balloon cells and can in some cases become transformed into glial tumors referred to as subependymal giant cell astrocytomas..."

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:SBH.png|thumb|upright=2.0|right| Heterotopia <ref name="imaging"/> ]]
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex. 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 
 
<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. 
Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 

Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. 
Type II Lissencephaly also includes: 

#Muscle-Eye-Brain Disease 
#Walker-Warburg Syndrome 
#Fukuyama Syndrome 
*'''Microlissencephaly'''

Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly, and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span.
 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Kallman Syndrome is associated with hypoplasia of the olfactory bulbs and olfactory cortex, called arhinencephaly, and lack of the sense of smell. [not yet changed into own words]

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

[[File:SchizencephalicBrain.jpg|thumb|left|upright=1.6| Schizencephaly <ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder characterised by a cleft(s) or lesion(s) on the brain surface, which is filled with CSF and lined by gray matter.
Schizencephaly can be bilateral or unilateral.

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly.

Schizencephaly commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
 
 
 
 
 
 
 
 
===Other Disorders===
<big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right| Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD) <ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome.
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

<html5media height="380" width="580">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref>
 

<ref> dimedcom (2013).Corpus callosum agenesis. [video] Available at: https://www.youtube.com/watch?v=M7e9JXGOWD4 [Accessed 6 Oct. 2017].</ref>

[[File:Corticogenesis of mouse and humans.jpeg|thumb|right|text-top|590px|'''Mouse vs Human Neurogenesis''']]

==Models and Research==
===Animal Models===

https://bmcneurosci.biomedcentral.com/articles/10.1186/1471-2202-11-75 (reelin in pig model)

Mice have often been used to study corticogenesis in mammals. Corticogenesis lasts from E11 to E19 in mice and lasts eight days, which is far shorter than human corticogenesis. While there are many similarities between human corticogenesis, the rodent brain is much smaller than that of a human’s and therefore, there are different types of progenitor cells involved in mice and the cortex does not expand as greatly. Humans have greater numbers of intermediate precursor cells (to aid in further differentiation) and outer radial glial cells compared those of mice. In addition, the SVZ does not split into the inner and outer subventricular zone, but stays intact as one. <ref>Dehay, C. and Kennedy, H. (2007). Cell-cycle control and cortical development. Nature Reviews Neuroscience, 8(6),438-450.</ref> The importance of reelin has also been greatly studied in mice. Studies showed that mutant mice have disruptions in the migration of neurons into their subsequent layers. By injecting thymidine at various time points of gestation into the female mice, researchers were able to track the development of various populations of neurons. Later developing neurons were unable to ascend past the already early formed neurons due to disruptions in reelin signaling (in the marginal zone). Instead, superficial layer neurons resided below the older, deep layer neurons. This inverted lamination comprises sensory and motor function.<ref> Caviness, V. (1982). Neocortical histogenesis in normal and reeler mice: A developmental study based upon [3H]thymidine autoradiography. Developmental Brain Research, 4(3), 293-302.</ref>
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Timeline and protocol of cerebral organoid development'''<ref><pubmed>25188634</pubmed></ref>]]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

==Glossary==

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
|'''Sulcus'''|| Sulci (plural) are grooves in the cerebral cortex.
|-
|'''Gyrus '''|| Gyri (plural) are folds/ridges in the cerebral cortex.
|-
|'''Fissures'''|| Large sulci.
|-
|'''Corticogenesis'''|| The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes.
|-
|'''Cajal-Retzius (CR) cells'''|| Cortical neurons that develop early on, at the same time as the preplate, and express an important glycoprotein known as reelin, which helps with the proper migration of neurons into their respective layers.
|-
|'''GABAergic Neurons'''|| Generate gamma aminobutyric acid (GABA) as their output, one of the two inhibitory neurotransmitters in the central nervous system (CNS).
|-
|'''Radial glial cells '''|| A class of distinct nonneuronal cells that are bipolar shaped and span the entire width of the cortex during development.
|-
|''' '''||
|-
|''' '''||
|-
|''' '''||
|-
|''' '''||
|-

|}

==INFO/ Research Links (temporary heading)==
 

https://www.youtube.com/watch?v=n6zQbTT0yoY 
https://www.youtube.com/watch?v=X-m0JDCw6TE 

https://www.youtube.com/watch?v=luXDQrmMoUU 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ 
http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue 

https://academic.oup.com/jnen/article/61/1/1/2916251 
https://pdfs.semanticscholar.org/67ea/2ce13f57f4ddbfb7033b6bb1328a5dff7742.pdf 
https://www.youtube.com/watch?v=l_nTggR7LTE 

For concept:
https://www.youtube.com/watch?v=dNngOlsLuGI

You might find this helpful (although you need to request copyright permission):

"Difference Between Cerebrum and Cerebral Cortex." DifferenceBetween.Com. August 7, 2012. < http://www.differencebetween.com/difference-between-cerebrum-and-vs-cerebral-cortex/ >

PubMed Searches: [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebral+Cortex+Development ''Cerebral Cortex Development''] | [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebrum+Development ''Cerebrum Development'']

BMC Dev Biol Search: [http://www.biomedcentral.com/bmcdevbiol/search/results?terms=Cerebral+Cortex+Development ''Cerebral Cortex Development'']

Recent papers

<pubmed limit=5>Cerebral+Cortex+Development</pubmed>

==References==

2017 Group Project 1

2017-10-25T10:45:55Z

Z5177691: /* Models and Research */

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Intro section cortex.jpg|thumb|right|350px| Fig.1. Cerebral cortex is the outermost layer of the cerebrum <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex surrounds the cerebrum, and is the largest part of the human brain. It is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres; it is around 2-4 mm in thickness, consists of the layer of grey matter and has ~ 10 billion nerve cell bodies and dendrites. 
[[File:Brain sectin showing cortex.jpg|thumb|left|300px| Fig 2. Section of the human brain <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]] 

The development of the cerebral cortex involves 3 main stages: proliferation/growth/differentiation, migration of neurons, and maturation/organisation/folding. The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. external pyramidal, IV. internal granular layer, V. internal pyramidal layer, VI. multiform layer. These individual layers organise the capacity for interconnections between both input and output signals. 
 
 
 
 
 
 

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref> 
[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|Figure 10: Anatomy of the human cerebral cortex <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]]

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull (see figure 10). The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri, as shown in figure 10. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri (see figure 10). Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>
 
'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}

==Functions of the Cerebral Cortex==
 
[[File:Cortical areas.png|thumb|right|text-top|450px|Figure 11: Cortical areas human cortex <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]
[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|Figure 12: Cortical Homonculus <ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]
The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas, as shown in Figure 11. <ref name="overall function"><pubmed>21653723</pubmed></ref>

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body (see figure 12). The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}
 
<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>

==Early Development of the Brain==

 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
[[File:Brain Development 2.png|400px|right|A longitudinal perspective of the neural tube, showing the primary brain vesicles divided into the five secondary subdivisions.|]]
*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five, as depicted in the image on the right. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.

'''Brain Flexures'''
[[File:Brain Development.png|400px|right|Lateral perspective of the neural tube, showing the three flexures, and five secondary subdivisions.|]]
During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures, as seen in the image to the right in proximity to the five secondary vesicles. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

[[File:Neural- cortex Cajal drawing 01.jpg |thumb|right|200px|Laminar and columnar organization of the cerebral cortex (Historical drawing by Cajal)]]

==Later Development: Development of the Cerebral Cortex==
 
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes. The diversity in neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned in above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contributes to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|400px|super|Key developmental zones in the human cortex]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone
**Subplate
*Cortical Plate: establishment of the 6 cortical layers form in this region between the subplate and the marginal zone

===Timeline of Corticogenesis===
 
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (e.g fate) of the neurons so that specific connections and cortical structure are achieved. "E" relates to embryonic day in relation to corticogenesis.
 

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along in order to expand the neocortex. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area as well as the preplate and many of the cells in the SVZ contribute to the later cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to the target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layers 6 is populated before layer 5; layer 5 is populated before layer 4 and so on <ref name="boulder"/>. Each layer condenses and the neurons are closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex such as sensory and motor function.
[[File:Corticogenesis.png|center| 700px|super|Corticogenesis from E30 to adult human brain]]

===Signalling involved in Cerebral Cortex Development===
 
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 1: Shh signalling increases the number of proliferating cells''']]
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.

[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 2: Cortex development in wild-type and ''reeler'' mice''' <ref>Gilmore, E. and Herrup, K. (1997). Cortical development: Layers of complexity. Current Biology, 7(4), pp.R231-R234. http://www.sciencedirect.com/science/article/pii/S0960982206001084 </ref>]]

'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 1) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 2). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|500px|'''Figure 3: Cortical thickness in the absence of Bmp7'''<ref><pubmed>22461901</pubmed></ref>]]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers. Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.
 
==Abnormalities associated with Cerebral Cortex Development==
[[File:Stages of development.png|thumb|right|text-top||520px|Main stages of cortical development where abnormalities may arise <ref name="imaging"/> ]]
 

The embryologic development of the cerebral cortex involves highly organised and complex events (as has been seen in the section 'Development of the cerebral cortex'). 

These events are generally divided by scientists into 3 major stages in cortical formation where crucial changes occur in neuronal cells; these stages include: 
1. Proliferation (or Growth), 
2. Migration, 
3. Organisation (or Maturation or Differentiation). 
 

Disruptions in these stages of cortical development, are the precedent that give rise to malformations or irregularities in the cerebral cortex (Fig. ). This section will explore some abnormalities that are commonly discussed in scientific literature.
 
 
 
 
===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder of uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers and very large cells called 'balloon' cells. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. 
[[File:Hemimegalencephaly.png|thumb|left|upright=1.3|Hemimegalencephaly <ref name="imaging"/> ]]

 
 

<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of a 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form a tumour-like, benign malformation) on part or all of the cerebral hemisphere.

Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. Clinical symptoms of this disease may include developmental delay, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.
[[File:Symptoms of microcephaly.png|thumb|right|upright=1.45|Microcephaly <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]]
 
 
 
 
 
 
<big><big>'''3) Microcephaly Vera'''</big></big>

Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs. 

'''Primary Microcephaly or Microcephaly Vera''' results only due to abnormal cortical development, specifically cell division or proliferation. It is a congenital malformation in which the circumference of the head is quite less than normal and is accompanied by mental retardation and sometimes epilepsy. 

References used to write: <ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>
<ref>Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
<ref>Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref>
<ref>Christopher A, C. (2017). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 

<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is thus called due to lesions seen that resembled potato tubers; and is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms) in the cortex. 

" Beneath the cortex, the brain in tuberous sclerosis also shows nodular collections of small cells along the surface of the lateral ventricle that resemble ventricular cells and are called subependymal nodules...or, more descriptively, “candle drippings.” These nodules often contain numerous balloon cells and can in some cases become transformed into glial tumors referred to as subependymal giant cell astrocytomas..."

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:SBH.png|thumb|upright=2.0|right| Heterotopia <ref name="imaging"/> ]]
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex. 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 
 
<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. 
Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 

Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. 
Type II Lissencephaly also includes: 

#Muscle-Eye-Brain Disease 
#Walker-Warburg Syndrome 
#Fukuyama Syndrome 
*'''Microlissencephaly'''

Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly, and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span.
 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Kallman Syndrome is associated with hypoplasia of the olfactory bulbs and olfactory cortex, called arhinencephaly, and lack of the sense of smell. [not yet changed into own words]

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

[[File:SchizencephalicBrain.jpg|thumb|left|upright=1.6| Schizencephaly <ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder characterised by a cleft(s) or lesion(s) on the brain surface, which is filled with CSF and lined by gray matter.
Schizencephaly can be bilateral or unilateral.

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly.

Schizencephaly commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
 
 
 
 
 
 
 
 
===Other Disorders===
<big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right| Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD) <ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome.
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

<html5media height="380" width="580">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref>
 

<ref> dimedcom (2013).Corpus callosum agenesis. [video] Available at: https://www.youtube.com/watch?v=M7e9JXGOWD4 [Accessed 6 Oct. 2017].</ref>

[[File:Corticogenesis of mouse and humans.jpeg|thumb|right|text-top|590px|'''Mouse vs Human Neurogenesis''']]

==Models and Research==
===Animal Models===

https://bmcneurosci.biomedcentral.com/articles/10.1186/1471-2202-11-75 (reelin in pig model)

Mice have often been used to study corticogenesis in mammals. Corticogenesis lasts from E11 to E19 in mice and lasts eight days, which is far shorter than human corticogenesis. While there are many similarities between human corticogenesis, the rodent brain is much smaller than that of a human’s and therefore, there are different types of progenitor cells involved in mice and the cortex does not expand as greatly. In addition, the SVZ does not split into the inner and outer subventricular zone, but stays intact as one. <ref>Dehay, C. and Kennedy, H. (2007). Cell-cycle control and cortical development. Nature Reviews Neuroscience, 8(6),438-450.</ref> The importance of reelin has also been greatly studied in mice. Studies showed that mutant mice have disruptions in the migration of neurons into their subsequent layers. By injecting thymidine at various time points of gestation into the female mice, researchers were able to track the development of various populations of neurons. Later developing neurons were unable to ascend past the already early formed neurons due to disruptions in reelin signaling (in the marginal zone). Instead, superficial layer neurons resided below the older, deep layer neurons. This inverted lamination comprises sensory and motor function.<ref> Caviness, V. (1982). Neocortical histogenesis in normal and reeler mice: A developmental study based upon [3H]thymidine autoradiography. Developmental Brain Research, 4(3), 293-302.</ref>
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Timeline and protocol of cerebral organoid development'''<ref><pubmed>25188634</pubmed></ref>]]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

==Glossary==

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
|'''Sulcus'''|| Sulci (plural) are grooves in the cerebral cortex.
|-
|'''Gyrus '''|| Gyri (plural) are folds/ridges in the cerebral cortex.
|-
|'''Fissures'''|| Large sulci.
|-
|'''Corticogenesis'''|| The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes.
|-
|'''Cajal-Retzius (CR) cells'''|| Cortical neurons that develop early on, at the same time as the preplate, and express an important glycoprotein known as reelin, which helps with the proper migration of neurons into their respective layers.
|-
|'''GABAergic Neurons'''|| Generate gamma aminobutyric acid (GABA) as their output, one of the two inhibitory neurotransmitters in the central nervous system (CNS).
|-
|'''Radial glial cells '''|| A class of distinct nonneuronal cells that are bipolar shaped and span the entire width of the cortex during development.
|-
|''' '''||
|-
|''' '''||
|-
|''' '''||
|-
|''' '''||
|-

|}

==INFO/ Research Links (temporary heading)==
 

https://www.youtube.com/watch?v=n6zQbTT0yoY 
https://www.youtube.com/watch?v=X-m0JDCw6TE 

https://www.youtube.com/watch?v=luXDQrmMoUU 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ 
http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue 

https://academic.oup.com/jnen/article/61/1/1/2916251 
https://pdfs.semanticscholar.org/67ea/2ce13f57f4ddbfb7033b6bb1328a5dff7742.pdf 
https://www.youtube.com/watch?v=l_nTggR7LTE 

For concept:
https://www.youtube.com/watch?v=dNngOlsLuGI

You might find this helpful (although you need to request copyright permission):

"Difference Between Cerebrum and Cerebral Cortex." DifferenceBetween.Com. August 7, 2012. < http://www.differencebetween.com/difference-between-cerebrum-and-vs-cerebral-cortex/ >

PubMed Searches: [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebral+Cortex+Development ''Cerebral Cortex Development''] | [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebrum+Development ''Cerebrum Development'']

BMC Dev Biol Search: [http://www.biomedcentral.com/bmcdevbiol/search/results?terms=Cerebral+Cortex+Development ''Cerebral Cortex Development'']

Recent papers

<pubmed limit=5>Cerebral+Cortex+Development</pubmed>

==References==

File:Corticogenesis of mouse and humans.jpeg

2017-10-25T10:40:45Z

Z5177691: /* Reference */

(z5178570)
==Description==
Corticogenesis in mice versus humans. The images are not to scale.

RGC: radial glial cell

oRG: outer radial glial cell

IPC: intermediate precursor cell

VZ: centricular zone

SVZ: subventricular zone

ISVZ: inner subventricular zone

OSVZ: outer subventricular zone

IZ: intermediate zone

CP: cortical plate

==Reference==
Original student image based upon: http://www.cell.com/trends/neurosciences/fulltext/S0166-2236(14)00211-2

<pubmed> PMC4334136 </pubmed>

==Copyright==
"Beginning six months after publication, I (z5178570) grant the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode."

File:Corticogenesis of mouse and humans.jpeg

2017-10-25T10:40:13Z

Z5177691: /* Description */

(z5178570)
==Description==
Corticogenesis in mice versus humans. The images are not to scale.

RGC: radial glial cell

oRG: outer radial glial cell

IPC: intermediate precursor cell

VZ: centricular zone

SVZ: subventricular zone

ISVZ: inner subventricular zone

OSVZ: outer subventricular zone

IZ: intermediate zone

CP: cortical plate

==Reference==
Original student image based upon: http://www.cell.com/trends/neurosciences/fulltext/S0166-2236(14)00211-2

<pubmed> PMC4334136 </pubmed>

Copyright:
"Beginning six months after publication, I (z5178570) grant the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode."

File:Corticogenesis of mouse and humans.jpeg

2017-10-25T10:39:47Z

Z5177691:

(z5178570)
==Description==
Corticogenesis in mice versus humans. The images are not to scale.
RGC: radial glial cell
oRG: outer radial glial cell
IPC: intermediate precursor cell
VZ: centricular zone
SVZ: subventricular zone
ISVZ: inner subventricular zone
OSVZ: outer subventricular zone
IZ: intermediate zone
CP: cortical plate

==Reference==
Original student image based upon: http://www.cell.com/trends/neurosciences/fulltext/S0166-2236(14)00211-2

<pubmed> PMC4334136 </pubmed>

Copyright:
"Beginning six months after publication, I (z5178570) grant the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode."

2017 Group Project 1

2017-10-25T10:19:36Z

Z5177691:

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Intro section cortex.jpg|thumb|right|350px| Fig.1. Cerebral cortex is the outermost layer of the cerebrum <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex surrounds the cerebrum, and is the largest part of the human brain. It is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres; it is around 2-4 mm in thickness, consists of the layer of grey matter and has ~ 10 billion nerve cell bodies and dendrites. 
[[File:Brain sectin showing cortex.jpg|thumb|left|300px| Fig 2. Section of the human brain <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]] 

The development of the cerebral cortex involves 3 main stages: proliferation/growth/differentiation, migration of neurons, and maturation/organisation/folding. The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. external pyramidal, IV. internal granular layer, V. internal pyramidal layer, VI. multiform layer. These individual layers organise the capacity for interconnections between both input and output signals.
 
 
 
 
 
 
 

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref>

[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|Figure 10: Anatomy of the human cerebral cortex <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]]

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull (see figure 10). The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri, as shown in figure 10. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri (see figure 10). Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>

<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>

'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}

==Functions of the Cerebral Cortex==
 
[[File:Cortical areas.png|thumb|right|text-top|450px|Figure 11: Cortical areas human cortex <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]
[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|Figure 12: Cortical Homonculus <ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]
The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas, as shown in Figure 11. <ref name="overall function"><pubmed>21653723</pubmed></ref>

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body (see figure 12). The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}

<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>
==Early Development of the Brain==

 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
[[File:Brain Development 2.png|400px|right|A longitudinal perspective of the neural tube, showing the primary brain vesicles divided into the five secondary subdivisions.|]]
*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five, as depicted in the image on the right. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.

'''Brain Flexures'''
[[File:Brain Development.png|400px|right|Lateral perspective of the neural tube, showing the three flexures, and five secondary subdivisions.|]]
During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures, as seen in the image to the right in proximity to the five secondary vesicles. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

[[File:Neural- cortex Cajal drawing 01.jpg |thumb|right|200px|Laminar and columnar organization of the cerebral cortex (Historical drawing by Cajal)]]

==Later Development:Development of the Cerebral Cortex==
 
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes. The diversity in neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned in above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contributes to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|400px|super|Key developmental zones in the human cortex]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone
**Subplate
*Cortical Plate: establishment of the 6 cortical layers form in this region between the subplate and the marginal zone

===Timeline of Corticogenesis===
 
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (e.g fate) of the neurons so that specific connections and cortical structure are achieved. "E" relates to embryonic day in relation to corticogenesis.
 

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along in order to expand the neocortex. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area as well as the preplate and many of the cells in the SVZ contribute to the later cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to the target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layers 6 is populated before layer 5; layer 5 is populated before layer 4 and so on <ref name="boulder"/>. Each layer condenses and the neurons are closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex such as sensory and motor function.
[[File:Corticogenesis.png|center| 700px|super|Corticogenesis from E30 to adult human brain]]

===Signalling involved in Cerebral Cortex Development===
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 1: Shh signalling increases the number of proliferating cells''']]
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.

[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 2: Cortex development in wild-type and ''reeler'' mice''' <ref>Gilmore, E. and Herrup, K. (1997). Cortical development: Layers of complexity. Current Biology, 7(4), pp.R231-R234. http://www.sciencedirect.com/science/article/pii/S0960982206001084 </ref>]]

'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 1) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 2). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|500px|'''Figure 3: Cortical thickness in the absence of Bmp7'''<ref><pubmed>22461901</pubmed></ref>]]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers. Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.

 
==Abnormalities associated with Cerebral Cortex Development==
[[File:Stages of development.png|thumb|right|text-top||400px|Main stages of cortical development where abnormalities may arise <ref name="imaging"/> ]]
 

The embryologic development of the cerebral cortex involves highly organised and complex events (as has been seen in the section 'Development of the cerebral cortex'). 

These events are generally divided by scientists into 3 major stages in cortical formation where crucial changes occur in neuronal cells; these stages include: 
1. Proliferation (or Growth), 
2. Migration, 
3. Organisation (or Maturation or Differentiation). 
 

Disruptions in these stages of cortical development, are the precedent that give rise to malformations or irregularities in the cerebral cortex (Fig. ). This section will explore some abnormalities that are commonly discussed in scientific literature.
 
 
 
 
===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder of uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers and very large cells called 'balloon' cells. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. 
[[File:Hemimegalencephaly.png|thumb|left|upright=1.3|Hemimegalencephaly <ref name="imaging"/> ]]

 
 

<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of a 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form a tumour-like, benign malformation) on part or all of the cerebral hemisphere.

Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. Clinical symptoms of this disease may include developmental delay, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.
[[File:Symptoms of microcephaly.png|thumb|right|upright=1.45|Microcephaly <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]]
 
 
 
 
 
 
<big><big>'''3) Microcephaly Vera'''</big></big>

Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs. 

'''Primary Microcephaly or Microcephaly Vera''' results only due to abnormal cortical development, specifically cell division or proliferation. It is a congenital malformation in which the circumference of the head is quite less than normal and is accompanied by mental retardation and sometimes epilepsy. 

References used to write: <ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>
<ref>Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
<ref>Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref>
<ref>Christopher A, C. (2017). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 

<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is thus called due to lesions seen that resembled potato tubers; and is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms) in the cortex. 

" Beneath the cortex, the brain in tuberous sclerosis also shows nodular collections of small cells along the surface of the lateral ventricle that resemble ventricular cells and are called subependymal nodules...or, more descriptively, “candle drippings.” These nodules often contain numerous balloon cells and can in some cases become transformed into glial tumors referred to as subependymal giant cell astrocytomas..."

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:SBH.png|thumb|upright=2.0|right| Heterotopia <ref name="imaging"/> ]]
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex. 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 

<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. 
Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 

Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. 
Type II Lissencephaly also includes: 

#Muscle-Eye-Brain Disease 
#Walker-Warburg Syndrome 
#Fukuyama Syndrome 
*'''Microlissencephaly'''

Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly, and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span.
 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Kallman Syndrome is associated with hypoplasia of the olfactory bulbs and olfactory cortex, called arhinencephaly, and lack of the sense of smell. [not yet changed into own words]

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

[[File:SchizencephalicBrain.jpg|thumb|left|upright=1.6| Schizencephaly <ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder characterised by a cleft(s) or lesion(s) on the brain surface, which is filled with CSF and lined by gray matter.
Schizencephaly can be bilateral or unilateral.

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly.

Schizencephaly commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
 
 
 
 
 
 
 
===Other Disorders===
<big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right| Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD) <ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome.
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

<html5media height="380" width="580">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref>
 

<ref> dimedcom (2013).Corpus callosum agenesis. [video] Available at: https://www.youtube.com/watch?v=M7e9JXGOWD4 [Accessed 6 Oct. 2017].</ref>

[[File:Corticogenesis of mouse and humans.jpeg|thumb|right|text-top|590px|'''Mouse vs Human Neurogenesis''']]

==Models and Research==
===Animal Models===

https://bmcneurosci.biomedcentral.com/articles/10.1186/1471-2202-11-75 (reelin in pig model)

Mice have often been used to study corticogenesis in mammals. Corticogenesis lasts from E11 to E19 in mice and lasts eight days. <ref>
Dehay, C. and Kennedy, H. (2007). Cell-cycle control and cortical development. Nature Reviews Neuroscience, 8(6),438-450.</ref> The importance of reelin has been greatly studied in mice. Studies showed that mutant mice have disruptions in the migration of neurons into their subsequent layers. By injecting thymidine at various time points of gestation into the female mice, researchers were able to track the development of various populations of neurons. Later developing neurons were unable to ascend past the already early formed neurons due to disruptions in reelin signaling (in the marginal zone). Instead, superficial layer neurons resided below the older, deep layer neurons. This inverted lamination comprises sensory and motor function.<ref> Caviness, V. (1982). Neocortical histogenesis in normal and reeler mice: A developmental study based upon [3H]thymidine autoradiography. Developmental Brain Research, 4(3), 293-302.</ref>
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Timeline and protocol of cerebral organoid development'''<ref><pubmed>25188634</pubmed></ref>]]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

==Glossary==

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
|'''Sulcus'''|| Sulci (plural) are grooves in the cerebral cortex.
|-
|'''Gyrus '''|| Gyri (plural) are folds/ridges in the cerebral cortex.
|-
|'''Fissures'''|| Large sulci.
|-
|'''Corticogenesis'''|| The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes.
|-
|'''Cajal-Retzius (CR) cells'''|| Cortical neurons that develop early on, at the same time as the preplate, and express an important glycoprotein known as reelin, which helps with the proper migration of neurons into their respective layers.
|-
|'''GABAergic Neurons'''|| Generate gamma aminobutyric acid (GABA) as their output, one of the two inhibitory neurotransmitters in the central nervous system (CNS).
|-
|'''Radial glial cells '''|| A class of distinct nonneuronal cells that are bipolar shaped and span the entire width of the cortex during development.
|-
|''' '''||
|-
|''' '''||
|-
|''' '''||
|-
|''' '''||
|-

|}

{{Glossary}}

==INFO/ Research Links (temporary heading)==
 

https://www.youtube.com/watch?v=n6zQbTT0yoY 
https://www.youtube.com/watch?v=X-m0JDCw6TE 

https://www.youtube.com/watch?v=luXDQrmMoUU 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ 
http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue 

https://academic.oup.com/jnen/article/61/1/1/2916251 
https://pdfs.semanticscholar.org/67ea/2ce13f57f4ddbfb7033b6bb1328a5dff7742.pdf 
https://www.youtube.com/watch?v=l_nTggR7LTE 

For concept:
https://www.youtube.com/watch?v=dNngOlsLuGI

You might find this helpful (although you need to request copyright permission):

"Difference Between Cerebrum and Cerebral Cortex." DifferenceBetween.Com. August 7, 2012. < http://www.differencebetween.com/difference-between-cerebrum-and-vs-cerebral-cortex/ >

PubMed Searches: [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebral+Cortex+Development ''Cerebral Cortex Development''] | [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebrum+Development ''Cerebrum Development'']

BMC Dev Biol Search: [http://www.biomedcentral.com/bmcdevbiol/search/results?terms=Cerebral+Cortex+Development ''Cerebral Cortex Development'']

Recent papers

<pubmed limit=5>Cerebral+Cortex+Development</pubmed>

==References==

2017 Group Project 1

2017-10-25T10:13:07Z

Z5177691:

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Intro section cortex.jpg|thumb|right|350px| Fig.1. Cerebral cortex is the outermost layer of the cerebrum <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex surrounds the cerebrum, and is the largest part of the human brain. It is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres; it is around 2-4 mm in thickness, consists of the layer of grey matter and has ~ 10 billion nerve cell bodies and dendrites. 
[[File:Brain sectin showing cortex.jpg|thumb|left|300px| Fig 2. Section of the human brain <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]] 

The development of the cerebral cortex involves 3 main stages: proliferation/growth/differentiation, migration of neurons, and maturation/organisation/folding. The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. external pyramidal, IV. internal granular layer, V. internal pyramidal layer, VI. multiform layer. These individual layers organise the capacity for interconnections between both input and output signals.
 
 
 
 
 
 
 

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref>

[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|Figure 10: Anatomy of the human cerebral cortex <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]]

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull (see figure 10). The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri, as shown in figure 10. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri (see figure 10). Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>

<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>

'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}

==Functions of the Cerebral Cortex==
 
[[File:Cortical areas.png|thumb|right|text-top|450px|Figure 11: Cortical areas human cortex <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]
[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|Figure 12: Cortical Homonculus <ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]
The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas, as shown in Figure 11. <ref name="overall function"><pubmed>21653723</pubmed></ref>

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body (see figure 12). The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}

<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>
==Early Development of the Brain==

 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
[[File:Brain Development 2.png|400px|right|A longitudinal perspective of the neural tube, showing the primary brain vesicles divided into the five secondary subdivisions.|]]
*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five, as depicted in the image on the right. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.

'''Brain Flexures'''
[[File:Brain Development.png|400px|right|Lateral perspective of the neural tube, showing the three flexures, and five secondary subdivisions.|]]
During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures, as seen in the image to the right in proximity to the five secondary vesicles. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

[[File:Neural- cortex Cajal drawing 01.jpg |thumb|right|200px|Laminar and columnar organization of the cerebral cortex (Historical drawing by Cajal)]]

==Later Development:Development of the Cerebral Cortex==
 
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes. The diversity in neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned in above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contributes to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|400px|super|Key developmental zones in the human cortex]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone
**Subplate
*Cortical Plate: establishment of the 6 cortical layers form in this region between the subplate and the marginal zone

===Timeline of Corticogenesis===
 
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (e.g fate) of the neurons so that specific connections and cortical structure are achieved. "E" relates to embryonic day in relation to corticogenesis.
 

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along in order to expand the neocortex. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area as well as the preplate and many of the cells in the SVZ contribute to the later cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to the target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layers 6 is populated before layer 5; layer 5 is populated before layer 4 and so on <ref name="boulder"/>. Each layer condenses and the neurons are closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex such as sensory and motor function.
[[File:Corticogenesis.png|center| 700px|super|Corticogenesis from E30 to adult human brain]]

===Signalling involved in Cerebral Cortex Development===
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 1: Shh signalling increases the number of proliferating cells''']]
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.

[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 2: Cortex development in wild-type and ''reeler'' mice''' <ref>Gilmore, E. and Herrup, K. (1997). Cortical development: Layers of complexity. Current Biology, 7(4), pp.R231-R234. http://www.sciencedirect.com/science/article/pii/S0960982206001084 </ref>]]

'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 1) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 2). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|500px|'''Figure 3: Cortical thickness in the absence of Bmp7'''<ref><pubmed>22461901</pubmed></ref>]]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers. Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.

 
==Abnormalities associated with Cerebral Cortex Development==
[[File:Stages of development.png|thumb|right|text-top||500px|Main stages of cortical development where abnormalities may arise <ref name="imaging"/> ]]
 

The embryologic development of the cerebral cortex involves highly organised and complex events (as has been seen in the section 'Development of the cerebral cortex'). 

These events are generally divided by scientists into 3 major stages in cortical formation where crucial changes occur in neuronal cells; these stages include: 
1. Proliferation (or Growth), 
2. Migration, 
3. Organisation (or Maturation or Differentiation). 
 

Disruptions in these stages of cortical development, are the precedent that give rise to malformations or irregularities in the cerebral cortex (Fig. ). This section will explore some abnormalities that are commonly discussed in scientific literature.
 
 
 
 
===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder of uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers and very large cells called 'balloon' cells. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. 
[[File:Hemimegalencephaly.png|thumb|left|upright=1.5|Hemimegalencephaly <ref name="imaging"/> ]]

 
 

<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of a 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form a tumour-like, benign malformation) on part or all of the cerebral hemisphere.

Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. Clinical symptoms of this disease may include developmental delay, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.
[[File:Symptoms of microcephaly.png|thumb|right|upright=1.45|Microcephaly <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]]
 
 
 
 
 
 
<big><big>'''3) Microcephaly Vera'''</big></big>

Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs. 

'''Primary Microcephaly or Microcephaly Vera''' results only due to abnormal cortical development, specifically cell division or proliferation. It is a congenital malformation in which the circumference of the head is quite less than normal and is accompanied by mental retardation and sometimes epilepsy. 

References used to write: <ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>
<ref>Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
<ref>Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref>
<ref>Christopher A, C. (2017). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 

<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is thus called due to lesions seen that resembled potato tubers; and is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms) in the cortex. 

" Beneath the cortex, the brain in tuberous sclerosis also shows nodular collections of small cells along the surface of the lateral ventricle that resemble ventricular cells and are called subependymal nodules...or, more descriptively, “candle drippings.” These nodules often contain numerous balloon cells and can in some cases become transformed into glial tumors referred to as subependymal giant cell astrocytomas..."

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:SBH.png|thumb|upright=2.0|right| Heterotopia <ref name="imaging"/> ]]
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex. 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 

<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. 
Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 

Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. 
Type II Lissencephaly also includes: 

#Muscle-Eye-Brain Disease 
#Walker-Warburg Syndrome 
#Fukuyama Syndrome 
*'''Microlissencephaly'''

Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly, and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span.
 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Kallman Syndrome is associated with hypoplasia of the olfactory bulbs and olfactory cortex, called arhinencephaly, and lack of the sense of smell. [not yet changed into own words]

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

[[File:SchizencephalicBrain.jpg|thumb|left|upright=1.6| Schizencephaly <ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder characterised by a cleft(s) or lesion(s) on the brain surface, which is filled with CSF and lined by gray matter.
Schizencephaly can be bilateral or unilateral.

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly.

Schizencephaly commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
 
 
 
 
 
 
 
===Other Disorders===
<big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right| Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD) <ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome.
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

<html5media height="380" width="580">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref>
 

<ref> dimedcom (2013).Corpus callosum agenesis. [video] Available at: https://www.youtube.com/watch?v=M7e9JXGOWD4 [Accessed 6 Oct. 2017].</ref>

[[File:Corticogenesis of mouse and humans.jpeg|thumb|right|text-top|590px|'''Mouse vs Human Neurogenesis''']]

==Models and Research==
===Animal Models===

https://bmcneurosci.biomedcentral.com/articles/10.1186/1471-2202-11-75 (reelin in pig model)

Mice have often been used to study corticogenesis in mammals. Corticogenesis lasts from E11 to E19 in mice and lasts eight days. <ref>
Dehay, C. and Kennedy, H. (2007). Cell-cycle control and cortical development. Nature Reviews Neuroscience, 8(6),438-450.</ref> The importance of reelin has been greatly studied in mice. Studies showed that mutant mice have disruptions in the migration of neurons into their subsequent layers. By injecting thymidine at various time points of gestation into the female mice, researchers were able to track the development of various populations of neurons. Later developing neurons were unable to ascend past the already early formed neurons due to disruptions in reelin signaling (in the marginal zone). Instead, superficial layer neurons resided below the older, deep layer neurons. This inverted lamination comprises sensory and motor function.<ref> Caviness, V. (1982). Neocortical histogenesis in normal and reeler mice: A developmental study based upon [3H]thymidine autoradiography. Developmental Brain Research, 4(3), 293-302.</ref>
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Timeline and protocol of cerebral organoid development'''<ref><pubmed>25188634</pubmed></ref>]]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

==Glossary==

{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
|'''Sulcus'''|| Sulci (plural) are grooves in the cerebral cortex.
|-
|'''Gyrus '''|| Gyri (plural) are folds/ridges in the cerebral cortex.
|-
|'''Fissures'''|| Large sulci.
|-
|'''Corticogenesis'''|| The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes.
|-
|'''Cajal-Retzius (CR) cells'''|| Cortical neurons that develop early on, at the same time as the preplate, and express an important glycoprotein known as reelin, which helps with the proper migration of neurons into their respective layers.
|-
|'''GABAergic Neurons'''|| Generate gamma aminobutyric acid (GABA) as their output, one of the two inhibitory neurotransmitters in the central nervous system (CNS).
|-
|'''Radial glial cells '''|| A class of distinct nonneuronal cells that are bipolar shaped and span the entire width of the cortex during development.
|-
|''' '''||
|-
|''' '''||
|-
|''' '''||
|-
|''' '''||
|-

|}

{{Glossary}}

==INFO/ Research Links (temporary heading)==
 

https://www.youtube.com/watch?v=n6zQbTT0yoY 
https://www.youtube.com/watch?v=X-m0JDCw6TE 

https://www.youtube.com/watch?v=luXDQrmMoUU 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ 
http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue 

https://academic.oup.com/jnen/article/61/1/1/2916251 
https://pdfs.semanticscholar.org/67ea/2ce13f57f4ddbfb7033b6bb1328a5dff7742.pdf 
https://www.youtube.com/watch?v=l_nTggR7LTE 

For concept:
https://www.youtube.com/watch?v=dNngOlsLuGI

You might find this helpful (although you need to request copyright permission):

"Difference Between Cerebrum and Cerebral Cortex." DifferenceBetween.Com. August 7, 2012. < http://www.differencebetween.com/difference-between-cerebrum-and-vs-cerebral-cortex/ >

PubMed Searches: [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebral+Cortex+Development ''Cerebral Cortex Development''] | [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebrum+Development ''Cerebrum Development'']

BMC Dev Biol Search: [http://www.biomedcentral.com/bmcdevbiol/search/results?terms=Cerebral+Cortex+Development ''Cerebral Cortex Development'']

Recent papers

<pubmed limit=5>Cerebral+Cortex+Development</pubmed>

==References==

2017 Group Project 1

2017-10-25T02:13:21Z

Z5177691: /* Functions of the Cerebral Cortex */

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Intro section cortex.jpg|thumb|right|350px| Fig.1. Cerebral cortex is the outermost layer of the cerebrum <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex surrounds the cerebrum, and is the largest part of the human brain. It is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres; it is around 2-4 mm in thickness, consists of the layer of grey matter and has ~ 10 billion nerve cell bodies and dendrites. 
[[File:Brain sectin showing cortex.jpg|thumb|left|300px| Fig 2. Section of the human brain <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]] 

The development of the cerebral cortex involves 3 main stages: proliferation/growth/differentiation, migration of neurons, and maturation/organisation/folding. The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. external pyramidal, IV. internal granular layer, V. internal pyramidal layer, VI. multiform layer. These individual layers organise the capacity for interconnections between both input and output signals.
 
 
 
 
 
 
 

==Early Development of the Brain==

 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.
[[File:Brain Development.png|400px|]]
'''Brain Flexures'''

During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

[[File:Neural- cortex Cajal drawing 01.jpg |thumb|right|200px|Laminar and columnar organization of the cerebral cortex (Historical drawing by Cajal)]]

==Development of the Cerebral Cortex==
 
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes. The diversity in neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned in above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contributes to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

getting refererence
<ref><pubmed>17514196</pubmed></ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|450px|super|Key developmental zones in the human cortex]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone
**Subplate
*Cortical Plate: establishment of the 6 cortical layers form in this region between the subplate and the marginal zone

===Timeline of Corticogenesis===
 
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (e.g fate) of the neurons so that specific connections and cortical structure are achieved. "E" relates to embryonic day in relation to corticogenesis.
 

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along in order to expand the neocortex. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area as well as the preplate and many of the cells in the SVZ contribute to the later cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to the target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layers 6 is populated before layer 5; layer 5 is populated before layer 4 and so on <ref name="boulder"/>. Each layer condenses and the neurons are closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex such as sensory and motor function.
[[File:Corticogenesis.png|center| 800px|super|Corticogenesis from E30 to adult human brain]]

===Signalling involved in Cerebral Cortex Development===
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 1: Shh signalling increases the number of proliferating cells''']]
 
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.
[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 2: Cortex development in wild-type and ''reeler'' mice''' <ref>Gilmore, E. and Herrup, K. (1997). Cortical development: Layers of complexity. Current Biology, 7(4), pp.R231-R234. http://www.sciencedirect.com/science/article/pii/S0960982206001084 </ref>]]
'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 1) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 2). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|400px|'''Figure 3: Cortical thickness in the absence of Bmp7'''<ref><pubmed>22461901</pubmed></ref>]]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers. Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.

 

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref>

[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|Anatomy of the human cerebral cortex <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]]

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull. The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri. Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>

<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>

'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}

==Functions of the Cerebral Cortex==
 
[[File:Cortical areas.png|thumb|right|text-top|450px|Cortical areas human cortex <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]
[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|Cortical Homonculus <ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]
The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas. <ref name="overall function"><pubmed>21653723</pubmed></ref>

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body. The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}

<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>

==Abnormalities associated with Cerebral Cortex Development==
[[File:Stages of development.png|thumb|right|text-top||600px|Main stages of cortical development where abnormalities may arise <ref name="imaging"/> ]]
 

The embryologic development of the cerebral cortex involves highly organised and complex events (as has been seen in the section 'Development of the cerebral cortex'). 

These events are generally divided by scientists into 3 major stages in cortical formation where crucial changes occur in neuronal cells; these stages include: 
1. Proliferation (or Growth), 
2. Migration, 
3. Organisation (or Maturation or Differentiation). 
 

Disruptions in these stages of cortical development, are the precedent that give rise to malformations or irregularities in the cerebral cortex (Fig. ). This section will explore some abnormalities that are commonly discussed in scientific literature.
 
 
 
 
 
 
===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder of uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers and very large cells called 'balloon' cells. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. 
[[File:Hemimegalencephaly.png|thumb|left|upright=1.5|Hemimegalencephaly <ref name="imaging"/> ]]

 
 

<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of a 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form a tumour-like, benign malformation) on part or all of the cerebral hemisphere.

Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. Clinical symptoms of this disease may include developmental delay, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.
[[File:Symptoms of microcephaly.png|thumb|right|upright=1.45|Microcephaly <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]]
 
 
 
 
 
 
<big><big>'''3) Microcephaly Vera'''</big></big>

Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs. 

'''Primary Microcephaly or Microcephaly Vera''' results only due to abnormal cortical development, specifically cell division or proliferation. It is a congenital malformation in which the circumference of the head is quite less than normal and is accompanied by mental retardation and sometimes epilepsy. 

References used to write: <ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>
<ref>Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
<ref>Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref>
<ref>Christopher A, C. (2017). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 

<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is thus called due to lesions seen that resembled potato tubers; and is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms) in the cortex. 

" Beneath the cortex, the brain in tuberous sclerosis also shows nodular collections of small cells along the surface of the lateral ventricle that resemble ventricular cells and are called subependymal nodules...or, more descriptively, “candle drippings.” These nodules often contain numerous balloon cells and can in some cases become transformed into glial tumors referred to as subependymal giant cell astrocytomas..."

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:SBH.png|thumb|upright=2.0|right| Heterotopia <ref name="imaging"/> ]]
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex. 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 

<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. 
Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 

Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. 
Type II Lissencephaly also includes: 

#Muscle-Eye-Brain Disease 
#Walker-Warburg Syndrome 
#Fukuyama Syndrome 
*'''Microlissencephaly'''

Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly, and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span.
 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Kallman Syndrome is associated with hypoplasia of the olfactory bulbs and olfactory cortex, called arhinencephaly, and lack of the sense of smell. [not yet changed into own words]

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

[[File:SchizencephalicBrain.jpg|thumb|left|upright=1.6| Schizencephaly <ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder characterised by a cleft(s) or lesion(s) on the brain surface, which is filled with CSF and lined by gray matter.
Schizencephaly can be bilateral or unilateral.

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly.

Schizencephaly commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
 
 
 
 
 
 
 
 
 
===Other Disorders===
<big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right| Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD) <ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome.
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

<html5media height="380" width="580">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref>
 

<ref> dimedcom (2013).Corpus callosum agenesis. [video] Available at: https://www.youtube.com/watch?v=M7e9JXGOWD4 [Accessed 6 Oct. 2017].</ref>

[[File:Corticogenesis of mouse and humans.jpeg|thumb|right|text-top|590px|'''Mouse vs Human Neurogenesis''']]

==Models and Research==
===Animal Models===

https://bmcneurosci.biomedcentral.com/articles/10.1186/1471-2202-11-75 (reelin in pig model)

Mice have often been used to study corticogenesis in mammals. Corticogenesis lasts from E11 to E19 in mice and lasts eight days. <ref>
Dehay, C. and Kennedy, H. (2007). Cell-cycle control and cortical development. Nature Reviews Neuroscience, 8(6),438-450.</ref> The importance of reelin has been greatly studied in mice. Studies showed that mutant mice have disruptions in the migration of neurons into their subsequent layers. By injecting thymidine at various time points of gestation into the female mice, researchers were able to track the development of various populations of neurons. Later developing neurons were unable to ascend past the already early formed neurons due to disruptions in reelin signaling (in the marginal zone). Instead, superficial layer neurons resided below the older, deep layer neurons. This inverted lamination comprises sensory and motor function.<ref> Caviness, V. (1982). Neocortical histogenesis in normal and reeler mice: A developmental study based upon [3H]thymidine autoradiography. Developmental Brain Research, 4(3), 293-302.</ref>
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Timeline and protocol of cerebral organoid development'''<ref><pubmed>25188634</pubmed></ref>]]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

===Future Questions===

http://www.sciencedirect.com/science/article/pii/S0736574804001364 (will most likely use this article)

http://www.sciencedirect.com/science/article/pii/S0149763406000522

https://academic.oup.com/cercor/article/14/7/721/375858/Thinning-of-the-Cerebral-Cortex-in-Aging

==Glossary==

{| class="wikitable"
! style="background:#f4a941" | Term
! style="background:#f4a941" | Definition
|-
| Sulcus || Sulci (plural) are grooves in the cerebral cortex
|-
| Gyrus || Gyri (plural) are folds/ridges in the cerebral cortex
|-
| Fissures || Large sulci
|-
|Corticogenesis || The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes
|-
|Cajal-Retzius (CR) cells || Cortical neurons that develop early on, at the same time as the preplate, and express an important glycoprotein known as reelin, which helps with the proper migration of neurons into their respective layers.
|-
|GABAergic Neurons || Generate gamma aminobutyric acid (GABA) as their output, one of the two inhibitory neurotransmitters in the central nervous system (CNS)
|-
|Radial glial cells || A class of distinct nonneuronal cells that are bipolar shaped and span the entire width of the cortex during development
|}

==INFO/ Research Links (temporary heading)==
 

https://www.youtube.com/watch?v=n6zQbTT0yoY 
https://www.youtube.com/watch?v=X-m0JDCw6TE 

https://www.youtube.com/watch?v=luXDQrmMoUU 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ 
http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue 

https://academic.oup.com/jnen/article/61/1/1/2916251 
https://pdfs.semanticscholar.org/67ea/2ce13f57f4ddbfb7033b6bb1328a5dff7742.pdf 
https://www.youtube.com/watch?v=l_nTggR7LTE 

For concept:
https://www.youtube.com/watch?v=dNngOlsLuGI

You might find this helpful (although you need to request copyright permission):

"Difference Between Cerebrum and Cerebral Cortex." DifferenceBetween.Com. August 7, 2012. < http://www.differencebetween.com/difference-between-cerebrum-and-vs-cerebral-cortex/ >

PubMed Searches: [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebral+Cortex+Development ''Cerebral Cortex Development''] | [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebrum+Development ''Cerebrum Development'']

BMC Dev Biol Search: [http://www.biomedcentral.com/bmcdevbiol/search/results?terms=Cerebral+Cortex+Development ''Cerebral Cortex Development'']

Recent papers

<pubmed limit=5>Cerebral+Cortex+Development</pubmed>

==References==

2017 Group Project 1

2017-10-23T12:47:59Z

Z5177691: /* Animal Models */

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Introcortex.jpg|thumb|right|350px| Fig.1. Cerebral cortex is the outermost layer of the cerebrum <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex surrounds the cerebrum, and is the largest part of the human brain. It is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres; it is around 2-4 mm in thickness, consists of the layer of grey matter and has ~ 10 billion nerve cell bodies and dendrites. 
[[File:Cortex-group project.jpg|thumb|left|300px| Fig 2. Section of the human brain <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]] 

The development of the cerebral cortex involves 3 main stages: proliferation/growth/differentiation, migration of neurons, and maturation/organisation/folding. The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. external pyramidal, IV. internal granular layer, V. internal pyramidal layer, VI. multiform layer. These individual layers organise the capacity for interconnections between both input and output signals.
 
 
 
 
 
 
 
==Early Development of the Brain==
( z5059949 )
 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.

'''Brain Flexures'''

During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

[[File:Neural- cortex Cajal drawing 01.jpg |thumb|right|200px|Laminar and columnar organization of the cerebral cortex (Historical drawing by Cajal)]]

==Development of Cerebral Cortex==
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes. The diversity in neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned in above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contributes to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

getting refererence
<ref><pubmed>17514196</pubmed></ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|450px|super|Key developmental zones in the human cortex]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone
**Subplate
*Cortical Plate: establishment of the 6 cortical layers form in this region between the subplate and the marginal zone

====Timeline of Corticogenesis====
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (e.g fate) of the neurons so that specific connections and cortical structure are achieved. "E" relates to embryonic day in relation to corticogenesis.

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along in order to expand the neocortex. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area as well as the preplate and many of the cells in the SVZ contribute to the later cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to the target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layers 6 is populated before layer 5; layer 5 is populated before layer 4 and so on <ref name="boulder"/>. Each layer condenses and the neurons are closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex such as sensory and motor function.
[[File:Corticogenesis.png|center| 800px|super|Corticogenesis from E30 to adult human brain]]

===Signalling involved in Cerebral Cortex Development===
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 1: Shh signalling increases the number of proliferating cells'''<ref><pubmed> 24653675 </pubmed></ref>]]
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.
[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 2: Cortex development in wild-type and ''reeler'' mice''' <ref>Gilmore, E. and Herrup, K. (1997). Cortical development: Layers of complexity. Current Biology, 7(4), pp.R231-R234. http://www.sciencedirect.com/science/article/pii/S0960982206001084 </ref>]]
'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 1) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 2). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|500px|'''Figure 3: Cortical thickness in the absence of Bmp7'''<ref><pubmed>22461901</pubmed></ref>]]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers. Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref>

[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|Anatomy of the human cerebral cortex <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]]

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull. The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri. Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>

<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>

'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}

==Functions of the Cerebral Cortex==

The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas. <ref name="overall function"><pubmed>21653723</pubmed></ref>

[[File:Cortical areas.png|thumb|right|text-top|450px|Cortical areas human cortex <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body. The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|Cortical Homonculus <ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}

<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>

==Abnormalities associated with Cerebral Cortex Development==
( z5093005 )
[[File:Stages of development.png|thumb|left|text-top||600px|Main stages of cortical development where abnormalities may arise <ref name="imaging"/> ]]

References used to write: <ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>
<ref>Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
<ref>Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref>
<ref>Christopher A, C. (2017). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 

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===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder of uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers and very large cells called 'balloon' cells. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. 
[[File:Hemimegalencephaly.png|thumb|left|upright=1.7|Hemimegalencephaly <ref name="imaging"/> ]]

 
 

<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of a 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form a tumour-like, benign malformation) on part or all of the cerebral hemisphere.

Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. Clinical symptoms of this disease may include developmental delay, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.
[[File:Symptoms of microcephaly.png|thumb|right|upright=1.2|Microcephaly <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]]
 
 
 
 
 
 
<big><big>'''3) Microcephaly Vera'''</big></big>

Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs. 

'''Primary Microcephaly or Microcephaly Vera''' results only due to abnormal cortical development, specifically cell division or proliferation. It is a congenital malformation in which the circumference of the head is quite less than normal and is accompanied by mental retardation and sometimes epilepsy.

<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is thus called due to lesions seen that resembled potato tubers; and is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms) in the cortex. 

" Beneath the cortex, the brain in tuberous sclerosis also shows nodular collections of small cells along the surface of the lateral ventricle that resemble ventricular cells and are called subependymal nodules...or, more descriptively, “candle drippings.” These nodules often contain numerous balloon cells and can in some cases become transformed into glial tumors referred to as subependymal giant cell astrocytomas..."

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:SBH.png|thumb|upright=2.0|right| Heterotopia <ref name="imaging"/> ]]
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex. 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 

<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. 
Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 

Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. 
Type II Lissencephaly also includes: 

#Muscle-Eye-Brain Disease 
#Walker-Warburg Syndrome 
#Fukuyama Syndrome 
*'''Microlissencephaly'''

Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly, and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span.
 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Kallman Syndrome is associated with hypoplasia of the olfactory bulbs and olfactory cortex, called arhinencephaly, and lack of the sense of smell. [not yet changed into own words]

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

[[File:SchizencephalicBrain.jpg|thumb|left|upright=1.6| Schizencephaly <ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder characterised by a cleft(s) or lesion(s) on the brain surface, which is filled with CSF and lined by gray matter.
Schizencephaly can be bilateral or unilateral.

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly.

Schizencephaly commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
 
 
 
 
 
 
 
 
 
===Other Disorders===
<big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right| Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD) <ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome.
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

<html5media height="410" width="600">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref>
 

<html5media height="410" width="600">https://www.youtube.com/watch?v=M7e9JXGOWD4</html5media>
<ref> dimedcom (2013).Corpus callosum agenesis. [video] Available at: https://www.youtube.com/watch?v=M7e9JXGOWD4 [Accessed 6 Oct. 2017].</ref>

==Models and Research==
===Animal Models===

https://bmcneurosci.biomedcentral.com/articles/10.1186/1471-2202-11-75 (reelin in pig model)
[[File:Corticogenesis of mouse and humans.jpeg |right|thumb|400px|'''Mouse vs Human Neurogenesis''']]
Mice have often been used to study corticogenesis in mammals. Corticogenesis lasts from E11 to E19 in mice and lasts eight days. <ref>
Dehay, C. and Kennedy, H. (2007). Cell-cycle control and cortical development. Nature Reviews Neuroscience, 8(6),438-450.</ref> The importance of reelin has been greatly studied in mice. Studies showed that mutant mice have disruptions in the migration of neurons into their subsequent layers. By injecting thymidine at various time points of gestation into the female mice, researchers were able to track the development of various populations of neurons. Later developing neurons were unable to ascend past the already early formed neurons due to disruptions in reelin signaling (in the marginal zone). Instead, superficial layer neurons resided below the older, deep layer neurons. This inverted lamination comprises sensory and motor function.<ref> Caviness, V. (1982). Neocortical histogenesis in normal and reeler mice: A developmental study based upon [3H]thymidine autoradiography. Developmental Brain Research, 4(3), 293-302.</ref>
 
 
 
 
 
 
 
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Timeline and protocol of cerebral organoid development'''<ref><pubmed>25188634</pubmed></ref>]]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

===Future Questions===

==Glossary==

{| class="wikitable"
! style="background:#f4a941" | Term
! style="background:#f4a941" | Definition
|-
| Sulcus || Sulci (plural) are grooves in the cerebral cortex
|-
| Gyrus || Gyri (plural) are folds/ridges in the cerebral cortex
|-
| Fissures || Large sulci
|-
|Corticogenesis || The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes
|-
|Cajal-Retzius (CR) cells || Cortical neurons that develop early on, at the same time as the preplate, and express an important glycoprotein known as reelin, which helps with the proper migration of neurons into their respective layers.
|}

==INFO/ Research Links (temporary heading)==
 

https://www.youtube.com/watch?v=n6zQbTT0yoY 
https://www.youtube.com/watch?v=X-m0JDCw6TE 

https://www.youtube.com/watch?v=luXDQrmMoUU 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ 
http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue 

https://academic.oup.com/jnen/article/61/1/1/2916251 
https://pdfs.semanticscholar.org/67ea/2ce13f57f4ddbfb7033b6bb1328a5dff7742.pdf 
https://www.youtube.com/watch?v=l_nTggR7LTE 

For concept:
https://www.youtube.com/watch?v=dNngOlsLuGI

You might find this helpful (although you need to request copyright permission):

"Difference Between Cerebrum and Cerebral Cortex." DifferenceBetween.Com. August 7, 2012. < http://www.differencebetween.com/difference-between-cerebrum-and-vs-cerebral-cortex/ >

PubMed Searches: [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebral+Cortex+Development ''Cerebral Cortex Development''] | [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebrum+Development ''Cerebrum Development'']

BMC Dev Biol Search: [http://www.biomedcentral.com/bmcdevbiol/search/results?terms=Cerebral+Cortex+Development ''Cerebral Cortex Development'']

Recent papers

<pubmed limit=5>Cerebral+Cortex+Development</pubmed>

==References==

2017 Group Project 1

2017-10-23T12:45:42Z

Z5177691: /* Animal Models */

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Introcortex.jpg|thumb|right|350px| Fig.1. Cerebral cortex is the outermost layer of the cerebrum <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex surrounds the cerebrum, and is the largest part of the human brain. It is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres; it is around 2-4 mm in thickness, consists of the layer of grey matter and has ~ 10 billion nerve cell bodies and dendrites. 
[[File:Cortex-group project.jpg|thumb|left|300px| Fig 2. Section of the human brain <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]] 

The development of the cerebral cortex involves 3 main stages: proliferation/growth/differentiation, migration of neurons, and maturation/organisation/folding. The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. external pyramidal, IV. internal granular layer, V. internal pyramidal layer, VI. multiform layer. These individual layers organise the capacity for interconnections between both input and output signals.
 
 
 
 
 
 
 
==Early Development of the Brain==
( z5059949 )
 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.

'''Brain Flexures'''

During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

[[File:Neural- cortex Cajal drawing 01.jpg |thumb|right|200px|Laminar and columnar organization of the cerebral cortex (Historical drawing by Cajal)]]

==Development of Cerebral Cortex==
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes. The diversity in neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned in above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contributes to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

getting refererence
<ref><pubmed>17514196</pubmed></ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|450px|super|Key developmental zones in the human cortex]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone
**Subplate
*Cortical Plate: establishment of the 6 cortical layers form in this region between the subplate and the marginal zone

====Timeline of Corticogenesis====
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (e.g fate) of the neurons so that specific connections and cortical structure are achieved. "E" relates to embryonic day in relation to corticogenesis.

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along in order to expand the neocortex. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area as well as the preplate and many of the cells in the SVZ contribute to the later cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to the target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layers 6 is populated before layer 5; layer 5 is populated before layer 4 and so on <ref name="boulder"/>. Each layer condenses and the neurons are closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex such as sensory and motor function.
[[File:Corticogenesis.png|center| 800px|super|Corticogenesis from E30 to adult human brain]]

===Signalling involved in Cerebral Cortex Development===
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 1: Shh signalling increases the number of proliferating cells'''<ref><pubmed> 24653675 </pubmed></ref>]]
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.
[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 2: Cortex development in wild-type and ''reeler'' mice''' <ref>Gilmore, E. and Herrup, K. (1997). Cortical development: Layers of complexity. Current Biology, 7(4), pp.R231-R234. http://www.sciencedirect.com/science/article/pii/S0960982206001084 </ref>]]
'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 1) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 2). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|500px|'''Figure 3: Cortical thickness in the absence of Bmp7'''<ref><pubmed>22461901</pubmed></ref>]]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers. Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref>

[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|Anatomy of the human cerebral cortex <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]]

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull. The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri. Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>

<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>

'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}

==Functions of the Cerebral Cortex==

The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas. <ref name="overall function"><pubmed>21653723</pubmed></ref>

[[File:Cortical areas.png|thumb|right|text-top|450px|Cortical areas human cortex <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body. The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|Cortical Homonculus <ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}

<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>

==Abnormalities associated with Cerebral Cortex Development==
( z5093005 )
[[File:Stages of development.png|thumb|left|text-top||600px|Main stages of cortical development where abnormalities may arise <ref name="imaging"/> ]]

References used to write: <ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>
<ref>Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
<ref>Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref>
<ref>Christopher A, C. (2017). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 

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===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder of uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers and very large cells called 'balloon' cells. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. 
[[File:Hemimegalencephaly.png|thumb|left|upright=1.7|Hemimegalencephaly <ref name="imaging"/> ]]

 
 

<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of a 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form a tumour-like, benign malformation) on part or all of the cerebral hemisphere.

Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. Clinical symptoms of this disease may include developmental delay, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.
[[File:Symptoms of microcephaly.png|thumb|right|upright=1.2|Microcephaly <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]]
 
 
 
 
 
 
<big><big>'''3) Microcephaly Vera'''</big></big>

Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs. 

'''Primary Microcephaly or Microcephaly Vera''' results only due to abnormal cortical development, specifically cell division or proliferation. It is a congenital malformation in which the circumference of the head is quite less than normal and is accompanied by mental retardation and sometimes epilepsy.

<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is thus called due to lesions seen that resembled potato tubers; and is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms) in the cortex. 

" Beneath the cortex, the brain in tuberous sclerosis also shows nodular collections of small cells along the surface of the lateral ventricle that resemble ventricular cells and are called subependymal nodules...or, more descriptively, “candle drippings.” These nodules often contain numerous balloon cells and can in some cases become transformed into glial tumors referred to as subependymal giant cell astrocytomas..."

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:SBH.png|thumb|upright=2.0|right| Heterotopia <ref name="imaging"/> ]]
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex. 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 

<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. 
Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 

Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. 
Type II Lissencephaly also includes: 

#Muscle-Eye-Brain Disease 
#Walker-Warburg Syndrome 
#Fukuyama Syndrome 
*'''Microlissencephaly'''

Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly, and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span.
 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Kallman Syndrome is associated with hypoplasia of the olfactory bulbs and olfactory cortex, called arhinencephaly, and lack of the sense of smell. [not yet changed into own words]

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

[[File:SchizencephalicBrain.jpg|thumb|left|upright=1.6| Schizencephaly <ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder characterised by a cleft(s) or lesion(s) on the brain surface, which is filled with CSF and lined by gray matter.
Schizencephaly can be bilateral or unilateral.

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly.

Schizencephaly commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
 
 
 
 
 
 
 
 
 
===Other Disorders===
<big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right| Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD) <ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome.
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

<html5media height="410" width="600">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref>
 

<html5media height="410" width="600">https://www.youtube.com/watch?v=M7e9JXGOWD4</html5media>
<ref> dimedcom (2013).Corpus callosum agenesis. [video] Available at: https://www.youtube.com/watch?v=M7e9JXGOWD4 [Accessed 6 Oct. 2017].</ref>

==Models and Research==
===Animal Models===

https://bmcneurosci.biomedcentral.com/articles/10.1186/1471-2202-11-75 (reelin in pig model)
[[File:Corticogenesis of mouse and humans.jpeg |right|thumb|400px|'''Mouse and Human Neurogenesis''']]
Mice have often been used to study corticogenesis in mammals. Corticogenesis lasts from E11 to E19 in mice and lasts eight days. <ref>
Dehay, C. and Kennedy, H. (2007). Cell-cycle control and cortical development. Nature Reviews Neuroscience, 8(6),438-450.</ref> The importance of reelin has been greatly studied in mice. Studies showed that mutant mice have disruptions in the migration of neurons into their subsequent layers. By injecting thymidine at various time points of gestation into the female mice, researchers were able to track the development of various populations of neurons. Later developing neurons were unable to ascend past the already early formed neurons due to disruptions in reelin signaling (in the marginal zone). Instead, superficial layer neurons resided below the older, deep layer neurons. This inverted lamination comprises sensory and motor function.<ref> Caviness, V. (1982). Neocortical histogenesis in normal and reeler mice: A developmental study based upon [3H]thymidine autoradiography. Developmental Brain Research, 4(3), 293-302.</ref>
 
 
 
 
 
 
 
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Timeline and protocol of cerebral organoid development'''<ref><pubmed>25188634</pubmed></ref>]]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

===Future Questions===

==Glossary==

{| class="wikitable"
! style="background:#f4a941" | Term
! style="background:#f4a941" | Definition
|-
| Sulcus || Sulci (plural) are grooves in the cerebral cortex
|-
| Gyrus || Gyri (plural) are folds/ridges in the cerebral cortex
|-
| Fissures || Large sulci
|-
|Corticogenesis || The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes
|-
|Cajal-Retzius (CR) cells || Cortical neurons that develop early on, at the same time as the preplate, and express an important glycoprotein known as reelin, which helps with the proper migration of neurons into their respective layers.
|}

==INFO/ Research Links (temporary heading)==
 

https://www.youtube.com/watch?v=n6zQbTT0yoY 
https://www.youtube.com/watch?v=X-m0JDCw6TE 

https://www.youtube.com/watch?v=luXDQrmMoUU 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ 
http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue 

https://academic.oup.com/jnen/article/61/1/1/2916251 
https://pdfs.semanticscholar.org/67ea/2ce13f57f4ddbfb7033b6bb1328a5dff7742.pdf 
https://www.youtube.com/watch?v=l_nTggR7LTE 

For concept:
https://www.youtube.com/watch?v=dNngOlsLuGI

You might find this helpful (although you need to request copyright permission):

"Difference Between Cerebrum and Cerebral Cortex." DifferenceBetween.Com. August 7, 2012. < http://www.differencebetween.com/difference-between-cerebrum-and-vs-cerebral-cortex/ >

PubMed Searches: [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebral+Cortex+Development ''Cerebral Cortex Development''] | [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebrum+Development ''Cerebrum Development'']

BMC Dev Biol Search: [http://www.biomedcentral.com/bmcdevbiol/search/results?terms=Cerebral+Cortex+Development ''Cerebral Cortex Development'']

Recent papers

<pubmed limit=5>Cerebral+Cortex+Development</pubmed>

==References==

2017 Group Project 1

2017-10-23T12:41:34Z

Z5177691: /* Animal Models */

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Introcortex.jpg|thumb|right|350px| Fig.1. Cerebral cortex is the outermost layer of the cerebrum <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex surrounds the cerebrum, and is the largest part of the human brain. It is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres; it is around 2-4 mm in thickness, consists of the layer of grey matter and has ~ 10 billion nerve cell bodies and dendrites. 
[[File:Cortex-group project.jpg|thumb|left|300px| Fig 2. Section of the human brain <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]] 

The development of the cerebral cortex involves 3 main stages: proliferation/growth/differentiation, migration of neurons, and maturation/organisation/folding. The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. external pyramidal, IV. internal granular layer, V. internal pyramidal layer, VI. multiform layer. These individual layers organise the capacity for interconnections between both input and output signals.
 
 
 
 
 
 
 
==Early Development of the Brain==
( z5059949 )
 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.

'''Brain Flexures'''

During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

[[File:Neural- cortex Cajal drawing 01.jpg |thumb|right|200px|Laminar and columnar organization of the cerebral cortex (Historical drawing by Cajal)]]

==Development of Cerebral Cortex==
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes. The diversity in neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned in above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contributes to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

getting refererence
<ref><pubmed>17514196</pubmed></ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|450px|super|Key developmental zones in the human cortex]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone
**Subplate
*Cortical Plate: establishment of the 6 cortical layers form in this region between the subplate and the marginal zone

====Timeline of Corticogenesis====
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (e.g fate) of the neurons so that specific connections and cortical structure are achieved. "E" relates to embryonic day in relation to corticogenesis.

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along in order to expand the neocortex. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area as well as the preplate and many of the cells in the SVZ contribute to the later cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to the target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layers 6 is populated before layer 5; layer 5 is populated before layer 4 and so on <ref name="boulder"/>. Each layer condenses and the neurons are closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex such as sensory and motor function.
[[File:Corticogenesis.png|center| 800px|super|Corticogenesis from E30 to adult human brain]]

===Signalling involved in Cerebral Cortex Development===
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 1: Shh signalling increases the number of proliferating cells'''<ref><pubmed> 24653675 </pubmed></ref>]]
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.
[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 2: Cortex development in wild-type and ''reeler'' mice''' <ref>Gilmore, E. and Herrup, K. (1997). Cortical development: Layers of complexity. Current Biology, 7(4), pp.R231-R234. http://www.sciencedirect.com/science/article/pii/S0960982206001084 </ref>]]
'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 1) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 2). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|500px|'''Figure 3: Cortical thickness in the absence of Bmp7'''<ref><pubmed>22461901</pubmed></ref>]]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers. Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref>

[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|Anatomy of the human cerebral cortex <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]]

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull. The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri. Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>

<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>

'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}

==Functions of the Cerebral Cortex==

The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas. <ref name="overall function"><pubmed>21653723</pubmed></ref>

[[File:Cortical areas.png|thumb|right|text-top|450px|Cortical areas human cortex <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body. The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|Cortical Homonculus <ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}

<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>

==Abnormalities associated with Cerebral Cortex Development==
( z5093005 )
[[File:Stages of development.png|thumb|left|text-top||600px|Main stages of cortical development where abnormalities may arise <ref name="imaging"/> ]]

References used to write: <ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>
<ref>Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
<ref>Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref>
<ref>Christopher A, C. (2017). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 

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===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder of uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers and very large cells called 'balloon' cells. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. 
[[File:Hemimegalencephaly.png|thumb|left|upright=1.7|Hemimegalencephaly <ref name="imaging"/> ]]

 
 

<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of a 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form a tumour-like, benign malformation) on part or all of the cerebral hemisphere.

Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. Clinical symptoms of this disease may include developmental delay, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.
[[File:Symptoms of microcephaly.png|thumb|right|upright=1.2|Microcephaly <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]]
 
 
 
 
 
 
<big><big>'''3) Microcephaly Vera'''</big></big>

Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs. 

'''Primary Microcephaly or Microcephaly Vera''' results only due to abnormal cortical development, specifically cell division or proliferation. It is a congenital malformation in which the circumference of the head is quite less than normal and is accompanied by mental retardation and sometimes epilepsy.

<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is thus called due to lesions seen that resembled potato tubers; and is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms) in the cortex. 

" Beneath the cortex, the brain in tuberous sclerosis also shows nodular collections of small cells along the surface of the lateral ventricle that resemble ventricular cells and are called subependymal nodules...or, more descriptively, “candle drippings.” These nodules often contain numerous balloon cells and can in some cases become transformed into glial tumors referred to as subependymal giant cell astrocytomas..."

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:SBH.png|thumb|upright=2.0|right| Heterotopia <ref name="imaging"/> ]]
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex. 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 

<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. 
Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 

Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. 
Type II Lissencephaly also includes: 

#Muscle-Eye-Brain Disease 
#Walker-Warburg Syndrome 
#Fukuyama Syndrome 
*'''Microlissencephaly'''

Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly, and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span.
 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Kallman Syndrome is associated with hypoplasia of the olfactory bulbs and olfactory cortex, called arhinencephaly, and lack of the sense of smell. [not yet changed into own words]

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

[[File:SchizencephalicBrain.jpg|thumb|left|upright=1.6| Schizencephaly <ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder characterised by a cleft(s) or lesion(s) on the brain surface, which is filled with CSF and lined by gray matter.
Schizencephaly can be bilateral or unilateral.

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly.

Schizencephaly commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
 
 
 
 
 
 
 
 
 
===Other Disorders===
<big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right| Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD) <ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome.
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

<html5media height="410" width="600">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref>
 

<html5media height="410" width="600">https://www.youtube.com/watch?v=M7e9JXGOWD4</html5media>
<ref> dimedcom (2013).Corpus callosum agenesis. [video] Available at: https://www.youtube.com/watch?v=M7e9JXGOWD4 [Accessed 6 Oct. 2017].</ref>

==Models and Research==
===Animal Models===

https://bmcneurosci.biomedcentral.com/articles/10.1186/1471-2202-11-75 (reelin in pig model)

Mice have often been used to study corticogenesis in mammals. Corticogenesis lasts from E11 to E19 in mice and lasts eight days. <ref>
Dehay, C. and Kennedy, H. (2007). Cell-cycle control and cortical development. Nature Reviews Neuroscience, 8(6),438-450.</ref> The importance of reelin has been greatly studied in mice. Studies showed that mutant mice have disruptions in the migration of neurons into their subsequent layers. By injecting thymidine at various time points of gestation into the female mice, researchers were able to track the development of various populations of neurons. Later developing neurons were unable to ascend past the already early formed neurons due to disruptions in reelin signaling (in the marginal zone). Instead, superficial layer neurons resided below the older, deep layer neurons. This inverted lamination comprises sensory and motor function.<ref> Caviness, V. (1982). Neocortical histogenesis in normal and reeler mice: A developmental study based upon [3H]thymidine autoradiography. Developmental Brain Research, 4(3), 293-302.</ref>

[[File:Corticogenesis of mouse and humans.jpeg |right|thumb|400px|'''Mouse and Human Neurogenesis''']]
 
 
 
 
 
 
 
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Timeline and protocol of cerebral organoid development'''<ref><pubmed>25188634</pubmed></ref>]]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

===Future Questions===

==Glossary==

{| class="wikitable"
! style="background:#f4a941" | Term
! style="background:#f4a941" | Definition
|-
| Sulcus || Sulci (plural) are grooves in the cerebral cortex
|-
| Gyrus || Gyri (plural) are folds/ridges in the cerebral cortex
|-
| Fissures || Large sulci
|-
|Corticogenesis || The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes
|-
|Cajal-Retzius (CR) cells || Cortical neurons that develop early on, at the same time as the preplate, and express an important glycoprotein known as reelin, which helps with the proper migration of neurons into their respective layers.
|}

==INFO/ Research Links (temporary heading)==
 

https://www.youtube.com/watch?v=n6zQbTT0yoY 
https://www.youtube.com/watch?v=X-m0JDCw6TE 

https://www.youtube.com/watch?v=luXDQrmMoUU 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ 
http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue 

https://academic.oup.com/jnen/article/61/1/1/2916251 
https://pdfs.semanticscholar.org/67ea/2ce13f57f4ddbfb7033b6bb1328a5dff7742.pdf 
https://www.youtube.com/watch?v=l_nTggR7LTE 

For concept:
https://www.youtube.com/watch?v=dNngOlsLuGI

You might find this helpful (although you need to request copyright permission):

"Difference Between Cerebrum and Cerebral Cortex." DifferenceBetween.Com. August 7, 2012. < http://www.differencebetween.com/difference-between-cerebrum-and-vs-cerebral-cortex/ >

PubMed Searches: [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebral+Cortex+Development ''Cerebral Cortex Development''] | [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebrum+Development ''Cerebrum Development'']

BMC Dev Biol Search: [http://www.biomedcentral.com/bmcdevbiol/search/results?terms=Cerebral+Cortex+Development ''Cerebral Cortex Development'']

Recent papers

<pubmed limit=5>Cerebral+Cortex+Development</pubmed>

==References==

2017 Group Project 1

2017-10-23T12:37:46Z

Z5177691: /* Animal Models */

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Introcortex.jpg|thumb|right|350px| Fig.1. Cerebral cortex is the outermost layer of the cerebrum <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex surrounds the cerebrum, and is the largest part of the human brain. It is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres; it is around 2-4 mm in thickness, consists of the layer of grey matter and has ~ 10 billion nerve cell bodies and dendrites. 
[[File:Cortex-group project.jpg|thumb|left|300px| Fig 2. Section of the human brain <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]] 

The development of the cerebral cortex involves 3 main stages: proliferation/growth/differentiation, migration of neurons, and maturation/organisation/folding. The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. external pyramidal, IV. internal granular layer, V. internal pyramidal layer, VI. multiform layer. These individual layers organise the capacity for interconnections between both input and output signals.
 
 
 
 
 
 
 
==Early Development of the Brain==
( z5059949 )
 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.

'''Brain Flexures'''

During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

[[File:Neural- cortex Cajal drawing 01.jpg |thumb|right|200px|Laminar and columnar organization of the cerebral cortex (Historical drawing by Cajal)]]

==Development of Cerebral Cortex==
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes. The diversity in neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned in above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contributes to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

getting refererence
<ref><pubmed>17514196</pubmed></ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|450px|super|Key developmental zones in the human cortex]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone
**Subplate
*Cortical Plate: establishment of the 6 cortical layers form in this region between the subplate and the marginal zone

====Timeline of Corticogenesis====
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (e.g fate) of the neurons so that specific connections and cortical structure are achieved. "E" relates to embryonic day in relation to corticogenesis.

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along in order to expand the neocortex. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area as well as the preplate and many of the cells in the SVZ contribute to the later cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to the target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layers 6 is populated before layer 5; layer 5 is populated before layer 4 and so on <ref name="boulder"/>. Each layer condenses and the neurons are closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex such as sensory and motor function.
[[File:Corticogenesis.png|center| 800px|super|Corticogenesis from E30 to adult human brain]]

===Signalling involved in Cerebral Cortex Development===
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 1: Shh signalling increases the number of proliferating cells'''<ref><pubmed> 24653675 </pubmed></ref>]]
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.
[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 2: Cortex development in wild-type and ''reeler'' mice''' <ref>Gilmore, E. and Herrup, K. (1997). Cortical development: Layers of complexity. Current Biology, 7(4), pp.R231-R234. http://www.sciencedirect.com/science/article/pii/S0960982206001084 </ref>]]
'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 1) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 2). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|500px|'''Figure 3: Cortical thickness in the absence of Bmp7'''<ref><pubmed>22461901</pubmed></ref>]]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers. Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref>

[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|Anatomy of the human cerebral cortex <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]]

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull. The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri. Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>

<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>

'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}

==Functions of the Cerebral Cortex==

The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas. <ref name="overall function"><pubmed>21653723</pubmed></ref>

[[File:Cortical areas.png|thumb|right|text-top|450px|Cortical areas human cortex <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body. The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|Cortical Homonculus <ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}

<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>

==Abnormalities associated with Cerebral Cortex Development==
( z5093005 )
[[File:Stages of development.png|thumb|left|text-top||600px|Main stages of cortical development where abnormalities may arise <ref name="imaging"/> ]]

References used to write: <ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>
<ref>Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
<ref>Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref>
<ref>Christopher A, C. (2017). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 

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===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder of uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers and very large cells called 'balloon' cells. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. 
[[File:Hemimegalencephaly.png|thumb|left|upright=1.7|Hemimegalencephaly <ref name="imaging"/> ]]

 
 

<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of a 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form a tumour-like, benign malformation) on part or all of the cerebral hemisphere.

Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. Clinical symptoms of this disease may include developmental delay, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.
[[File:Symptoms of microcephaly.png|thumb|right|upright=1.2|Microcephaly <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]]
 
 
 
 
 
 
<big><big>'''3) Microcephaly Vera'''</big></big>

Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs. 

'''Primary Microcephaly or Microcephaly Vera''' results only due to abnormal cortical development, specifically cell division or proliferation. It is a congenital malformation in which the circumference of the head is quite less than normal and is accompanied by mental retardation and sometimes epilepsy.

<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is thus called due to lesions seen that resembled potato tubers; and is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms) in the cortex. 

" Beneath the cortex, the brain in tuberous sclerosis also shows nodular collections of small cells along the surface of the lateral ventricle that resemble ventricular cells and are called subependymal nodules...or, more descriptively, “candle drippings.” These nodules often contain numerous balloon cells and can in some cases become transformed into glial tumors referred to as subependymal giant cell astrocytomas..."

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:SBH.png|thumb|upright=2.0|right| Heterotopia <ref name="imaging"/> ]]
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex. 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 

<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. 
Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 

Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. 
Type II Lissencephaly also includes: 

#Muscle-Eye-Brain Disease 
#Walker-Warburg Syndrome 
#Fukuyama Syndrome 
*'''Microlissencephaly'''

Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly, and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span.
 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Kallman Syndrome is associated with hypoplasia of the olfactory bulbs and olfactory cortex, called arhinencephaly, and lack of the sense of smell. [not yet changed into own words]

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

[[File:SchizencephalicBrain.jpg|thumb|left|upright=1.6| Schizencephaly <ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder characterised by a cleft(s) or lesion(s) on the brain surface, which is filled with CSF and lined by gray matter.
Schizencephaly can be bilateral or unilateral.

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly.

Schizencephaly commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
 
 
 
 
 
 
 
 
 
===Other Disorders===
<big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right| Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD) <ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome.
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

<html5media height="410" width="600">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref>
 

<html5media height="410" width="600">https://www.youtube.com/watch?v=M7e9JXGOWD4</html5media>
<ref> dimedcom (2013).Corpus callosum agenesis. [video] Available at: https://www.youtube.com/watch?v=M7e9JXGOWD4 [Accessed 6 Oct. 2017].</ref>

==Models and Research==
===Animal Models===

https://bmcneurosci.biomedcentral.com/articles/10.1186/1471-2202-11-75 (reelin in pig model)

Mice have often been used to study corticogenesis in mammals. Corticogenesis lasts from E11 to E19 in mice and lasts eight days. <ref>
Dehay, C. and Kennedy, H. (2007). Cell-cycle control and cortical development. Nature Reviews Neuroscience, 8(6), pp.438-450.</ref> The importance of reelin has been greatly studied in mice. Studies showed that mutant mice have disruptions in the migration of neurons into their subsequent layers. By injecting thymidine at various time points of gestation into the female mice, researchers were able to track the development of various populations of neurons. Later developing neurons were unable to ascend past the already early formed neurons due to disruptions in reelin signaling (in the marginal zone). Instead, superficial layer neurons resided below the older, deep layer neurons. This inverted lamination comprises sensory and motor function.<ref> Caviness, V. (1982). Neocortical histogenesis in normal and reeler mice: A developmental study based upon [3H]thymidine autoradiography. Developmental Brain Research, 4(3), pp.293-302.</ref>

[[File:Corticogenesis of mouse and humans.jpeg |left|thumb|600px|'''Mouse and Human Neurogenesis''']]
 
 
 
 
 
 
 
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Timeline and protocol of cerebral organoid development'''<ref><pubmed>25188634</pubmed></ref>]]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

===Future Questions===

==Glossary==

{| class="wikitable"
! style="background:#f4a941" | Term
! style="background:#f4a941" | Definition
|-
| Sulcus || Sulci (plural) are grooves in the cerebral cortex
|-
| Gyrus || Gyri (plural) are folds/ridges in the cerebral cortex
|-
| Fissures || Large sulci
|-
|Corticogenesis || The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes
|-
|Cajal-Retzius (CR) cells || Cortical neurons that develop early on, at the same time as the preplate, and express an important glycoprotein known as reelin, which helps with the proper migration of neurons into their respective layers.
|}

==INFO/ Research Links (temporary heading)==
 

https://www.youtube.com/watch?v=n6zQbTT0yoY 
https://www.youtube.com/watch?v=X-m0JDCw6TE 

https://www.youtube.com/watch?v=luXDQrmMoUU 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ 
http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue 

https://academic.oup.com/jnen/article/61/1/1/2916251 
https://pdfs.semanticscholar.org/67ea/2ce13f57f4ddbfb7033b6bb1328a5dff7742.pdf 
https://www.youtube.com/watch?v=l_nTggR7LTE 

For concept:
https://www.youtube.com/watch?v=dNngOlsLuGI

You might find this helpful (although you need to request copyright permission):

"Difference Between Cerebrum and Cerebral Cortex." DifferenceBetween.Com. August 7, 2012. < http://www.differencebetween.com/difference-between-cerebrum-and-vs-cerebral-cortex/ >

PubMed Searches: [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebral+Cortex+Development ''Cerebral Cortex Development''] | [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebrum+Development ''Cerebrum Development'']

BMC Dev Biol Search: [http://www.biomedcentral.com/bmcdevbiol/search/results?terms=Cerebral+Cortex+Development ''Cerebral Cortex Development'']

Recent papers

<pubmed limit=5>Cerebral+Cortex+Development</pubmed>

==References==

2017 Group Project 1

2017-10-23T12:35:40Z

Z5177691: /* Animal Models */

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Introcortex.jpg|thumb|right|350px| Fig.1. Cerebral cortex is the outermost layer of the cerebrum <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex surrounds the cerebrum, and is the largest part of the human brain. It is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres; it is around 2-4 mm in thickness, consists of the layer of grey matter and has ~ 10 billion nerve cell bodies and dendrites. 
[[File:Cortex-group project.jpg|thumb|left|300px| Fig 2. Section of the human brain <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]] 

The development of the cerebral cortex involves 3 main stages: proliferation/growth/differentiation, migration of neurons, and maturation/organisation/folding. The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. external pyramidal, IV. internal granular layer, V. internal pyramidal layer, VI. multiform layer. These individual layers organise the capacity for interconnections between both input and output signals.
 
 
 
 
 
 
 
==Early Development of the Brain==
( z5059949 )
 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.

'''Brain Flexures'''

During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

[[File:Neural- cortex Cajal drawing 01.jpg |thumb|right|200px|Laminar and columnar organization of the cerebral cortex (Historical drawing by Cajal)]]

==Development of Cerebral Cortex==
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes. The diversity in neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned in above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contributes to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

getting refererence
<ref><pubmed>17514196</pubmed></ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|450px|super|Key developmental zones in the human cortex]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone
**Subplate
*Cortical Plate: establishment of the 6 cortical layers form in this region between the subplate and the marginal zone

====Timeline of Corticogenesis====
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (e.g fate) of the neurons so that specific connections and cortical structure are achieved. "E" relates to embryonic day in relation to corticogenesis.

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along in order to expand the neocortex. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area as well as the preplate and many of the cells in the SVZ contribute to the later cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to the target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layers 6 is populated before layer 5; layer 5 is populated before layer 4 and so on <ref name="boulder"/>. Each layer condenses and the neurons are closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex such as sensory and motor function.
[[File:Corticogenesis.png|center| 800px|super|Corticogenesis from E30 to adult human brain]]

===Signalling involved in Cerebral Cortex Development===
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 1: Shh signalling increases the number of proliferating cells'''<ref><pubmed> 24653675 </pubmed></ref>]]
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.
[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 2: Cortex development in wild-type and ''reeler'' mice''' <ref>Gilmore, E. and Herrup, K. (1997). Cortical development: Layers of complexity. Current Biology, 7(4), pp.R231-R234. http://www.sciencedirect.com/science/article/pii/S0960982206001084 </ref>]]
'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 1) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 2). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|500px|'''Figure 3: Cortical thickness in the absence of Bmp7'''<ref><pubmed>22461901</pubmed></ref>]]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers. Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref>

[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|Anatomy of the human cerebral cortex <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]]

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull. The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri. Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>

<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>

'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}

==Functions of the Cerebral Cortex==

The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas. <ref name="overall function"><pubmed>21653723</pubmed></ref>

[[File:Cortical areas.png|thumb|right|text-top|450px|Cortical areas human cortex <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body. The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|Cortical Homonculus <ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}

<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>

==Abnormalities associated with Cerebral Cortex Development==
( z5093005 )
[[File:Stages of development.png|thumb|left|text-top||600px|Main stages of cortical development where abnormalities may arise <ref name="imaging"/> ]]

References used to write: <ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>
<ref>Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
<ref>Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref>
<ref>Christopher A, C. (2017). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 

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===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder of uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers and very large cells called 'balloon' cells. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. 
[[File:Hemimegalencephaly.png|thumb|left|upright=1.7|Hemimegalencephaly <ref name="imaging"/> ]]

 
 

<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of a 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form a tumour-like, benign malformation) on part or all of the cerebral hemisphere.

Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. Clinical symptoms of this disease may include developmental delay, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.
[[File:Symptoms of microcephaly.png|thumb|right|upright=1.2|Microcephaly <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]]
 
 
 
 
 
 
<big><big>'''3) Microcephaly Vera'''</big></big>

Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs. 

'''Primary Microcephaly or Microcephaly Vera''' results only due to abnormal cortical development, specifically cell division or proliferation. It is a congenital malformation in which the circumference of the head is quite less than normal and is accompanied by mental retardation and sometimes epilepsy.

<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is thus called due to lesions seen that resembled potato tubers; and is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms) in the cortex. 

" Beneath the cortex, the brain in tuberous sclerosis also shows nodular collections of small cells along the surface of the lateral ventricle that resemble ventricular cells and are called subependymal nodules...or, more descriptively, “candle drippings.” These nodules often contain numerous balloon cells and can in some cases become transformed into glial tumors referred to as subependymal giant cell astrocytomas..."

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:SBH.png|thumb|upright=2.0|right| Heterotopia <ref name="imaging"/> ]]
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex. 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 

<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. 
Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 

Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. 
Type II Lissencephaly also includes: 

#Muscle-Eye-Brain Disease 
#Walker-Warburg Syndrome 
#Fukuyama Syndrome 
*'''Microlissencephaly'''

Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly, and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span.
 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Kallman Syndrome is associated with hypoplasia of the olfactory bulbs and olfactory cortex, called arhinencephaly, and lack of the sense of smell. [not yet changed into own words]

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

[[File:SchizencephalicBrain.jpg|thumb|left|upright=1.6| Schizencephaly <ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder characterised by a cleft(s) or lesion(s) on the brain surface, which is filled with CSF and lined by gray matter.
Schizencephaly can be bilateral or unilateral.

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly.

Schizencephaly commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
 
 
 
 
 
 
 
 
 
===Other Disorders===
<big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right| Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD) <ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome.
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

<html5media height="410" width="600">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref>
 

<html5media height="410" width="600">https://www.youtube.com/watch?v=M7e9JXGOWD4</html5media>
<ref> dimedcom (2013).Corpus callosum agenesis. [video] Available at: https://www.youtube.com/watch?v=M7e9JXGOWD4 [Accessed 6 Oct. 2017].</ref>

==Models and Research==
===Animal Models===

https://bmcneurosci.biomedcentral.com/articles/10.1186/1471-2202-11-75 (reelin in pig model)

Mice have often been used to study corticogenesis in mammals. Corticogenesis lasts from E11 to E19 in mice and lasts eight days. (cell cycle control) The importance of reelin has been greatly studied in mice. Studies showed that mutant mice have disruptions in the migration of neurons into their subsequent layers. By injecting thymidine at various time points of gestation into the female mice, researchers were able to track the development of various populations of neurons. Later developing neurons were unable to ascend past the already early formed neurons due to disruptions in reelin signaling (in the marginal zone). Instead, superficial layer neurons resided below the older, deep layer neurons. This inverted lamination comprises sensory and motor function. (reeler mice)

Dehay, C. and Kennedy, H. (2007). Cell-cycle control and cortical development. Nature Reviews Neuroscience, 8(6), pp.438-450.

[[File:Corticogenesis of mouse and humans.jpeg |left|thumb|600px|'''Mouse and Human Neurogenesis''']]
 
 
 
 
 
 
 
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Timeline and protocol of cerebral organoid development'''<ref><pubmed>25188634</pubmed></ref>]]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

===Future Questions===

==Glossary==

{| class="wikitable"
! style="background:#f4a941" | Term
! style="background:#f4a941" | Definition
|-
| Sulcus || Sulci (plural) are grooves in the cerebral cortex
|-
| Gyrus || Gyri (plural) are folds/ridges in the cerebral cortex
|-
| Fissures || Large sulci
|-
|Corticogenesis || The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes
|-
|Cajal-Retzius (CR) cells || Cortical neurons that develop early on, at the same time as the preplate, and express an important glycoprotein known as reelin, which helps with the proper migration of neurons into their respective layers.
|}

==INFO/ Research Links (temporary heading)==
 

https://www.youtube.com/watch?v=n6zQbTT0yoY 
https://www.youtube.com/watch?v=X-m0JDCw6TE 

https://www.youtube.com/watch?v=luXDQrmMoUU 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ 
http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue 

https://academic.oup.com/jnen/article/61/1/1/2916251 
https://pdfs.semanticscholar.org/67ea/2ce13f57f4ddbfb7033b6bb1328a5dff7742.pdf 
https://www.youtube.com/watch?v=l_nTggR7LTE 

For concept:
https://www.youtube.com/watch?v=dNngOlsLuGI

You might find this helpful (although you need to request copyright permission):

"Difference Between Cerebrum and Cerebral Cortex." DifferenceBetween.Com. August 7, 2012. < http://www.differencebetween.com/difference-between-cerebrum-and-vs-cerebral-cortex/ >

PubMed Searches: [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebral+Cortex+Development ''Cerebral Cortex Development''] | [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebrum+Development ''Cerebrum Development'']

BMC Dev Biol Search: [http://www.biomedcentral.com/bmcdevbiol/search/results?terms=Cerebral+Cortex+Development ''Cerebral Cortex Development'']

Recent papers

<pubmed limit=5>Cerebral+Cortex+Development</pubmed>

==References==

2017 Group Project 1

2017-10-23T11:55:56Z

Z5177691: /* Timeline of Corticogenesis */

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Introcortex.jpg|thumb|right|350px| Fig.1. Cerebral cortex is the outermost layer of the cerebrum <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex surrounds the cerebrum, and is the largest part of the human brain. It is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres; it is around 2-4 mm in thickness, consists of the layer of grey matter and has ~ 10 billion nerve cell bodies and dendrites. 
[[File:Cortex-group project.jpg|thumb|left|300px| Fig 2. Section of the human brain <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]] 

The development of the cerebral cortex involves 3 main stages: proliferation/growth/differentiation, migration of neurons, and maturation/organisation/folding. The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. external pyramidal, IV. internal granular layer, V. internal pyramidal layer, VI. multiform layer. These individual layers organise the capacity for interconnections between both input and output signals.
 
 
 
 
 
 
 
==Early Development of the Brain==
( z5059949 )
 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.

'''Brain Flexures'''

During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

[[File:Neural- cortex Cajal drawing 01.jpg |thumb|right|200px|Laminar and columnar organization of the cerebral cortex (Historical drawing by Cajal)]]

==Development of Cerebral Cortex==
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes. The diversity in neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned in above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contributes to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

getting refererence
<ref><pubmed>17514196</pubmed></ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|450px|super|Key developmental zones in the human cortex]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone
**Subplate
*Cortical Plate: establishment of the 6 cortical layers form in this region between the subplate and the marginal zone

====Timeline of Corticogenesis====
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (e.g fate) of the neurons so that specific connections and cortical structure are achieved. "E" relates to embryonic day in relation to corticogenesis.

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along in order to expand the neocortex. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area as well as the preplate and many of the cells in the SVZ contribute to the later cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to the target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layers 6 is populated before layer 5; layer 5 is populated before layer 4 and so on <ref name="boulder"/>. Each layer condenses and the neurons are closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex such as sensory and motor function.
[[File:Corticogenesis.png|center| 800px|super|Corticogenesis from E30 to adult human brain]]

===Signalling involved in Cerebral Cortex Development===
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 1: Shh signalling increases the number of proliferating cells'''<ref><pubmed> 24653675 </pubmed></ref>]]
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.
[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 2: Cortex development in wild-type and ''reeler'' mice''' <ref>Gilmore, E. and Herrup, K. (1997). Cortical development: Layers of complexity. Current Biology, 7(4), pp.R231-R234. http://www.sciencedirect.com/science/article/pii/S0960982206001084 </ref>]]
'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 1) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 2). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|500px|'''Figure 3: Cortical thickness in the absence of Bmp7'''<ref><pubmed>22461901</pubmed></ref>]]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers. Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref>

[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|Anatomy of the human cerebral cortex <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]]

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull. The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri. Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>

<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>

'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}

==Functions of the Cerebral Cortex==

The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas. <ref name="overall function"><pubmed>21653723</pubmed></ref>

[[File:Cortical areas.png|thumb|right|text-top|450px|Cortical areas human cortex <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body. The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|Cortical Homonculus <ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}

<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>

==Abnormalities associated with Cerebral Cortex Development==
( z5093005 )
[[File:Stages of development.png|thumb|left|text-top||600px|Main stages of cortical development where abnormalities may arise <ref name="imaging"/> ]]

References used to write: <ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>
<ref>Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
<ref>Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref>
<ref>Christopher A, C. (2017). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 

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===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder of uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers and very large cells called 'balloon' cells. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. 
[[File:Hemimegalencephaly.png|thumb|left|upright=1.7|Hemimegalencephaly <ref name="imaging"/> ]]

 
 

<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of a 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form a tumour-like, benign malformation) on part or all of the cerebral hemisphere.

Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. Clinical symptoms of this disease may include developmental delay, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.
[[File:Symptoms of microcephaly.png|thumb|right|upright=1.2|Microcephaly <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]]
 
 
 
 
 
 
<big><big>'''3) Microcephaly Vera'''</big></big>

Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs. 

'''Primary Microcephaly or Microcephaly Vera''' results only due to abnormal cortical development, specifically cell division or proliferation. It is a congenital malformation in which the circumference of the head is quite less than normal and is accompanied by mental retardation and sometimes epilepsy.

<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is thus called due to lesions seen that resembled potato tubers; and is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms) in the cortex. 

" Beneath the cortex, the brain in tuberous sclerosis also shows nodular collections of small cells along the surface of the lateral ventricle that resemble ventricular cells and are called subependymal nodules...or, more descriptively, “candle drippings.” These nodules often contain numerous balloon cells and can in some cases become transformed into glial tumors referred to as subependymal giant cell astrocytomas..."

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:SBH.png|thumb|upright=2.0|right| Heterotopia <ref name="imaging"/> ]]
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex. 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 

<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. 
Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 

Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. 
Type II Lissencephaly also includes: 

#Muscle-Eye-Brain Disease 
#Walker-Warburg Syndrome 
#Fukuyama Syndrome 
*'''Microlissencephaly'''

Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly, and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span.
 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Kallman Syndrome is associated with hypoplasia of the olfactory bulbs and olfactory cortex, called arhinencephaly, and lack of the sense of smell. [not yet changed into own words]

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

[[File:SchizencephalicBrain.jpg|thumb|left|upright=1.6| Schizencephaly <ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder characterised by a cleft(s) or lesion(s) on the brain surface, which is filled with CSF and lined by gray matter.
Schizencephaly can be bilateral or unilateral.

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly.

Schizencephaly commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
 
 
 
 
 
 
 
 
 
===Other Disorders===
<big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right| Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD) <ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome.
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

<html5media height="410" width="600">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref>
 

<html5media height="410" width="600">https://www.youtube.com/watch?v=M7e9JXGOWD4</html5media>
<ref> dimedcom (2013).Corpus callosum agenesis. [video] Available at: https://www.youtube.com/watch?v=M7e9JXGOWD4 [Accessed 6 Oct. 2017].</ref>

==Models and Research==
===Animal Models===

https://bmcneurosci.biomedcentral.com/articles/10.1186/1471-2202-11-75 (reelin in pig model)

[[File:Corticogenesis of mouse and humans.jpeg |left|thumb|600px|'''Mouse and Human Neurogenesis''']]
 
 
 
 
 
 
 
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Timeline and protocol of cerebral organoid development'''<ref><pubmed>25188634</pubmed></ref>]]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

===Future Questions===

==Glossary==

{| class="wikitable"
! style="background:#f4a941" | Term
! style="background:#f4a941" | Definition
|-
| Sulcus || Sulci (plural) are grooves in the cerebral cortex
|-
| Gyrus || Gyri (plural) are folds/ridges in the cerebral cortex
|-
| Fissures || Large sulci
|-
|Corticogenesis || The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes
|-
|Cajal-Retzius (CR) cells || Cortical neurons that develop early on, at the same time as the preplate, and express an important glycoprotein known as reelin, which helps with the proper migration of neurons into their respective layers.
|}

==INFO/ Research Links (temporary heading)==
 

https://www.youtube.com/watch?v=n6zQbTT0yoY 
https://www.youtube.com/watch?v=X-m0JDCw6TE 

https://www.youtube.com/watch?v=luXDQrmMoUU 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ 
http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue 

https://academic.oup.com/jnen/article/61/1/1/2916251 
https://pdfs.semanticscholar.org/67ea/2ce13f57f4ddbfb7033b6bb1328a5dff7742.pdf 
https://www.youtube.com/watch?v=l_nTggR7LTE 

For concept:
https://www.youtube.com/watch?v=dNngOlsLuGI

You might find this helpful (although you need to request copyright permission):

"Difference Between Cerebrum and Cerebral Cortex." DifferenceBetween.Com. August 7, 2012. < http://www.differencebetween.com/difference-between-cerebrum-and-vs-cerebral-cortex/ >

PubMed Searches: [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebral+Cortex+Development ''Cerebral Cortex Development''] | [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebrum+Development ''Cerebrum Development'']

BMC Dev Biol Search: [http://www.biomedcentral.com/bmcdevbiol/search/results?terms=Cerebral+Cortex+Development ''Cerebral Cortex Development'']

Recent papers

<pubmed limit=5>Cerebral+Cortex+Development</pubmed>

==References==

2017 Group Project 1

2017-10-23T11:48:37Z

Z5177691: /* Development of Cerebral Cortex */

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Introcortex.jpg|thumb|right|350px| Fig.1. Cerebral cortex is the outermost layer of the cerebrum <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex surrounds the cerebrum, and is the largest part of the human brain. It is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres; it is around 2-4 mm in thickness, consists of the layer of grey matter and has ~ 10 billion nerve cell bodies and dendrites. 
[[File:Cortex-group project.jpg|thumb|left|300px| Fig 2. Section of the human brain <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]] 

The development of the cerebral cortex involves 3 main stages: proliferation/growth/differentiation, migration of neurons, and maturation/organisation/folding. The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. external pyramidal, IV. internal granular layer, V. internal pyramidal layer, VI. multiform layer. These individual layers organise the capacity for interconnections between both input and output signals.
 
 
 
 
 
 
 
==Early Development of the Brain==
( z5059949 )
 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.

'''Brain Flexures'''

During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

[[File:Neural- cortex Cajal drawing 01.jpg |thumb|right|200px|Laminar and columnar organization of the cerebral cortex (Historical drawing by Cajal)]]

==Development of Cerebral Cortex==
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes. The diversity in neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned in above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contributes to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

getting refererence
<ref><pubmed>17514196</pubmed></ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|450px|super|Key developmental zones in the human cortex]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone
**Subplate
*Cortical Plate: establishment of the 6 cortical layers form in this region between the subplate and the marginal zone

====Timeline of Corticogenesis====
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (e.g fate) of the neurons so that specific connections and cortical structure are achieved. "E" relates to embryonic day in relation to corticogenesis.

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along in order to expand the neocortex. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area as well as the preplate and many of the cells in the SVZ contribute to the later cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to the target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layers 6 is populated before layer 5; layer 5 is populated before layer 4 and so on <ref name="boulder"/>. Each layer condenses and the neurons are closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex.
[[File:Corticogenesis.png|center| 800px|super|Corticogenesis from E30 to adult human brain]]

===Signalling involved in Cerebral Cortex Development===
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 1: Shh signalling increases the number of proliferating cells'''<ref><pubmed> 24653675 </pubmed></ref>]]
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.
[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 2: Cortex development in wild-type and ''reeler'' mice''' <ref>Gilmore, E. and Herrup, K. (1997). Cortical development: Layers of complexity. Current Biology, 7(4), pp.R231-R234. http://www.sciencedirect.com/science/article/pii/S0960982206001084 </ref>]]
'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 1) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 2). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|500px|'''Figure 3: Cortical thickness in the absence of Bmp7'''<ref><pubmed>22461901</pubmed></ref>]]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers. Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref>

[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|Anatomy of the human cerebral cortex <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]]

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull. The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri. Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>

<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>

'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}

==Functions of the Cerebral Cortex==

The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas. <ref name="overall function"><pubmed>21653723</pubmed></ref>

[[File:Cortical areas.png|thumb|right|text-top|450px|Cortical areas human cortex <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body. The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|Cortical Homonculus <ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}

<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>

==Abnormalities associated with Cerebral Cortex Development==
( z5093005 )
[[File:Stages of development.png|thumb|left|text-top||600px|Main stages of cortical development where abnormalities may arise <ref name="imaging"/> ]]

References used to write: <ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>
<ref>Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
<ref>Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref>
<ref>Christopher A, C. (2017). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 

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===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder of uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers and very large cells called 'balloon' cells. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. 
[[File:Hemimegalencephaly.png|thumb|left|upright=1.7|Hemimegalencephaly <ref name="imaging"/> ]]

 
 

<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of a 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form a tumour-like, benign malformation) on part or all of the cerebral hemisphere.

Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. Clinical symptoms of this disease may include developmental delay, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.
[[File:Symptoms of microcephaly.png|thumb|right|upright=1.2|Microcephaly <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]]
 
 
 
 
 
 
<big><big>'''3) Microcephaly Vera'''</big></big>

Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs. 

'''Primary Microcephaly or Microcephaly Vera''' results only due to abnormal cortical development, specifically cell division or proliferation. It is a congenital malformation in which the circumference of the head is quite less than normal and is accompanied by mental retardation and sometimes epilepsy.

<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is thus called due to lesions seen that resembled potato tubers; and is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms) in the cortex. 

" Beneath the cortex, the brain in tuberous sclerosis also shows nodular collections of small cells along the surface of the lateral ventricle that resemble ventricular cells and are called subependymal nodules...or, more descriptively, “candle drippings.” These nodules often contain numerous balloon cells and can in some cases become transformed into glial tumors referred to as subependymal giant cell astrocytomas..."

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:SBH.png|thumb|upright=2.0|right| Heterotopia <ref name="imaging"/> ]]
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex. 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 

<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. 
Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 

Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. 
Type II Lissencephaly also includes: 

#Muscle-Eye-Brain Disease 
#Walker-Warburg Syndrome 
#Fukuyama Syndrome 
*'''Microlissencephaly'''

Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly, and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span.
 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Kallman Syndrome is associated with hypoplasia of the olfactory bulbs and olfactory cortex, called arhinencephaly, and lack of the sense of smell. [not yet changed into own words]

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

[[File:SchizencephalicBrain.jpg|thumb|left|upright=1.6| Schizencephaly <ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder characterised by a cleft(s) or lesion(s) on the brain surface, which is filled with CSF and lined by gray matter.
Schizencephaly can be bilateral or unilateral.

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly.

Schizencephaly commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
 
 
 
 
 
 
 
 
 
===Other Disorders===
<big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right| Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD) <ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome.
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

<html5media height="410" width="600">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref>
 

<html5media height="410" width="600">https://www.youtube.com/watch?v=M7e9JXGOWD4</html5media>
<ref> dimedcom (2013).Corpus callosum agenesis. [video] Available at: https://www.youtube.com/watch?v=M7e9JXGOWD4 [Accessed 6 Oct. 2017].</ref>

==Models and Research==
===Animal Models===

https://bmcneurosci.biomedcentral.com/articles/10.1186/1471-2202-11-75 (reelin in pig model)

[[File:Corticogenesis of mouse and humans.jpeg |left|thumb|600px|'''Mouse and Human Neurogenesis''']]
 
 
 
 
 
 
 
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Timeline and protocol of cerebral organoid development'''<ref><pubmed>25188634</pubmed></ref>]]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

===Future Questions===

==Glossary==

{| class="wikitable"
! style="background:#f4a941" | Term
! style="background:#f4a941" | Definition
|-
| Sulcus || Sulci (plural) are grooves in the cerebral cortex
|-
| Gyrus || Gyri (plural) are folds/ridges in the cerebral cortex
|-
| Fissures || Large sulci
|-
|Corticogenesis || The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes
|-
|Cajal-Retzius (CR) cells || Cortical neurons that develop early on, at the same time as the preplate, and express an important glycoprotein known as reelin, which helps with the proper migration of neurons into their respective layers.
|}

==INFO/ Research Links (temporary heading)==
 

https://www.youtube.com/watch?v=n6zQbTT0yoY 
https://www.youtube.com/watch?v=X-m0JDCw6TE 

https://www.youtube.com/watch?v=luXDQrmMoUU 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ 
http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue 

https://academic.oup.com/jnen/article/61/1/1/2916251 
https://pdfs.semanticscholar.org/67ea/2ce13f57f4ddbfb7033b6bb1328a5dff7742.pdf 
https://www.youtube.com/watch?v=l_nTggR7LTE 

For concept:
https://www.youtube.com/watch?v=dNngOlsLuGI

You might find this helpful (although you need to request copyright permission):

"Difference Between Cerebrum and Cerebral Cortex." DifferenceBetween.Com. August 7, 2012. < http://www.differencebetween.com/difference-between-cerebrum-and-vs-cerebral-cortex/ >

PubMed Searches: [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebral+Cortex+Development ''Cerebral Cortex Development''] | [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebrum+Development ''Cerebrum Development'']

BMC Dev Biol Search: [http://www.biomedcentral.com/bmcdevbiol/search/results?terms=Cerebral+Cortex+Development ''Cerebral Cortex Development'']

Recent papers

<pubmed limit=5>Cerebral+Cortex+Development</pubmed>

==References==

2017 Group Project 1

2017-10-23T11:44:28Z

Z5177691: /* Glossary */

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Introcortex.jpg|thumb|right|350px| Fig.1. Cerebral cortex is the outermost layer of the cerebrum <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex surrounds the cerebrum, and is the largest part of the human brain. It is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres; it is around 2-4 mm in thickness, consists of the layer of grey matter and has ~ 10 billion nerve cell bodies and dendrites. 
[[File:Cortex-group project.jpg|thumb|left|300px| Fig 2. Section of the human brain <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]] 

The development of the cerebral cortex involves 3 main stages: proliferation/growth/differentiation, migration of neurons, and maturation/organisation/folding. The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. external pyramidal, IV. internal granular layer, V. internal pyramidal layer, VI. multiform layer. These individual layers organise the capacity for interconnections between both input and output signals.
 
 
 
 
 
 
 
==Early Development of the Brain==
( z5059949 )
 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.

'''Brain Flexures'''

During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

[[File:Neural- cortex Cajal drawing 01.jpg |thumb|right|200px|Laminar and columnar organization of the cerebral cortex (Historical drawing by Cajal)]]

==Development of Cerebral Cortex==
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes. The diversity in neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned in above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contributes to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

getting refererence
<ref><pubmed>17514196</pubmed></ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|450px|super|Key developmental zones in the human cortex]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone:
**Subplate:
*Cortical Plate: where the 6 layers of the cortex form, exists in between the subplate and the marginal zone

====Timeline of Corticogenesis====
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (e.g fate) of the neurons so that specific connections and cortical structure are achieved. "E" relates to embryonic day in relation to corticogenesis.

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along in order to expand the neocortex. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area as well as the preplate and many of the cells in the SVZ contribute to the later cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to the target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layers 6 is populated before layer 5; layer 5 is populated before layer 4 and so on <ref name="boulder"/>. Each layer condenses and the neurons are closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex.
[[File:Corticogenesis.png|center| 800px|super|Corticogenesis from E30 to adult human brain]]

===Signalling involved in Cerebral Cortex Development===
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 1: Shh signalling increases the number of proliferating cells'''<ref><pubmed> 24653675 </pubmed></ref>]]
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.
[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 2: Cortex development in wild-type and ''reeler'' mice''' <ref>Gilmore, E. and Herrup, K. (1997). Cortical development: Layers of complexity. Current Biology, 7(4), pp.R231-R234. http://www.sciencedirect.com/science/article/pii/S0960982206001084 </ref>]]
'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 1) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 2). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|500px|'''Figure 3: Cortical thickness in the absence of Bmp7'''<ref><pubmed>22461901</pubmed></ref>]]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers. Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref>

[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|Anatomy of the human cerebral cortex <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]]

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull. The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri. Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>

<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>

'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}

==Functions of the Cerebral Cortex==

The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas. <ref name="overall function"><pubmed>21653723</pubmed></ref>

[[File:Cortical areas.png|thumb|right|text-top|450px|Cortical areas human cortex <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body. The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|Cortical Homonculus <ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}

<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>

==Abnormalities associated with Cerebral Cortex Development==
( z5093005 )
[[File:Stages of development.png|thumb|left|text-top||600px|Main stages of cortical development where abnormalities may arise <ref name="imaging"/> ]]

References used to write: <ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>
<ref>Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
<ref>Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref>
<ref>Christopher A, C. (2017). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 

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===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder of uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers and very large cells called 'balloon' cells. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. 
[[File:Hemimegalencephaly.png|thumb|left|upright=1.7|Hemimegalencephaly <ref name="imaging"/> ]]

 
 

<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of a 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form a tumour-like, benign malformation) on part or all of the cerebral hemisphere.

Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. Clinical symptoms of this disease may include developmental delay, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.
[[File:Symptoms of microcephaly.png|thumb|right|upright=1.2|Microcephaly <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]]
 
 
 
 
 
 
<big><big>'''3) Microcephaly Vera'''</big></big>

Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs. 

'''Primary Microcephaly or Microcephaly Vera''' results only due to abnormal cortical development, specifically cell division or proliferation. It is a congenital malformation in which the circumference of the head is quite less than normal and is accompanied by mental retardation and sometimes epilepsy.

<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is thus called due to lesions seen that resembled potato tubers; and is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms) in the cortex. 

" Beneath the cortex, the brain in tuberous sclerosis also shows nodular collections of small cells along the surface of the lateral ventricle that resemble ventricular cells and are called subependymal nodules...or, more descriptively, “candle drippings.” These nodules often contain numerous balloon cells and can in some cases become transformed into glial tumors referred to as subependymal giant cell astrocytomas..."

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:SBH.png|thumb|upright=2.0|right| Heterotopia <ref name="imaging"/> ]]
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex. 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 

<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. 
Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 

Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. 
Type II Lissencephaly also includes: 

#Muscle-Eye-Brain Disease 
#Walker-Warburg Syndrome 
#Fukuyama Syndrome 
*'''Microlissencephaly'''

Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly, and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span.
 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Kallman Syndrome is associated with hypoplasia of the olfactory bulbs and olfactory cortex, called arhinencephaly, and lack of the sense of smell. [not yet changed into own words]

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

[[File:SchizencephalicBrain.jpg|thumb|left|upright=1.6| Schizencephaly <ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder characterised by a cleft(s) or lesion(s) on the brain surface, which is filled with CSF and lined by gray matter.
Schizencephaly can be bilateral or unilateral.

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly.

Schizencephaly commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
 
 
 
 
 
 
 
 
 
===Other Disorders===
<big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right| Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD) <ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome.
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

<html5media height="410" width="600">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref>
 

<html5media height="410" width="600">https://www.youtube.com/watch?v=M7e9JXGOWD4</html5media>
<ref> dimedcom (2013).Corpus callosum agenesis. [video] Available at: https://www.youtube.com/watch?v=M7e9JXGOWD4 [Accessed 6 Oct. 2017].</ref>

==Models and Research==
===Animal Models===

https://bmcneurosci.biomedcentral.com/articles/10.1186/1471-2202-11-75 (reelin in pig model)

[[File:Corticogenesis of mouse and humans.jpeg |left|thumb|600px|'''Mouse and Human Neurogenesis''']]
 
 
 
 
 
 
 
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Timeline and protocol of cerebral organoid development'''<ref><pubmed>25188634</pubmed></ref>]]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

===Future Questions===

==Glossary==

{| class="wikitable"
! style="background:#f4a941" | Term
! style="background:#f4a941" | Definition
|-
| Sulcus || Sulci (plural) are grooves in the cerebral cortex
|-
| Gyrus || Gyri (plural) are folds/ridges in the cerebral cortex
|-
| Fissures || Large sulci
|-
|Corticogenesis || The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes
|-
|Cajal-Retzius (CR) cells || Cortical neurons that develop early on, at the same time as the preplate, and express an important glycoprotein known as reelin, which helps with the proper migration of neurons into their respective layers.
|}

==INFO/ Research Links (temporary heading)==
 

https://www.youtube.com/watch?v=n6zQbTT0yoY 
https://www.youtube.com/watch?v=X-m0JDCw6TE 

https://www.youtube.com/watch?v=luXDQrmMoUU 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ 
http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue 

https://academic.oup.com/jnen/article/61/1/1/2916251 
https://pdfs.semanticscholar.org/67ea/2ce13f57f4ddbfb7033b6bb1328a5dff7742.pdf 
https://www.youtube.com/watch?v=l_nTggR7LTE 

For concept:
https://www.youtube.com/watch?v=dNngOlsLuGI

You might find this helpful (although you need to request copyright permission):

"Difference Between Cerebrum and Cerebral Cortex." DifferenceBetween.Com. August 7, 2012. < http://www.differencebetween.com/difference-between-cerebrum-and-vs-cerebral-cortex/ >

PubMed Searches: [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebral+Cortex+Development ''Cerebral Cortex Development''] | [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebrum+Development ''Cerebrum Development'']

BMC Dev Biol Search: [http://www.biomedcentral.com/bmcdevbiol/search/results?terms=Cerebral+Cortex+Development ''Cerebral Cortex Development'']

Recent papers

<pubmed limit=5>Cerebral+Cortex+Development</pubmed>

==References==

2017 Group Project 1

2017-10-23T11:38:04Z

Z5177691: /* Development of Cerebral Cortex */

=Cerebral Cortex=
{{ANAT2341Project2017header}}


==Introduction==
[[File:Introcortex.jpg|thumb|right|350px| Fig.1. Cerebral cortex is the outermost layer of the cerebrum <ref>Thomas, A. (2015). [image] Available at: http://slideplayer.com/slide/6617450/ [Accessed 23 Oct. 2017].</ref> ]]
 
The cerebral cortex surrounds the cerebrum, and is the largest part of the human brain. It is thought to be the main control centre, playing an essential role in cognitive function, memory, sensation and association.The cerebral cortex differs from the cerebrum because, the cerebral cortex is the outermost layer of the cerebral hemispheres; it is around 2-4 mm in thickness, consists of the layer of grey matter and has ~ 10 billion nerve cell bodies and dendrites. 
[[File:Cortex-group project.jpg|thumb|left|300px| Fig 2. Section of the human brain <ref>Mikayla D (2017). 23. [image] Available at: https://psych-brain-trust.wikispaces.com/Thalamus [Accessed 23 Oct. 2017].</ref> ]] 

The development of the cerebral cortex involves 3 main stages: proliferation/growth/differentiation, migration of neurons, and maturation/organisation/folding. The cortex is organised into six horizontal layers. I. Molecular layer, II. External granular layer , III. external pyramidal, IV. internal granular layer, V. internal pyramidal layer, VI. multiform layer. These individual layers organise the capacity for interconnections between both input and output signals.
 
 
 
 
 
 
 
==Early Development of the Brain==
( z5059949 )
 

The brain begins to develop during the third week of pregnancy when the neural plate and neural tube are derived from the outer most layer of embryonic cells, that is the neuroectoderm. The development of the brain is from the neural plate which folds to form the neural groove and then curls forming the neural tube, which is cranial to the fourth pair of somites, and eventually, forms the three primary brain vesicles <ref name="lecture"> Embryology.med.unsw.edu.au. (2017). Lecture - Ectoderm Development - Embryology. [online] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Ectoderm_Development. </ref>.

Neuroprogenitor cells proliferate, migrate, and differentiate to form specific areas of the brain <ref name="textbook"/>.

During week four fusion of the neural folds in the cranial region and closure of the rostral neuropore form three primary brain vesicles from which the brain develops <ref name="lecture"/>:
*Forebrain/Prosecephalon
*Midbrain/Mesencephalon
*Hindbrain/Rhombencephalon

From the three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five. These are fundamental divisions of the adult brain and communicate freely with each other <ref name="Gray"> Gray, H. (1977). Gray's Anatomy. New York, New York: Crown Publishers, Inc. </ref>. They are <ref name ="textbook"> Moore, K., Persaud, T. and Torchia, M. (2015). The developing human. Philadelphia, PA: Elsevier. </ref>:
*Telencephalon: endbrain, forms cerebral hemispheres - derived from Prosecephalon
*Diencephalon: between brain, forms optic outgrowth - derived from Prosecephalon
*Mesencephalon: undivided
*Metencephalon: posterior to the brain, gives rise to the pons (bulbous expansion consisting of white matter tracts serving the cerebellum) <ref name ="ebook"/> - derived from Rhombencephalon
*Myelencephalon: gives rise to the medulla oblongata - derived from Rhombencephalon
In the beginning, these five divisions are uniform in size and shape but quickly differentiate at various rates <ref name="Gray"/>.

As the telencephalon is the region that develops into the cerebral cortex, we will discuss this region specifically in more detail. The telencephalon is the utmost rostral region of the brain vesicles, and consists of:
*The median region: the lamina terminalis, with the cavity forming the anterior part of the third ventricle <ref name ="discovery"> Pansky, B. (n.d.). Chapter 155. The Brain: The Telencephalon (first Vesicle) - Review of Medical Embryology Book - LifeMap Discovery. [online] Discovery.lifemapsc.com. Available at: https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-155-the-brain-the-telencephalon-first-vesicle. </ref>
*Two lateral diverticula: the cerebral hemispheres <ref name="textbook"/>
The cerebral hemispheres grow simultaneously in lateral, longitudinal and parietal directions <ref name="discovery"/>, and originally are in communication with the third ventricle cavity via the interventricular foramina <ref name="textbook"/>. Upon expansion, the cerebral hemispheres eventually cover the diencephalon, midbrain and hindbrain, where they will eventually congregate at the midline, resulting in the flattening of each hemispheres medial surfaces <ref name="textbook"/>. During the sixth week the corpus striatum emerges as an obvious swelling in the floor of both of the cerebral hemispheres. the floors expand at a slower rate compared to the hemispheres thin cortical walls, as it contains large crpus striatum, causing the cerebral hemispheres to become a c shape <ref name="textbook"/>. This growth and curvature of the cerebral hemispheres does have consequential effects on the shape of the lateral ventricles, which too become c-shaped and fill with cerebrospinal fluid (CSF). Each hemispheres caudal ends turn ventrally, and then rostrally resulting in the formation of the temporal lobe.
The telencephalon is further subdivided into a dorsal pallium and a cenrtral subpallium. The dorsal pallium forms the large neuronal nuclei of the basal ganglia (corpus striatum, globus pallidus) <ref name="ebook"/>. These structures are essential for fulfilling commands from the cerebral hemispheres, and appear as lateral outpouchings of the pallium growing at a fast rate in order to cover the mesencephalon and diencephalon. The cortex is formed by the pallium, or vault, of each hemisphere.

'''Brain Flexures'''

During the fifth week, the embryonic brain undergoes rapid growth, folding the neural tube, consequently resulting in three brain flexures. These are <ref name="lecture"/>:
*Cephalic flexure - centered at the midbrain region and pushes mesencephalon upwards being the first fold to develop, ventral folding of the brain tube <ref name ="ebook"> Schoenwolf, G., Bleyl, S., Brauer, P. and Francis-West, P. (2015). Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, pp.197-233. </ref>
*Cervical flexure - between brain stem and spinal cord at the junction of the spinal cord and hindbrain, ventral folding of the brain tube <ref name="ebook"/>
*Pontine flexure - beings at the developing pons, generates the fourth ventricle; produced in the opposite direction - dorsal folding <ref name="ebook"/> - as a result of later unequal brain growth, resulting in the thinning of the roof of the hindbrain <ref name="Gray"/>.
The primordial brain initially has the same basic structure as the developing spinal cord, however, consideration variations in the outline of transverse sections at different levels of the brain and in the position of the gray and white matter are produced by the brain flexures <ref name="textbook"/>. The sulcus limitans (the floor of the fourth ventricle) extends cranially to the junction of the midbrain and forebrain, and the alar and basal plates are recognisable only in the midbrain and hindbrain <ref name="textbook"/>.

[[File:Neural- cortex Cajal drawing 01.jpg |thumb|right|200px|Laminar and columnar organization of the cerebral cortex (Historical drawing by Cajal)]]

==Development of Cerebral Cortex==
Corticogenesis refers to the development of the cerebral cortex, the outer portion of the cerebrum, into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes. The diversity in neurons contributes to the complex circuitry involved in the mammalian cortex. The large size of the cortex distinguishes humans from other mammals because it corresponds to a larger capacity to perform behavioral and cognitive tasks. <ref name="boulder"><pubmed> 18209730 </pubmed></ref> As mentioned in above in “Early Development of the Brain,” the cerebral cortex is derived from telencephalon, the rostral end of the neural tube. Origins of various neuronal subtypes come from the pallium (roof) and the subpallium (base) sections of the telencephalon which contributes to the overall laminar and columnar organization of the cortex. <ref name="migration">Marin, O., & Rubenstein, J. L. R. (2003). Cell migration in the forebrain. Annual Review of Neuroscience, 26, 441-83.</ref>

getting refererence
<ref><pubmed>17514196</pubmed></ref>

 
'''Main classes of neurons''' <ref name="logic"><pubmed> PMC3876965 </pubmed></ref>
*'''Projection neurons:''' excitatory neurons (glutamatergic) with axons that project to distant targets and are generated by progenitors in the dorsal pallium of the telencephalon. The have a typical pyramidal structure and send signals to various regions of the brain and neocortex.
*'''Interneurons:''' inhibitory neurons (GABAergic) that have local connections within the cortex and are generated in the subpallium of the telecephalon in the ventral proliferative zone. These neurons have to migrate to the neocortex area.
[[File:Stage 22 image 217.jpg |thumb|right|450px|super|Key developmental zones in the human cortex]]

 
'''Key developmental zones in the human cortex: '''
*Ventricular zone
*Subventricular zone
**Inner Subventricular Zone
**Outer Subventricular zone
*Intermediate Zone
*Preplate: neural progenitor cells split into 2 regions
**Marginal zone:
**Subplate:
*Cortical Plate: where the 6 layers of the cortex form, exists in between the subplate and the marginal zone

====Timeline of Corticogenesis====
The dorsolateral wall of the telencephalon is initially made up of undifferentiated neuroepithelial cells at the beginning of development. The cells are neural stem cells, capable of dividing into various neuronal subtypes. <ref name="boulder"/> The timing of birth for these neuronal subtypes determines the location (e.g fate) of the neurons so that specific connections and cortical structure are achieved. "E" relates to embryonic day in relation to corticogenesis.

{| class="wikitable"
! style="background:#f4a941" | DAY
! style="background:#f4a941" | DEVELOPMENT
|-
| E30|| Progenitors in the dorsal telencephalon divide symmetrically and give rise to the initial '''ventricular zone (VZ)''', a single layer of cells that attach their "feet" to the cerebral wall and divide. These neurons lay adjacent to the ventricular surface. <ref name="boulder"/>
|-
| E31-32 || Dividing cells from the VZ begin to differentiate into "pioneer" neurons to form the '''preplate.''' These neurons migrate radially and tangentially from the VZ to the pial surface in an upward fashion. These cells are often referred to as '''radial glial cells (RGCs)''' because they contain radial fibers that span the entire embryonic wall from the VZ to the pial surface. These fibers create a "scaffolding" for subsequent migrating neurons to attach to and travel along in order to expand the neocortex. These cells are multipotent cells that divide asymmetrically to produce intermediate precursor cells that can become projection neurons, astrocytes, and oligodendrocytes <ref name="cerebral"><pubmed> PMC4334136 </pubmed></ref> . In addition to RGCs, '''Cajal-Retzius (CR) cells''' are another type of early born neurons that develop at the same time as the preplate. These cells express reelin, an important signaling factor for migrating neurons to properly organize into their destined layers. They remain in the marginal zone when the preplate splits into two (see E50-55).<ref name="migration"/> The preplate is referred to as heterogeneous because it contains many developing cell types.
|-
| E40-45 || Cells in the VZ continue to divide symmetrically and give rise to another zone known as the '''subventricular zone (SVZ)'''. This proliferative layer lies above the ventricular zone and is not attached to the ventricular surface. Radial glial cells also populate this area as well as the preplate and many of the cells in the SVZ contribute to the later cortical neurons. The SVZ also separates into the outer subventricular zone (OSVZ) and the inner subventricular zone (ISVZ). The OSVZ continues to expand as it produces more migrating immature neurons and intermediate precursor cells. <ref name="cerebral"/>
|-
| E50-55|| The preplate begins to split into two subsections: the '''marginal zone''' and the '''subplate.''' An intermediate zone forms below the subplate and contains only migrating cells (migrating to the target destination) and no intermediate precursor cells. The '''cortical plate''' also begins to form in between the two regions <ref name="logic"/>. Newly born neurons that migrate to the cortical plate are developed '''"inside out"'''. This term "inside-out" means that earlier born cells populate the deep layers first and later born neurons populate the superficial layers of the neocortex by migrating past the deep layers. Therefore, layers 6 is populated before layer 5; layer 5 is populated before layer 4 and so on <ref name="boulder"/>. Each layer condenses and the neurons are closely packed. As the layers form, the cortex expands.
|}
Migration and division of all six layers of the cortex is completed during the third trimester.<ref name="boulder"/> Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex.
[[File:Corticogenesis.png|center| 800px|super|Corticogenesis from E30 to adult human brain]]

===Signalling involved in Cerebral Cortex Development===
[[File:Screen Shot 2017-10-15 at 13.31.05.png |thumb|right|text-top|500px| '''Figure 1: Shh signalling increases the number of proliferating cells'''<ref><pubmed> 24653675 </pubmed></ref>]]
Cell signalling is an essential part of the laminar patterning of the cerebral cortex into its 6 distinct, radially organised layers. There is a large network of interweaving signalling pathways that are responsible for the formation of this sophisticated anatomical structure and its functioning. There is still much debate about the exact pathways and signalling molecules that lead to this specific patterning, however some factors contributing to the control of cortical differentiation have been uncovered.
[[File:Cortical plate development.jpg |thumb|left|text-top|350px| '''Figure 2: Cortex development in wild-type and ''reeler'' mice''' <ref>Gilmore, E. and Herrup, K. (1997). Cortical development: Layers of complexity. Current Biology, 7(4), pp.R231-R234. http://www.sciencedirect.com/science/article/pii/S0960982206001084 </ref>]]
'''Sonic Hedgehog''' (Shh) is a morphogen involved in regulating the development of many different tissue types. During the development of the neocortex, Shh plays a role in controlling the proliferation and survival of cortical progenitor cells along with the specification of cerebral cortex GABAergic neurons. <ref><pubmed>20159447</pubmed></ref>

It has been shown that blockade of Shh in murine models with cyclopamine has effects on cortical neurogenesis, with indications that Shh morphogen could be play a role in the control of cell cycle length, cell growth and the process of cell division of the dorsal telencephalon progenitors during early corticogenesis (Fig. 1) <ref><pubmed> 24653675 </pubmed></ref>

'''Reelin''' is one of the more well understood signalling pathways involved in corticogenesis. Cajal-Retzuis cells with are located in the marginal zone (MZ) secrete Reelin (an extracellular matrix glycoprotein). Through studies that examine the absence of Reelin in reeler mutant mice, neuronal migration is significantly altered (Fig. 2). Additionally, Reelin has been shown to have a crucial role in inducing branching and specific positioning of radial glial cells (RGC), in that the distribution of Reelin within the MZ defines the specific location of radially migrating neurons, and is essential for the characteristic ‘inside-out’ pattern of the six cortical layers. <ref><pubmed>25246510</pubmed></ref>

'''Notch''' signalling molecular pathway is also crucial to corticogenesis. It is thought that there is an important interplay between this pathways and Reelin, as deficits of both result in impaired migration and altered morphology. <ref><pubmed>2913541</pubmed></ref> Both signalling pathways are involved in the expression of the radial glial gene, BLBP, which could be significant in the development of radial glial cells. 5.
Although generally considered a developmental pathway, studies have shown the importance of Notch signalling in the adult brain, through distinguishing the balance between maintenance of neural stem cells and differentiation. These new understandings have implications for therapeutic approaches to neurodegenerative diseases. <ref><pubmed>21505516</pubmed></ref>
[[File:Cortical thickness in Bmp7 knockouts.png |thumb|right|text-top|500px|'''Figure 3: Cortical thickness in the absence of Bmp7'''<ref><pubmed>22461901</pubmed></ref>]]

'''Bmp7''' in addition to cell intrinsic factots there are also estristic signalling factors to take into account, for example Bone Morphogenitic Protein 7 (Bmp7) with debate ongoing as to its promotion or inhibition of neurogenesis. Deletion of Bmp7 in murine models has been shown to result in reduced thickening of the cortex, likely due to the changed differentiation of progenitor cells from the subventricular zone to the upper layers. Bmp7 regulates the expression of gene Ngn2, which in Bmp7 knock out models appeared to be majorly reduced, perhaps playing a role in the development of deep layer neurons. <ref><pubmed>22461901</pubmed></ref>

The signalling pathways that underlie corticogenesis are very complicated and the exact mechanisms are still under continuous investigation. Further research will only improve understanding of this network of intertwining factors and potentially lead to better appreciation of neurodevelopmental conditions and thus innovative therapeutic approaches.

==Anatomy of the Cerebral Cortex==
 
The cerebral cortex is a convoluted layer of grey matter on the outer surface of the cerebrum. Grey matter is neuronal tissue containing neuronal cell bodies. In humans the cortex has a thickness of 2-3mm however it's surface area is many hundred square centimetres allowing an increased cortical surface to occupy small cranial volume. The cortex in humans contains 10 billion densely packed nerve cells (10% of the neurons in the brain). The human neocortex is the most phylogenetically developed structure of the brain compared to other species. The folding in larger mammals is important to allow addition and evolution of a greater diversity of functional areas. As the folding is highly preserved across individuals this allows the different sections sepearted by gyri and sulci to be labelled. <ref name= "cortex anatomy"><pubmed>17580069</pubmed></ref>

[[File:Anatomy cerebral cortex.png|thumb|none|text-top|500px|Anatomy of the human cerebral cortex <ref name="drawing">Handwritten Tutorials (2012). Brain Anatomy 1- Gross Cortical Anatomy (Lateral Surface). [video] Available at: https://www.youtube.com/watch?v=woIZaLiy-eA [Accessed 5 Oct. 2017].</ref>]]

The longitudinal fissure divides the cortex into the left and right hemispheres, which are connected at the midline by the longitudinal fissure. Each hemisphere is then divided into four lobes (frontal, temporal, parietal and occipital) which are labeled by their relation to bones of the skull. The frontal lobe is separated from the temporal lobe by the lateral sulcus also known as the Sylvian fissure. The Rolandic fissure (central sulcus) divides the frontal and parietal lobe and the parietal and occipital lobes are distinguished by the parieto-occipital sulcus. <ref><pubmed>19763105</pubmed></ref>

The frontal lobe is subdivided by the superior and inferior frontal sulci into the superior, middle and inferior frontal gyri. The frontal operculum is formed by the inferior frontal gyrus and is divided into the pars orbitalis, pars triangularis and pars opercularis. These are triangular gyri and are listed in order of anterior to posterior. <ref name="cortex anatomy"/>

The temporal lobe can also be subdivided by the superior and inferior temporal sulci. These subdivisions include the superior, middle and inferior temporal gyri. Lateral to the midbrain on the inferior temporal lobe surface is the parahippocampal gryus. The occipitotemporal gyrus, also named fusiform gyrus, lies between the inferior temporal gyrus and the parahippocampal gyrus. Within the parietal lobe the angular gryrus lies above the superior temporal sulcus. Above the angular gyrus, the supramrginal gyrus lies above the lateral sulcus. Below the angular gyrus, the lateral occipital gyrus lies above the inferioir temporal sulcus. <ref name="cortex anatomy"/>

<html5media height="400" width="600">https://www.youtube.com/watch?v=woIZaLiy-eA</html5media>
<ref name="drawing"/>

'''Layers of the Cortex'''

{| class="wikitable"
|-
| Layer 1||
outermost layer (pial surface)

molecular layer with few scattered neurons

mainly extensions of pyramidal neuron apical dendrite tufts with some spiny stellate cells

inputs to apical tufts are crucial for feedback interactions in cortex in associative learning and attention <ref><pubmed>8747184</pubmed></ref>

|-
| Layer 2||
external granular layer

contains small pyramidal neurons and many stellate neurons

pyrimidal neurons are excitatory <ref name="layers"><pubmed>17553419</pubmed></ref>

|-
| Layer 3||
external pyramidal layer

small and medium sized pyramidal neurons

non-pyramidal neurons with orientated intracortical axons

layers 1,2 and 3 are the main target for interhemisphere corticocortical afferent fibres

layer 3 is the main source for cortiocortical efferent fibres

|-
| Layer 4||
internal granular layer

many different types of stellate and pyramidal neurons

main target for thalamocortical afferents from thalamus type C neurons and intra-hemispheric corticocortical afferents <ref><pubmed>9622234</pubmed></ref>

|-
| Layer 5||
internal pyramidal layer

large pyramidal neurons

give rise to axons leaving cortex and run down to subcortical structures e.g. basal ganglia

In the primary motor cortex of the frontal lobe, layer 5 contains Betz cells and their axons travel through the internal capsule, the brain stem and the spinal cord forming the corticospinal tract, which is the main pathway for voluntary motor control

cortical areas with no layer 5 are named agranular and cortical areas with an undeveloped layer 5 are named dysgranular <ref name="layers"/>

|-
| Layer 6||
polymorphic/ multiform layer

few large pyramidal neurons

many small spindle like pyramidal and multiform neurons

sends efferent fibres to thalamus and forms exact reciprocal interconnection between thalamus and cortex

these connections are both inhibitory and excitatory <ref><pubmed>19447861</pubmed></ref>

|}

==Functions of the Cerebral Cortex==

The cerebral cortex controls memory, movement, perception, cognition, consciousness, awareness and language. Majority of the connections in the cortex are from one cortex area to the other rather than with other structures. However, the cortex is connected to structures below it such as the basal ganglia and thalamus. The cortex communicates with these structures; information is sent along efferent connections and received by afferent connections.
Majority of the sensory information in the brain is sent to the cortex by the thalamus and olfactory information is send to the olfactory cortex through the olfactory bulb. The cortex can be split into three cortical areas (cortices for plural) based on their function; sensory, motor and association areas. <ref name="overall function"><pubmed>21653723</pubmed></ref>

[[File:Cortical areas.png|thumb|right|text-top|450px|Cortical areas human cortex <ref>Guyton, A & Hall, J (2017). Functions of Specific Cortical Areas. Available at http://www.brainkart.com/article/Functions-of-Specific-Cortical-Areas_19753/. </ref>]]

Primary cortices have simpler functions including direct sensory input (vision, hearing and somatic sensation) or directly producing eye and limb movements. The association cortices functions are more complex and include memory, language, abstraction, creativity, judgement, emotion, attention and movement synthesis. <ref name= "overall function"/>

Sensory areas receive and process information from the senses including visual, hearing and somatosensory information. The primary sensory areas receive sensory inputs from the thalamus. The sensory area in each hemisphere receives sensory information from the opposite side of the body. The sensory cortex is organised as shown in figure and provides a map of the body also known as a homunculus. A cortical homunculus is a model used to represent the area and proportions of motor and sensory functioning in the human body. The size of the body part represents the innervation density, for example the fingers and lips have a higher number and more complex sensory and motor connections. They require more cortical area for the processing of finer sensation. <ref><pubmed>9931268</pubmed></ref>

[[File:Homonculus Sensory and Motor Cortex .png|thumb|right|text-top|450px|Cortical Homonculus <ref> Bust, A & Kellogg, D. (2015). Homunculus: Somatosensory and Somatomotor Cortex. EBM Consult [online] Available at https://www.ebmconsult.com/articles/homunculus-sensory-motor-cortex#jump_ss_100125. </ref> ]]

The motor areas control voluntary movements and like the sensory areas, the motor area in the left hemisphere controls the movement for the right side of the body and vice versa. The basal ganglia receive input from the motor areas as well as the midbrain (substantia nigra) and also sends signals back to these areas aiding the control of motor movements. <ref><pubmed>29042690</pubmed></ref>

The association areas produce perceptual experience and involve functions such as abstract thinking and language. The parietal, temporal and occipital lobes assimilate information stored as memories and sensory information. The association areas connect distant areas of the cortex. <ref name= "overall function"/>

{| class="wikitable"
! style="background:#f4a941" | Cortical Area
! style="background:#f4a941" | Function
|-
| Primary motor cortex|| Executes voluntary movement
|-
| Primary visual cortex || Receives and processes visual information
|-
| Primary somatosensory cortex || Receives and processes somatosensory information such as heat, pain and pressure
|-
| Primary auditory cortex || Receives and processes auditory information
|-
| Motor association cortex (premotor cortex) || Selects voluntary movements
|-
|Auditory association area || Complex processing of auditory information

|-
|Sensory association area || Complex processing of multi sensory information
|-
|Visual association area || Complex processing of visual information
|-
|Prefrontal cortex || Involved in organising thoughts and actions to match internal goals. These include planning complex cognitive behaviour, making executive decisions, expressing personality, social awareness and storing short term memories. <ref><pubmed>28978697</pubmed></ref>
|-
|Broca's area (speech centre) || Speech production and articulation <ref name="speech"><pubmed>25218167</pubmed></ref>
|-
|Wernickes area || Speech comprehension <ref name="speech"/>
|}

<html5media height="400" width="600">https://www.youtube.com/watch?v=n6zQbTT0yoY</html5media>
<ref>Learn Some (2016). Cerebral Cortex. [video] Available at: https://www.youtube.com/watch?v=n6zQbTT0yoY [Accessed 5 Oct. 2017].</ref>

==Abnormalities associated with Cerebral Cortex Development==
( z5093005 )
[[File:Stages of development.png|thumb|left|text-top||600px|Main stages of cortical development where abnormalities may arise <ref name="imaging"/> ]]

References used to write: <ref name="imaging">Mahfouz, M. (2015). Imaging of cortical formation disorders - DRE 4 - Prof. Dr Mamdouh Mahfouz. [video] Available at: https://www.youtube.com/watch?v=l_nTggR7LTE [Accessed 23 Sep. 2017].</ref>
<ref>Squier, W. and Jansen, A. (2010). Abnormal development of the human cerebral cortex. Journal of Anatomy, [online] 217(4), pp.312-323. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ [Accessed 23 Sep. 2017]. </ref>
<ref>Pang, T., Atefy, R. and Sheen, V. (2008). Malformations of Cortical Development. The Neurologist, [online] 14(3), pp.181-191. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ [Accessed 23 Sep. 2017]. </ref>
<ref>Christopher A, C. (2017). Genetic Malformations of the Human Cerebral Cortex. Neuron, [online] 23(1), pp.19 - 29. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue [Accessed 23 Sep. 2017].</ref> 

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===Disorders due to the abnormal proliferation, growth or differentiation of neuroblasts ===
 
<big><big>'''1) Focal cortical dysplasia (FCD)'''</big></big>

'''Focal cortical dysplasia (FCD)''' is heterogeneous developmental disorder of uncertain etiology. Focal Cortical Dysplasia is characterised by neurons arranged abnormally in the focal areas of the cerebral cortex as well as disorganisation of layers and very large cells called 'balloon' cells. FCD can affect the areas throughout the brain but occurs dominantly in the frontal and temporal lobes of the cerebral cortex.

In all patients who present with epilepsy, FCD is the cause for about approximately 25% of them. FCD can be of two types: Type I and Type II. 
[[File:Hemimegalencephaly.png|thumb|left|upright=1.7|Hemimegalencephaly <ref name="imaging"/> ]]

 
 

<big><big>'''2) Hemimegalencephaly'''</big></big>

A rare congenital disorder that also results from the abnormal proliferation of neuroblasts is Hemimegalencephaly. 

'''Hemimegalencephaly''' is a developmental disorder which consists of a 'hamartomatous' overgrowth (where normal mature cells and tissues normally present in an area of the body, form a tumour-like, benign malformation) on part or all of the cerebral hemisphere.

Hemimegalencephaly accounts for 0.2% of cases of childhood epilepsy. Clinical symptoms of this disease may include developmental delay, paralysis of one side of the body and blindness over half the field of vision; but the most significant symptom is ''seizures'' as 90% of patients present with this symptom.
[[File:Symptoms of microcephaly.png|thumb|right|upright=1.2|Microcephaly <ref>USDA & Felipe Dana/AP and Creative Commons License(CC) (2017). Understanding Zika. [online] Goinvo.com. Available at: http://www.goinvo.com/features/zika/ [Accessed 4 Oct. 2017].</ref>]]
 
 
 
 
 
 
<big><big>'''3) Microcephaly Vera'''</big></big>

Microcephaly or 'small brain', can be caused by abnormal cell proliferation or cell division along with the involvement of other organs. 

'''Primary Microcephaly or Microcephaly Vera''' results only due to abnormal cortical development, specifically cell division or proliferation. It is a congenital malformation in which the circumference of the head is quite less than normal and is accompanied by mental retardation and sometimes epilepsy.

<big><big>'''4) Tuberous Sclerosis Complex'''</big></big>

Tuberous sclerosis complex (TSC) is a multi-organ disease resulting from mutations of certain genes, and is usually classified under defects of early cell proliferation and growth although it is also associated with defects of neuronal migration.

Tuberous sclerosis complex (TSC) is thus called due to lesions seen that resembled potato tubers; and is characterised by benign abnormal mass of cells (tumors, cysts, and other malformations including hamartomas and neoplasms) in the cortex. 

" Beneath the cortex, the brain in tuberous sclerosis also shows nodular collections of small cells along the surface of the lateral ventricle that resemble ventricular cells and are called subependymal nodules...or, more descriptively, “candle drippings.” These nodules often contain numerous balloon cells and can in some cases become transformed into glial tumors referred to as subependymal giant cell astrocytomas..."

===Disorders due to abnormal neuronal migration ===
 
<big><big>''' 5) Heterotopia'''</big></big>
[[File:SBH.png|thumb|upright=2.0|right| Heterotopia <ref name="imaging"/> ]]
Migration of neurons occurs during the 8th week of development, along radial glial fibers (RGF). RGFs can be damaged due to ischemia, which can be caused by infection resulting from trauma or metabolic errors. 
RGF damage leads to the migration process arresting at the wrong time, resulting in abnormal or ectopic locations of neurons of the cortex. This condition is known as '''Heterotopia.'''
There are different types of heterotopia:

*'''Subcortical band heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-cortical regions of the cerebral cortex. 

*'''Periventricular heterotopia/ sub-ependymal heterotopia:''' 

In this type of heterotopia, ectopic locations of neurons, seen as nodules, occur in the sub-ependymal or periventricular area of gray matter of cerebral cortex. 

*'''Focal heterotopia:''' 

In this type of heterotopia, abnormal location of neurons result in focal masses within deep white matter of cerebral cortex. 

<big><big>'''6) Lissencephaly'''</big></big>

'''Lissencephaly''' is a congenital cortex malformation, in which gyri (and sulci) of the cerebral cortex are absent (agyria) or largely absent (pachgyria), resulting in a smooth surface of the brain. The normal lamination or layers fail to form and the cerebral cortex usually has only 4 of the typical 6 layers. Like most congenital brain disorders, the etiology of Lissencephaly is uncertain. 
Lissencephaly has also been associated with other abnormalities including corpus callosum hypoplasia, small brain stem and gray matter heterotopia. 

Lissencephaly is generally characterised by the following features:

*Total agyria (gyri and sulci absent resulting in 'smooth brain')

*Pachygyria (gyri can be seen but are very few compared to normal brain)

*Agyric brain with areas of pachygyria

*Vertically oriented Sylvian fissures of the brain, giving the brain an 'hourglass' configuration 

Lissencephaly is of different types; even so common clinical symptoms are 'epilepsy' and 'severe mental retardation'. Types of Lissencephaly are the following: 

*'''Classical (Type I) Lissencephaly'''- results from neuronal undermigration (failed or incomplete neuronal migration) due to varying causes like mutation; additional clinical features include motor deficits. Patients often also have microcephaly [discussed later in Microlissencephaly]. 

*'''Cobblestone (Type II) lissencephaly'''- results from overmigration, where neurons migrate from the cortex into the overlying leptomeninges, causing diverse disruptions of the basement membrane; the cortex has a 'cobblestone' type of nodular appearance and additional clinical features include various eye abnormalities, congenital muscular dystrophies, hypotonia and generalized weakness in infancy. 
Type II Lissencephaly also includes: 

#Muscle-Eye-Brain Disease 
#Walker-Warburg Syndrome 
#Fukuyama Syndrome 
*'''Microlissencephaly'''

Microlissencephaly occurs when Type I Lissencephaly occurs in ''combination'' with congenital Microcephaly, and presents with severe symptoms including seizures, spasticity, severe developmetal delay and short life span.
 
 
<big><big>'''7) Kallmann Syndrome'''</big></big>

The Kallman Syndrome is syndrome which results from the migration of neurons that secrete leuteinizing hormone-releasing hormone (LHRH) from the olfactory placode to the hypothalamus, causing congenital hypogonadism (since LHRH is necessary for normal gonadal function).

Kallman Syndrome is associated with hypoplasia of the olfactory bulbs and olfactory cortex, called arhinencephaly, and lack of the sense of smell. [not yet changed into own words]

===Disorders due to abnormal cortical maturation and organization/folding===
 
<big><big>'''8) Polymicrogyria'''</big></big>

If the neurons of the cerebral cortex successfully complete the proliferation and migration stages, but during the last organisation stage, distribute abnormally then multiple small undulating gyri can result. This condition is called '''Polymicrogyria (PMG)''', in which, the gyri become extremely small (hence the term micro) and their number is greater than normal. The cerebral cortex in this condition is flat and thickened, similar to that of pachygyria or agyria, and contains numerous small gyri. 

Polymicrogyria is usually focal. It is most commonly 'perisylvian' (around the Sylvian fissure) and can be 'bilateral' or 'unilateral'. The most common sites, in descending order, are the frontal lobe, parietal lobe, temporal lobe and then occipital lobe. 

[[File:SchizencephalicBrain.jpg|thumb|left|upright=1.6| Schizencephaly <ref>PRWeb (2013). Schizencephalic Brain. [image] Available at: http://www.prweb.com/releases/2013/7/prweb3350774.htm [Accessed 5 Oct. 2017].</ref>]]

<big><big>'''9) Schizencephaly'''</big></big>

'''Schizencephaly''' is an organisational developmental disorder characterised by a cleft(s) or lesion(s) on the brain surface, which is filled with CSF and lined by gray matter.
Schizencephaly can be bilateral or unilateral.

The clefts can be small with closed walls in '''Type I or Closed lip type''' schizencephaly; or the clefts can be large with free communication between the ventricle and subarachnoid spaces in '''Type II or Open lip type''' schizencephaly.

Schizencephaly commonly involves the parasylvian regions, and severity of the disease correlates with the extent of the clefts. 
 
 
 
 
 
 
 
 
 
===Other Disorders===
<big><big>''' 12) Fetal Alcohol Spectrum Disorder (FASD)'''</big></big>

[[File:FASface.jpg|thumb|right| Facial features appearance in Fetal Alcohol Spetrum Disorder (FASD) <ref> MarkHill,embryology.med.unsw.edu.au (2017). Facial Appearance of Fetal Alcohol Syndrome (FAS). [image] Available at: https://embryology.med.unsw.edu.au/embryology/index.php/File:FASface.jpg [Accessed 5 Oct. 2017].</ref> ]]
 
'''Fetal Alcohol Spectrum Disorder (FASD)''' refers collectively to the malformations that occur in children due to maternal alcohol consumption during pregnancy. This results from the effects of ethanol as it crosses the placental barrier. The mechanism for these abnormalities developing is complicated and not entirely clear, but various studies show that ethanol disrupts all major processes of fetal CNS development and causes toxicity of blood (as fetal liver cannot yet detoxify ethanol well).
 

The three major indications (that also help form the diagnoses) for FASD are facial dysmorphology, growth deficits and central nervous system defects. These conditions result in immense physiological and psychological impacts on the child. Fetal Alcohol Syndrome (FAS) is an acute form of FASD.

On average, FASD is diagnosed in a child between 3-10 years. It is of utmost importance however that the diagnosis is done as early as possible so that timely interventions could be taken in order to lessen the severity of the symptoms that result from this syndrome.
<ref>Leigland, L., Ford, M., Lerch, J. and Kroenke, C. (2013). The Influence of Fetal Ethanol Exposure on Subsequent Development of the Cerebral Cortex as Revealed by Magnetic Resonance Imaging. Alcoholism: Clinical and Experimental Research, 37(6), pp.924-932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670687/ [Accessed 5 Oct. 2017].</ref>
 

<big><big>'''13) Corpus Callosum Agenesis'''</big></big>

<html5media height="410" width="600">https://www.youtube.com/watch?v=7zOa3LLrHKc</html5media>
<ref>Ezzo - Izzo, D. (2007). How the Body Works : The Corpus Callosum. [video] Available at: https://www.youtube.com/watch?v=7zOa3LLrHKc [Accessed 23 Sep. 2017].</ref>
 

<html5media height="410" width="600">https://www.youtube.com/watch?v=M7e9JXGOWD4</html5media>
<ref> dimedcom (2013).Corpus callosum agenesis. [video] Available at: https://www.youtube.com/watch?v=M7e9JXGOWD4 [Accessed 6 Oct. 2017].</ref>

==Models and Research==
===Animal Models===

https://bmcneurosci.biomedcentral.com/articles/10.1186/1471-2202-11-75 (reelin in pig model)

[[File:Corticogenesis of mouse and humans.jpeg |left|thumb|600px|'''Mouse and Human Neurogenesis''']]
 
 
 
 
 
 
 
 
 
 
 

===Current Research===

'''3D Organoids'''
[[File:3D Organoids.jpg|thumb|right|text-top|600px|'''Timeline and protocol of cerebral organoid development'''<ref><pubmed>25188634</pubmed></ref>]]
One of the limiting steps in research at present is the lack of models that can accurately recapitulate the developmental changes and pathophysiology of the human brain. Although it is recognized that certain fundamentals of brain development are conserved in mammalian brains there are distinct differences that should be considered when studying the human brain. <ref><pubmed>28845922</pubmed></ref>

Currently there has been the development of 3 dimensional models, derived from stem cells that can be used to mimic the evolution of the human brain, and have been deemed advantageous over previous in vitro models. This method, as first described by Lancaster et al. can, in a 1-2 month period be reproduced in a tissue culture room give rise to the developing parts of the human brain, including the cerebral cortex. This is established using a protocol human pluripotent stem cells (PSCs). PSCs separate to single cells before rearranging to form embryoid bodies, which are prompted to form neuroectoderm in a medium that prevents either endoderm or mesoderm development. At day 11-15 of this protocol the tissues undergo neuroepithelial bud expansion after being transferred to Matrigel droplets. The final stage of the process involves the tissues being transferred to an agitator (either spinning bioreactor, or orbital shaking plate) which allows for more substantial growth of the brain regions due to better nutrient and oxygen supply. <ref><pubmed>25188634</pubmed></ref>

===Future Questions===

==Glossary==

{| class="wikitable"
! style="background:#f4a941" | Term
! style="background:#f4a941" | Definition
|-
| Sulcus || Sulci (plural) are grooves in the cerebral cortex
|-
| Gyrus || Gyri (plural) are folds/ridges in the cerebral cortex
|-
| Fissures || Large sulci
|-
|Corticogenesis || The development of the cerebral cortex into its six layers. It involves a sequential process of migration and differentiation of neocortical projection neurons into a laminated structure that contains a diverse set of neuronal subtypes
|}

==INFO/ Research Links (temporary heading)==
 

https://www.youtube.com/watch?v=n6zQbTT0yoY 
https://www.youtube.com/watch?v=X-m0JDCw6TE 

https://www.youtube.com/watch?v=luXDQrmMoUU 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992410/ 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547618/ 
http://www.cell.com/neuron/fulltext/S0896-6273(00)80749-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627300807497%3Fshowall%3Dtrue 

https://academic.oup.com/jnen/article/61/1/1/2916251 
https://pdfs.semanticscholar.org/67ea/2ce13f57f4ddbfb7033b6bb1328a5dff7742.pdf 
https://www.youtube.com/watch?v=l_nTggR7LTE 

For concept:
https://www.youtube.com/watch?v=dNngOlsLuGI

You might find this helpful (although you need to request copyright permission):

"Difference Between Cerebrum and Cerebral Cortex." DifferenceBetween.Com. August 7, 2012. < http://www.differencebetween.com/difference-between-cerebrum-and-vs-cerebral-cortex/ >

PubMed Searches: [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebral+Cortex+Development ''Cerebral Cortex Development''] | [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebrum+Development ''Cerebrum Development'']

BMC Dev Biol Search: [http://www.biomedcentral.com/bmcdevbiol/search/results?terms=Cerebral+Cortex+Development ''Cerebral Cortex Development'']

Recent papers

<pubmed limit=5>Cerebral+Cortex+Development</pubmed>

==References==