Embryology - User contributions [en-gb]

2014 Group Project 7

2014-10-30T04:08:49Z

Z3418981: /* Current Research */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, receiving and integration of information from all parts of the human body, serving as the processing center of the body's nervous system. The CNS controls all of the body functions (sensory and motor) and consists of 2 main organs: The Brain and Spinal Cord.

The brain is the body's control center consisting of 3 main components; forebrain, midbrain and hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures such as hypothalamus and thalamus, which are responsible in motor control, autonomic function control and relaying sensory information. The midbrain along with the hindbrain together forms the brain-stem which has many important functions such as regulating the cardiac and respiratory systems.

The spinal cord is a cylindrical-shaped structure composed of nerve fiber bundles and is connected to the brain via the brain-stalk formed from the midbrain and hindbrain. The spinal cord is running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. It plays the important role of transmitting information from body organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into ascending bundles, which transmits sensory information from the body to the brain, and descending bundles which transmits motor function information from the brain to the body.

Neurulation occurs in the embryonic period during which ectoderm forms initial structures of the CNS and folds upon itself to form the neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the prosencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon further divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain. <ref name="PMID9349978"><pubmed> 9349978</pubmed></ref><ref name="PMID10532616"><pubmed>10532616</pubmed></ref>
During the fetal period, there is ongoing growth in the size, weight and surface area of the brain and spinal cord. Microscopically, the cellular processes during this period can be divided into: cell proliferation, cell migration, cell differentiation and cell death. Neural development will continue after birth with substantial growth, death and reorganization of the cells.

In this website, the fetal development of CNS is being discussed with the focus being on cellular processes of brain development. Some current research models and findings as well as historic findings will be mentioned as well. In addition, the major abnormalities associated with CNS during fetal period and neural tube defects that occur during embryonic period but will further carry on to fetal development will be discussed too.

==Development during fetal period==

===Cellular process===

In the developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. There are cascades of events in which the earlier occurring processes may influence the subsequent occurring ones, but a late-occurring event cannot influence the earlier ones.

[[File:Schematic_representation_of_the_timeline_of_human_neural_development.jpg|700px]]

A simplified timeline of human neural development (modified) <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

This simplified graph shows a timeline for major events of neural development that occur during fetal and postnatal periods. These events, which are summarized in the following table, are broadly classified by cell multiplication, cell migration, growth and differentiation and angiogenesis:

{| class="wikitable"
|-
! Major Events !! Descriptions
|-
| Cell multiplication ||
* Neurons are proliferated and generated from neural stem cells and progenitor cells (precursor cells) in a process known as neurogenesis in 2nd trimester.
* Cell death and Gliogenesis (glial cells (such as astrocytes) deriving from multipotent neural stem cells) occur in the 3rd trimester.
* Local gliogenesis continues postnatally.
|-
| Cell migration ||
* Neuronal migration is maximised during 2nd trimester while glial migration is maximised during 3rd trimester
|-
| Growth and differentiation ||
* Axonal and dendritic arborisation (fine branching structures at the end of nerve fibers) appear by the end of fetal period.
* Synaptogenesis (formation of synapses) and electrical activity is maximised in 3rd trimester (and continued postnatally).
* Cell death due to over-innervation can be observed in late fetal and postnatal period.
* Myelination occurs in late fetal and postnatal period (vast majority of postnatal growth in brain is due to myelination).
|-
| Angiogenesis ||
* Oxidative metabolism can be seen in late fetal period.
* Capillary networks develop postnatally.
|}

'''1. cell proliferation'''

[[Image:Somatosensory cortex of E20 rat.jpeg|frame|500x500px|Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) <ref name="PMID22272298"><pubmed>22272298</pubmed></ref>]]

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref name="PMID4203033"><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that is comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref name="PMID5414696"><pubmed>5414696</pubmed></ref>. In some parts of the developing CNS, this is the only proliferative zone and therefore it is assumed that the ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref name="PMID7204662"><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref name="PMID12764033"><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia of most parts of the brain are produced in this zone, therefore it is important to the adult brain <ref name="PMID8523077"><pubmed>8523077</pubmed></ref>. In some parts of the brain, production of a significant number of neurons is seen in this zone <ref name="PMID9712307"><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes to large number of cells in the neocortex, which is the youngest structure in the brain <ref name="PMID1713238"><pubmed>1713238</pubmed></ref>. Unlike the ventricular zone, the proliferating cells do not move through the cell cycle.

'''2. cell migration'''
[[Image:CNS_passive.jpg|frame|200x150px|Passive cell displacement and outside-to-inside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]
[[Image:CNS_active.jpg|frame|350x250px|Active cell migration and inside-to-outside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]

* This is the process that influences the final cell position. In this process, cells produced from the two ventricular zones migrate.

* The postmitotic young neurons migrate from the proliferation site into their ultimate position in two different ways:

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus <ref name="PMID489804"><pubmed>489804</pubmed></ref>, hypothalamus <ref name="PMID5029133"><pubmed>5029133</pubmed></ref>, spinal cord <ref name="PMID4407392"><pubmed>4407392</pubmed></ref>, dentate gyrus of the hippocampal formation <ref name="PMID17533671"><pubmed>17533671</pubmed></ref> and many regions of the brainstem.
# Active migration: Active participation of the moving cells is required for the cell displacement. Neurons move at a greater distance than passive migration, and the migrating young neurons bypass the previously generated cells (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structures including cerebral cortex and several subcortical areas <ref name="PMID17533671"><pubmed>17533671</pubmed></ref>.

{| style="width:20%; height:170px" align="center"
|-
| [[Image:Internurons migration in cerebral cortex.jpg|frame|200x400px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex <ref name="PMID17726524"><pubmed>17726524</pubmed></ref>]]
|}

'''3. cell differentiation'''<ref name="PMID10532616"><pubmed>10532616</pubmed></ref>

* This is the process which begins after the migration of neuronal and glial cells to their final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, the axon and dendrites of each neuron grow out.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: One neuron innervates many cells. These connections will be eliminated after the reduction of the projection area.
#Convergent transient connections: Several neurons innervate one target neuron. Only one of these neuronal connections is found in the adult brain.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs. Two mechanisms: axonal retraction and neuronal pruning <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death. Neurons die because they fail to establish projections.

* Critical for appropriate brain development

 

=== Brain Development ===

* The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells. By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

* The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

[[Image:Brain ventricles and ganglia development 03.jpg|frame|200x200px|Increase in size of of brain and ventricles <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]
[[Image:Brain fissure development 02.jpg|frame|200x200px|Increase in size of brain fissure <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]

* The gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding.

* The brain development begins rostral in GW8, proceeding caudally until it is complete at GW22 <ref><pubmed>560818</pubmed></ref>

* The formation of Secondary Sulci is between GW30-35, while the formation of of Tertiary Sulci begins during GW36 and into the postnatal period.

* Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

* Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

* The major fibre pathways make up the brain white matter

* As development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Neuron Production'''

* The human brain contains billions of neurons which are produced by mid-gestation during fetal development <ref><pubmed>8361683</pubmed></ref>

* Processes of Neuronal production is initiated by first increasing the size of the neural progenitor cell population within the body, these cells are mitotic in nature and are capable of forming new cells.

* Initially (from the end of gastrulation through to embryonic day 42), the neural progenitor cell population is increased greatly when the progenitor cells divide through 'symmetrical' mode of cell division. Multiple repeats of the cell division occur throughout this period. This 'symmetrical' division method brings about the formation of 2 new identical neural progenitor cells

* Mode of cell division changes from a symmetrical cell division type to an 'asymmetrical' cell division from the beginning of E42. This asymmetrical cell division forms 2 different cell types; one Neural progenitor & one Neuron <ref><pubmed>12764028 </pubmed></ref>

* Newly formed neural progenitor cells remains to undergo more processes of cell division whereas the newly formed neuron moves into position in the developing neocortex

'''Neuron Migration''' <ref name="PMID21042938"><pubmed>21042938</pubmed></ref>

Outlined above was a broad summary on neuron migration. Neuron migration in the cortex will be covered below in more detail.

* The ventricular zone (VZ) is where the majority of neurons migrate radially out and into the neocortex. The type of migration utilised here is referred to as somal translocation where the neuron cell body translocates out of the VZ and into the outer brain region with the nucleus moving across the cytoplasm and into the outer brain region.

* With increasing brain size, somal translocation is no longer efficient for neuronal migration out of VZ. Since greater distances are evident, radial glial guides are adopted to allow the migration of neurons to continue. Similar to somal translocation, these cell populations establish a scaffolding system where neurons can attach to (basal process occurs) and then move into the developing cortical plate. These cell populations are comprised of neural progenitor cells and are therefore able to support mass neuron migration.

* Another mode of transport utilised by neurons situated within a second zone of the ventral telencephalon is referred to as tangential migration. The neurons here migrate tangentially to the cortical mantle whilst adopting different signalling pathways (guidance molecules) as opposed to radial migration. As a result of neuronal migration, a 6-layered structure forms within the developing neocortex.

* Once completion of the pre-plate has occurred, two regions are formed which are the subplate (SP) and the marginal zone (MZ).In between these two regions, the cortical plate arises as well. Earliest neuron arrival forms the deepest layer of the cortex: cortical layer 6. More superficial layers of the cortex will develop with continuous cell migration. It is important to note that a specific cell class is located within the MZ in which the Cajal-Retzius cells (CR) reside. CR's are important for correct neuron positioning within the cortical layers as well as having an inhibitory effect on neuron migration. Rheelin, a molecular signal produced by the CR's is important here as it stops neurons from migrating and signals them to up their corresponding positions.

'''Folding: sulcation and gyration'''

[[Image:Dev anat 01.jpg|frame|200x200px|Simplified external lateral (left) view of the brain growth]]

* During the fifth and sixth month of gestation, the smooth cortex begins to fold by sulcation and gyration. <ref name=PMID21571694><pubmed>21571694</pubmed></ref>

# Sulcation: This is the development of sulci, including primary and secondary. The formation of primary sulci involves the appearance of shallow grooves on the surface of the brain, which then becomes more deeply infolded, while the formation of secondary sulci is due to the development of side branches of the primary ones <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.
# Gyration: This is the development of gyrus that occurs during late fetal development until the end of the pregnancy or after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>. This process is the formation of tertiary sulci, which is the formation of other side branches of the secondary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

{| class="wikitable"
|-
! Weeks of gestation !! Visible anatomical details
|-
| 20-21 || smooth, with the impression of "lissencephalic" brain; wide Sylvian fissures; visible interhemispheric fissure and parieto-occipital fissure
|-
| 22-23 || beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || smooth cerebral cortex surface; visible shallow grooves in the central sulci, interparietal sulci and superior temporal sulci; start of opercularization of Sylvian fissures; presence of calcarine fissures and cingular sulci
|-
| 26 || presence of central and collateral sulci
|-
| 27 || presence of marginal and precentral sulci
|-
| 28 || presence of postcentral and intraparietal sulci
|-
| 29 || presence of superior and inferior frontal sulci; narrower Sylvian fissure; clear corpus callosum; bright white matter; dark cortical ribbon
|-
| 30-31 || beginning of infolding of cortex which is first apparent in the occipital lobe; narrower ventricular system and subarachnoid spaces
|-
| 32 || presence of superior and inferior temporal sulci
|-
| 33 || presence of external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration; compactly and extensively folded cortex
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

Table of the process of sulcation and gyration <ref name=PMID20608424><pubmed>20608424</pubmed></ref>

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations <ref><pubmed>7472570</pubmed></ref>

|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini is now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

==Current research models and findings==

===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.
{|
|-bgcolor="ECCEF5"
|

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.
|}

{|
|-bgcolor="CED8F6"
|The following recent studies use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

** Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

** The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

** The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.
|}

{|
|-bgcolor="CED8F6"
|
'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.
|}

{|
|-bgcolor="ECCEF5"
|
In the following studies new models and imaging techniques have been employed to gain a better understanding of the changes in brains of patients with schizophrenia

'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

Moreover, in the following study, a neuroimaging technique known as Proton Magnetic Resonance Spectroscopy (1H-MRS) is used to examine the brain of patients with schizophrenia:

'''Multimodal neuroimaging of frontal white matter microstructure in early phase schizophrenia: the impact of early adolescent cannabis use'''
<ref><pubmed> 3852698 </pubmed></ref>

[[Image:Online_placement_of_the_1H-MRS_volume_of_interest_.jpg|400x400px|frame|Proton magnetic resonance spectroscopy (1H-MRS) is used to examine the white matter tissue in brain of patients with schizophrenia. The image shows online placement of the 1H-MRS volume of interest.The 1H-MRS volume of interest is placed parallel to the AC-PC line (AC =anterior commissure, PC = posterior commissure). <ref><pubmed> 3852698 </pubmed></ref>]]

* The neurochemical used in this technique is N-acetylaspartate (NAA), a free amino acid that has a peak resonance at 2.02 ppm on the spectral profile in the 1H-MRS of human brain.
* In vivo concentration levels of NAA are higher in white matter compared to gray matter.
* Post-mortem studies have demonstrated that NAA is produced in neurons, transported into white matter and broken down into aspartate and acetate in oligodendrocytes. <ref><pubmed>17275978</pubmed></ref> NAA catabolism is thus closely related to the metabolism of myelin, since it provides a crucial source of acetate which is necessary for the formation of myelin from lipid.
* Therefore due to abnormal myelin biosynthesis in schizophrenia, brain tissues can be examined by 1H-MRS studies as long as the targeted brain region involves a single tissue type (white matter) that provides the necessary information regarding the catabolic cycle of NAA.

|}

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]

Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.

* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period).

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation. <ref><pubmed>15806441</pubmed></ref>

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.<ref><pubmed>21215908</pubmed></ref>

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.<ref><pubmed>1400921</pubmed></ref>

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.<ref><pubmed>25283616</pubmed></ref>

===Fetal Alcohol Syndrome===

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status. <ref><pubmed> 24904907 </pubmed></ref>

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.<ref><pubmed> 23809349 </pubmed></ref>

{| class="wikitable"
|-
| [[File:Fetal alcohol syndrome.jpg|500px]] || [[File:Ethanol fetal neural.jpg|400px]]
|-
| The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref>|| A mechanism of the effect of ethanol on neural stem cells (NSCs). Ethanol promotes asymmetrical cell division, the formation of radial glial-like cells, leading to the premature depletion of the VZ and its NSCs, and the thickening and cell proliferation in SVZ. The increased migration during early differentiation of ethanol-treated NSCs also leads to the appearance of subpial heterotopias<ref name="PMID22623924"><pubmed>22623924</pubmed></ref>

|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

* All degrees of iodine deficiency (mild: 50-99 μg/day, moderate: 20-49 μg/day and severe≤20 μg/day) affect thyroid function of both mother and the neonate as well as mental development of the child. The damage increases with the degree of deficiency; overt endemic cretinism is the most severe consequence.

* Iodine deficiency disorders refer to complications that arise when the recommended dietary allowance of iodine is not met. These complications include thyroid function abnormalities and when iodine deficiency is severe, endemic goitre and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality.

* Iodine deficiency represents the world’s greatest cause of preventable brain damage and mental retardation, resulting of a loss of 10-15 IQ points globally. Therefore it is essential that the recommended dietary requirement for iodine is met, especially during pregnancy and lactation (200–300 μg/day). <ref><pubmed>10750030</pubmed></ref>

* Clinical manifestations of hypothyroidism include: Myxedematous facies (condition characterized by thickening of the skin, blunting of the senses and intellect, and laboured speech), jaundice, a puffy face and a wide posterior fontanelle with open sutures. The nasal bridge is flat. The mouth may be slightly open revealing macroglossia. Further examination would reveal bradycardia and a protuberant abdomen with a large umbilical hernia. Neurologic examination findings include hypotonia with delayed reflexes. Skin may be cool to touch and mottled in appearance due to circulatory compromise.<ref><pubmed>2903524</pubmed></ref>

===Abnormalities associated with apoptosis and migration of cells in the fetal CNS===

* The migration of cells and cell death are critically important to fetal brain and CNS development. Abnormalities in each of these processes, programmed cell death (apoptosis) in particular, have been shown to result in severe developmental abnormalities in experimental animals. Apoptosis is critically important for appropriate brain development; certain areas in brain may experience up to 50% cell death. <ref><pubmed> 11589424 </pubmed></ref>

* In an experiment conducted by kuida et. al 1996, it was observed that mice that were deficient for CPP32 (a protease responsible for apoptosis), were born at a lower frequency than expected, were smaller in size compared to the normal mice and died at an early age. Brain development is significantly affected in CPP32-deficient mice resulting in a variety of hyperplasia and disorganised cell development. <ref><pubmed>8934524</pubmed></ref>

* On the other hand, disrupted neuronal migration can lead to an abnormality in cell position. When this happens, the neurons are said to be heterotopic. Abnormalities in neuronal migration have been studied extensively in human cerebral cortex where these defects are associated with a variety of syndromes and diseases, ranging from behavioural disorders (including some forms of schizophrenia, dyslexia and autism) to extremely severe mental retardation and failure to thrive. <ref><pubmed>10532616</pubmed></ref>

===Neural Tube Defects===

Neural tube is formed during the embryonic period but the associated abnormalities carry on to fetal development. If the neural tube does not close or fuse together properly, then openings remain in the brain or the spinal cord which can lead to various neural tube defects.

{| class="wikitable"
|-
! Abnormalities !! Descriptions
|-
| '''Anencephaly''' ||
* A neural tube defect involving abnormal development of the brain and incomplete skull formation leading to high infant mortality rates with infants being stillborn or dying within a few hours after birth.
* The failure of the neural tube to close around the 23rd and 26th day into embryonic development is characteristic of this condition. As a result, the forebrain is severely affected where the cerebrum does not grow and hence partial growth occurs only. The cerebrum has a key importance in maintaining thought, consciousness and coordination whilst having no intact cerebrum rules out the probability of the affected fetus gaining consciousness.
* Increasing one's dietary intake of folic acid notably reduces the incidence of neural tube defects. Consuming 0.4mg of folic acid is sufficient to induce these results.
* Since incomplete skull formation occurs, brain tissue becomes exposed due to the absence of bone covering and therefore leading to further complications. <ref><pubmed>25032496 </pubmed></ref>
|-
| '''Encephaloceles''' ||
* Another neural tube defect in which a sac-like projection (including membrane covering) occurs around the 3-4 week of embryonic development in which neural tube closure has not successfully occurred. The location of these protrusions varies but can be naso-frontal (nose and head), naso-ethmoidal (nose and ethmoid bone), naso-orbital (nose and eyes), meningocele (cerebrospinal fluid and membrane covering) and encephalomeningocele (meningocele with brain tissue as well).
* These sac-like protrusions lead to a variety of abnormal effects which include cerebro-spinal fluid build-up in brain, microcephaly, hydrocephaly, mental retardation, developmental problems, uncoordinated muscle movement and seizures. Consumption of folic acid again has been shown to significantly reduce the occurrence of encephaloceles in infants. <ref><pubmed>11151720</pubmed></ref>
|-
| '''Hydranencephaly''' ||
* A very rare neural tube defect in which the cerebral hemispheres are destroyed (necrotic tissue) with the occupied space being replaced by cerebro-spinal fluid, cortex and white matter remnants within a membranous sac. Interestingly, this condition can also develop in the postnatal peroid due to viral infections or traumatic brain injury. The brain stem may remain intact and functioning in hydranencephalic infants.
* Accompanied with this condition are many effects in which include seizures, hydrocephalus, increases in head circumference, impairment in vision/ body temperature regulation and cerebral palsy. Infants affected by hydranencephaly live typically short lives being no longer than 1 year of age. Lastly, there are no viable treatment options for this condition and only supportive care is available. <ref><pubmed>23112982</pubmed></ref>
|-
| '''Iniencephaly''' ||
* Another neural tube defect involving severe backward bending of the head (retroflexion) with subsequent spinal distortions as well. Affected infants have no neck and hence the scalp of the head is directly joined to the skin of the back (also skin of the face connected to skin of the chest). Other conditions that develop along with iniencephaly are cyclopia, cephalocele and anencephaly. The development of this condition is not solely due to one factor but from various causes (both genetic and environmental factors).
* There are specific factors that have been shown to increase the occurrence of this condition. Malnutrition, reduced folic acid intake and elevated levels of homocysteine in blood are environmental factors that increase the risk of iniencephaly <ref><pubmed> 22408660 </pubmed></ref>. Intake of certain drugs such as anti-histamines and sulphonamide/tetracycline (antibiotics) have also increases this risk <ref><pubmed> 22439066 </pubmed></ref>. Furthermore obesity has been shown to have a significant effect on the incidence of iniencephaly with 1.7-3 fold increase <ref><pubmed> 18538144 </pubmed></ref>.
* In terms of treatment, folic acid supplementation as well as avoiding certain drugs such as those outlined above significantly reduces the occurrence of this condition. <ref><pubmed>10719321</pubmed></ref>
|-
| '''Spina Bifida Cystica''' ||
* A neural tube defect which involves either the formation of a meningocele or myelomeningocele. Of the two, the meningocele, is the least debilitating in that a cyst-like structure forms when the neural tube does not close properly. The membrane (meninges) is pushed into openings of the vertebrae where spinal fluid builds up within the cyst. The myelomeningocele leads to severe problems as the portion of the nueral tube that is unfused allows the spinal cord to protrude through. As a result, neuronal tissue is highly exposed due to myeloschisis as well as infections and hence may lead to severe complications.
|-
| '''Spina Bifida Occulta''' ||
* A neural tube defect that has minimal complications in comparison to other defects. Furthermore, this defect is hidden in that a tethered spinal cord may arise as well as a thicker filum terminale and diastematomyelia (spinal cord split into two). It is also important to note that no cysts form as opposed to the other more severe spina bifida defects. <ref><pubmed>24009034</pubmed></ref>

|}

<references/>

2014 Group Project 7

2014-10-30T01:15:05Z

Z3418981: /* Brain Development */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, receiving and integration of information from all parts of the human body, serving as the processing center of the body's nervous system. The CNS controls all of the body functions (sensory and motor) and consists of 2 main organs: The Brain and Spinal Cord.

The brain is the body's control center consisting of 3 main components; forebrain, midbrain and hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures such as hypothalamus and thalamus, which are responsible in motor control, autonomic function control and relaying sensory information. The midbrain along with the hindbrain together forms the brain-stem which has many important functions such as regulating the cardiac and respiratory systems.

The spinal cord is a cylindrical-shaped structure composed of nerve fiber bundles and is connected to the brain via the brain-stalk formed from the midbrain and hindbrain. The spinal cord is running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. It plays the important role of transmitting information from body organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into ascending bundles, which transmits sensory information from the body to the brain, and descending bundles which transmits motor function information from the brain to the body.

Neurulation occurs in the embryonic period during which ectoderm forms initial structures of the CNS and folds upon itself to form the neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the prosencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon further divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain. <ref name="PMID9349978"><pubmed> 9349978</pubmed></ref><ref name="PMID10532616"><pubmed>10532616</pubmed></ref>
During the fetal period, there is ongoing growth in the size, weight and surface area of the brain and spinal cord. Microscopically, the cellular processes during this period can be divided into: cell proliferation, cell migration, cell differentiation and cell death. Neural development will continue after birth with substantial growth, death and reorganization of the cells.

In this website, the fetal development of CNS is being discussed with the focus being on cellular processes of brain development. Some current research models and findings as well as historic findings will be mentioned as well. In addition, the major abnormalities associated with CNS during fetal period and neural tube defects that occur during embryonic period but will further carry on to fetal development will be discussed too.

==Development during fetal period==

===Cellular process===

In the developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. There are cascades of events in which the earlier occurring processes may influence the subsequent occurring ones, but a late-occurring event cannot influence the earlier ones.

[[File:Schematic_representation_of_the_timeline_of_human_neural_development.jpg|700px]]

A simplified timeline of human neural development (modified) <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

This simplified graph shows a timeline for major events of neural development that occur during fetal and postnatal periods. These events, which are summarized in the following table, are broadly classified by cell multiplication, cell migration, growth and differentiation and angiogenesis:

{| class="wikitable"
|-
! Major Events !! Descriptions
|-
| Cell multiplication ||
* Neurons are proliferated and generated from neural stem cells and progenitor cells (precursor cells) in a process known as neurogenesis in 2nd trimester.
* Cell death and Gliogenesis (glial cells (such as astrocytes) deriving from multipotent neural stem cells) occur in the 3rd trimester.
* Local gliogenesis continues postnatally.
|-
| Cell migration ||
* Neuronal migration is maximised during 2nd trimester while glial migration is maximised during 3rd trimester
|-
| Growth and differentiation ||
* Axonal and dendritic arborisation (fine branching structures at the end of nerve fibers) appear by the end of fetal period.
* Synaptogenesis (formation of synapses) and electrical activity is maximised in 3rd trimester (and continued postnatally).
* Cell death due to over-innervation can be observed in late fetal and postnatal period.
* Myelination occurs in late fetal and postnatal period (vast majority of postnatal growth in brain is due to myelination).
|-
| Angiogenesis ||
* Oxidative metabolism can be seen in late fetal period.
* Capillary networks develop postnatally.
|}

'''1. cell proliferation'''

[[Image:Somatosensory cortex of E20 rat.jpeg|frame|500x500px|Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) <ref name="PMID22272298"><pubmed>22272298</pubmed></ref>]]

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref name="PMID4203033"><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that is comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref name="PMID5414696"><pubmed>5414696</pubmed></ref>. In some parts of the developing CNS, this is the only proliferative zone and therefore it is assumed that the ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref name="PMID7204662"><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref name="PMID12764033"><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia of most parts of the brain are produced in this zone, therefore it is important to the adult brain <ref name="PMID8523077"><pubmed>8523077</pubmed></ref>. In some parts of the brain, production of a significant number of neurons is seen in this zone <ref name="PMID9712307"><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes to large number of cells in the neocortex, which is the youngest structure in the brain <ref name="PMID1713238"><pubmed>1713238</pubmed></ref>. Unlike the ventricular zone, the proliferating cells do not move through the cell cycle.

'''2. cell migration'''
[[Image:CNS_passive.jpg|frame|200x150px|Passive cell displacement and outside-to-inside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]
[[Image:CNS_active.jpg|frame|350x250px|Active cell migration and inside-to-outside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]

* This is the process that influences the final cell position. In this process, cells produced from the two ventricular zones migrate.

* The postmitotic young neurons migrate from the proliferation site into their ultimate position in two different ways:

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus <ref name="PMID489804"><pubmed>489804</pubmed></ref>, hypothalamus <ref name="PMID5029133"><pubmed>5029133</pubmed></ref>, spinal cord <ref name="PMID4407392"><pubmed>4407392</pubmed></ref>, dentate gyrus of the hippocampal formation <ref name="PMID17533671"><pubmed>17533671</pubmed></ref> and many regions of the brainstem.
# Active migration: Active participation of the moving cells is required for the cell displacement. Neurons move at a greater distance than passive migration, and the migrating young neurons bypass the previously generated cells (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structures including cerebral cortex and several subcortical areas <ref name="PMID17533671"><pubmed>17533671</pubmed></ref>.

{| style="width:20%; height:170px" align="center"
|-
| [[Image:Internurons migration in cerebral cortex.jpg|frame|200x400px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex <ref name="PMID17726524"><pubmed>17726524</pubmed></ref>]]
|}

'''3. cell differentiation'''<ref name="PMID10532616"><pubmed>10532616</pubmed></ref>

* This is the process which begins after the migration of neuronal and glial cells to their final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, the axon and dendrites of each neuron grow out.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: One neuron innervates many cells. These connections will be eliminated after the reduction of the projection area.
#Convergent transient connections: Several neurons innervate one target neuron. Only one of these neuronal connections is found in the adult brain.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs. Two mechanisms: axonal retraction and neuronal pruning <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death. Neurons die because they fail to establish projections.

* Critical for appropriate brain development

 

=== Brain Development ===

* The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells. By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

* The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

[[Image:Brain ventricles and ganglia development 03.jpg|frame|200x200px|Increase in size of of brain and ventricles <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]
[[Image:Brain fissure development 02.jpg|frame|200x200px|Increase in size of brain fissure <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]

* The gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding.

* The brain development begins rostral in GW8, proceeding caudally until it is complete at GW22 <ref><pubmed>560818</pubmed></ref>

* The formation of Secondary Sulci is between GW30-35, while the formation of of Tertiary Sulci begins during GW36 and into the postnatal period.

* Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

* Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

* The major fibre pathways make up the brain white matter

* As development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Neuron Production'''

* The human brain contains billions of neurons which are produced by mid-gestation during fetal development <ref><pubmed>8361683</pubmed></ref>

* Processes of Neuronal production is initiated by first increasing the size of the neural progenitor cell population within the body, these cells are mitotic in nature and are capable of forming new cells.

* Initially (from the end of gastrulation through to embryonic day 42), the neural progenitor cell population is increased greatly when the progenitor cells divide through 'symmetrical' mode of cell division. Multiple repeats of the cell division occur throughout this period. This 'symmetrical' division method brings about the formation of 2 new identical neural progenitor cells

* Mode of cell division changes from a symmetrical cell division type to an 'asymmetrical' cell division from the beginning of E42. This asymmetrical cell division forms 2 different cell types; one Neural progenitor & one Neuron <ref><pubmed>12764028 </pubmed></ref>

* Newly formed neural progenitor cells remains to undergo more processes of cell division whereas the newly formed neuron moves into position in the developing neocortex

'''Neuron Migration''' <ref name="PMID21042938"><pubmed>21042938</pubmed></ref>

Outlined above was a broad summary on neuron migration. Neuron migration in the cortex will be covered below in more detail.

* The ventricular zone (VZ) is where the majority of neurons migrate radially out and into the neocortex. The type of migration utilised here is referred to as somal translocation where the neuron cell body translocates out of the VZ and into the outer brain region with the nucleus moving across the cytoplasm and into the outer brain region.

* With increasing brain size, somal translocation is no longer efficient for neuronal migration out of VZ. Since greater distances are evident, radial glial guides are adopted to allow the migration of neurons to continue. Similar to somal translocation, these cell populations establish a scaffolding system where neurons can attach to (basal process occurs) and then move into the developing cortical plate. These cell populations are comprised of neural progenitor cells and are therefore able to support mass neuron migration.

* Another mode of transport utilised by neurons situated within a second zone of the ventral telencephalon is referred to as tangential migration. The neurons here migrate tangentially to the cortical mantle whilst adopting different signalling pathways (guidance molecules) as opposed to radial migration. As a result of neuronal migration, a 6-layered structure forms within the developing neocortex.

* Once completion of the pre-plate has occurred, two regions are formed which are the subplate (SP) and the marginal zone (MZ).In between these two regions, the cortical plate arises as well. Earliest neuron arrival forms the deepest layer of the cortex: cortical layer 6. More superficial layers of the cortex will develop with continuous cell migration. It is important to note that a specific cell class is located within the MZ in which the Cajal-Retzius cells (CR) reside. CR's are important for correct neuron positioning within the cortical layers as well as having an inhibitory effect on neuron migration. Rheelin, a molecular signal produced by the CR's is important here as it stops neurons from migrating and signals them to up their corresponding positions.

'''Folding: sulcation and gyration'''

[[Image:Dev anat 01.jpg|frame|200x200px|Simplified external lateral (left) view of the brain growth]]

* During the fifth and sixth month of gestation, the smooth cortex begins to fold by sulcation and gyration. <ref name=PMID21571694><pubmed>21571694</pubmed></ref>

# Sulcation: This is the development of sulci, including primary and secondary. The formation of primary sulci involves the appearance of shallow grooves on the surface of the brain, which then becomes more deeply infolded, while the formation of secondary sulci is due to the development of side branches of the primary ones <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.
# Gyration: This is the development of gyrus that occurs during late fetal development until the end of the pregnancy or after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>. This process is the formation of tertiary sulci, which is the formation of other side branches of the secondary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

{| class="wikitable"
|-
! Weeks of gestation !! Visible anatomical details
|-
| 20-21 || smooth, with the impression of "lissencephalic" brain; wide Sylvian fissures; visible interhemispheric fissure and parieto-occipital fissure
|-
| 22-23 || beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || smooth cerebral cortex surface; visible shallow grooves in the central sulci, interparietal sulci and superior temporal sulci; start of opercularization of Sylvian fissures; presence of calcarine fissures and cingular sulci
|-
| 26 || presence of central and collateral sulci
|-
| 27 || presence of marginal and precentral sulci
|-
| 28 || presence of postcentral and intraparietal sulci
|-
| 29 || presence of superior and inferior frontal sulci; narrower Sylvian fissure; clear corpus callosum; bright white matter; dark cortical ribbon
|-
| 30-31 || beginning of infolding of cortex which is first apparent in the occipital lobe; narrower ventricular system and subarachnoid spaces
|-
| 32 || presence of superior and inferior temporal sulci
|-
| 33 || presence of external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration; compactly and extensively folded cortex
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

Table of the process of sulcation and gyration <ref name=PMID20608424><pubmed>20608424</pubmed></ref>

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations <ref><pubmed>7472570</pubmed></ref>

|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini is now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

==Current research models and findings==

===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.
{|
|-bgcolor="ECCEF5"
|

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.
|}

{|
|-bgcolor="CED8F6"
|The following recent studies use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

** Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

** The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

** The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.
|}

{|
|-bgcolor="CED8F6"
|
'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.
|}

{|
|-bgcolor="ECCEF5"
|
In the following studies new models and imaging techniques have been employed to gain a better understanding of the changes in brains of patients with schizophrenia

'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

Moreover, in the following study, a neuroimaging technique known as Proton Magnetic Resonance Spectroscopy (1H-MRS) is used to examine the brain of patients with schizophrenia.

'''Multimodal neuroimaging of frontal white matter microstructure in early phase schizophrenia: the impact of early adolescent cannabis use'''
<ref><pubmed> 3852698 </pubmed></ref>

[[Image:Online_placement_of_the_1H-MRS_volume_of_interest_.jpg|400x400px|frame|Proton magnetic resonance spectroscopy (1H-MRS) is used to examine the white matter tissue in brain of patients with schizophrenia. The image shows online placement of the 1H-MRS volume of interest.The 1H-MRS volume of interest is placed parallel to the AC-PC line (AC =anterior commissure, PC = posterior commissure). <ref><pubmed> 3852698 </pubmed></ref>]]

* The neurochemical used in this technique is N-acetylaspartate (NAA), a free amino acid that has a peak resonance at 2.02 ppm on the spectral profile in the 1H-MRS of human brain.
* In vivo concentration levels of NAA are higher in white matter compared to gray matter.
* Post-mortem studies have demonstrated that NAA is produced in neurons, transported into white matter and broken down into aspartate and acetate in oligodendrocytes. <ref><pubmed>17275978</pubmed></ref> NAA catabolism is thus closely related to the metabolism of myelin, since it provides a crucial source of acetate which is necessary for the formation of myelin from lipid.
* Therefore due to abnormal myelin biosynthesis in schizophrenia, brain tissues can be examined by 1H-MRS studies as long as the targeted brain region involves a single tissue type (white matter) that provides the necessary information regarding the catabolic cycle of NAA.

|}

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]

Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.

* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period).

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation. <ref><pubmed>15806441</pubmed></ref>

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.<ref><pubmed>21215908</pubmed></ref>

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.<ref><pubmed>1400921</pubmed></ref>

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.<ref><pubmed>25283616</pubmed></ref>

===Fetal Alcohol Syndrome===

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status. <ref><pubmed> 24904907 </pubmed></ref>

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.<ref><pubmed> 23809349 </pubmed></ref>

{| class="wikitable"
|-
| [[File:Fetal alcohol syndrome.jpg|500px]] || [[File:Ethanol fetal neural.jpg|400px]]
|-
| The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref>|| A mechanism of the effect of ethanol on neural stem cells (NSCs). Ethanol promotes asymmetrical cell division, the formation of radial glial-like cells, leading to the premature depletion of the VZ and its NSCs, and the thickening and cell proliferation in SVZ. The increased migration during early differentiation of ethanol-treated NSCs also leads to the appearance of subpial heterotopias<ref name="PMID22623924"><pubmed>22623924</pubmed></ref>

|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

* All degrees of iodine deficiency (mild: 50-99 μg/day, moderate: 20-49 μg/day and severe≤20 μg/day) affect thyroid function of both mother and the neonate as well as mental development of the child. The damage increases with the degree of deficiency; overt endemic cretinism is the most severe consequence.

* Iodine deficiency disorders refer to complications that arise when the recommended dietary allowance of iodine is not met. These complications include thyroid function abnormalities and when iodine deficiency is severe, endemic goitre and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality.

* Iodine deficiency represents the world’s greatest cause of preventable brain damage and mental retardation, resulting of a loss of 10-15 IQ points globally. Therefore it is essential that the recommended dietary requirement for iodine is met, especially during pregnancy and lactation (200–300 μg/day). <ref><pubmed>10750030</pubmed></ref>

* Clinical manifestations of hypothyroidism include: Myxedematous facies (condition characterized by thickening of the skin, blunting of the senses and intellect, and laboured speech), jaundice, a puffy face and a wide posterior fontanelle with open sutures. The nasal bridge is flat. The mouth may be slightly open revealing macroglossia. Further examination would reveal bradycardia and a protuberant abdomen with a large umbilical hernia. Neurologic examination findings include hypotonia with delayed reflexes. Skin may be cool to touch and mottled in appearance due to circulatory compromise.<ref><pubmed>2903524</pubmed></ref>

===Abnormalities associated with apoptosis and migration of cells in the fetal CNS===

* The migration of cells and cell death are critically important to fetal brain and CNS development. Abnormalities in each of these processes, programmed cell death (apoptosis) in particular, have been shown to result in severe developmental abnormalities in experimental animals. Apoptosis is critically important for appropriate brain development; certain areas in brain may experience up to 50% cell death. <ref><pubmed> 11589424 </pubmed></ref>

* In an experiment conducted by kuida et. al 1996, it was observed that mice that were deficient for CPP32 (a protease responsible for apoptosis), were born at a lower frequency than expected, were smaller in size compared to the normal mice and died at an early age. Brain development is significantly affected in CPP32-deficient mice resulting in a variety of hyperplasia and disorganised cell development. <ref><pubmed>8934524</pubmed></ref>

* On the other hand, disrupted neuronal migration can lead to an abnormality in cell position. When this happens, the neurons are said to be heterotopic. Abnormalities in neuronal migration have been studied extensively in human cerebral cortex where these defects are associated with a variety of syndromes and diseases, ranging from behavioural disorders (including some forms of schizophrenia, dyslexia and autism) to extremely severe mental retardation and failure to thrive. <ref><pubmed>10532616</pubmed></ref>

===Neural Tube Defects===

Neural tube is formed during the embryonic period but the associated abnormalities carry on to fetal development. If the neural tube does not close or fuse together properly, then openings remain in the brain or the spinal cord which can lead to various neural tube defects.

{| class="wikitable"
|-
! Abnormalities !! Descriptions
|-
| '''Anencephaly''' ||
* A neural tube defect involving abnormal development of the brain and incomplete skull formation leading to high infant mortality rates with infants being stillborn or dying within a few hours after birth.
* The failure of the neural tube to close around the 23rd and 26th day into embryonic development is characteristic of this condition. As a result, the forebrain is severely affected where the cerebrum does not grow and hence partial growth occurs only. The cerebrum has a key importance in maintaining thought, consciousness and coordination whilst having no intact cerebrum rules out the probability of the affected fetus gaining consciousness.
* Increasing one's dietary intake of folic acid notably reduces the incidence of neural tube defects. Consuming 0.4mg of folic acid is sufficient to induce these results.
* Since incomplete skull formation occurs, brain tissue becomes exposed due to the absence of bone covering and therefore leading to further complications. <ref><pubmed>25032496 </pubmed></ref>
|-
| '''Encephaloceles''' ||
* Another neural tube defect in which a sac-like projection (including membrane covering) occurs around the 3-4 week of embryonic development in which neural tube closure has not successfully occurred. The location of these protrusions varies but can be naso-frontal (nose and head), naso-ethmoidal (nose and ethmoid bone), naso-orbital (nose and eyes), meningocele (cerebrospinal fluid and membrane covering) and encephalomeningocele (meningocele with brain tissue as well).
* These sac-like protrusions lead to a variety of abnormal effects which include cerebro-spinal fluid build-up in brain, microcephaly, hydrocephaly, mental retardation, developmental problems, uncoordinated muscle movement and seizures. Consumption of folic acid again has been shown to significantly reduce the occurrence of encephaloceles in infants. <ref><pubmed>11151720</pubmed></ref>
|-
| '''Hydranencephaly''' ||
* A very rare neural tube defect in which the cerebral hemispheres are destroyed (necrotic tissue) with the occupied space being replaced by cerebro-spinal fluid, cortex and white matter remnants within a membranous sac. Interestingly, this condition can also develop in the postnatal peroid due to viral infections or traumatic brain injury. The brain stem may remain intact and functioning in hydranencephalic infants.
* Accompanied with this condition are many effects in which include seizures, hydrocephalus, increases in head circumference, impairment in vision/ body temperature regulation and cerebral palsy. Infants affected by hydranencephaly live typically short lives being no longer than 1 year of age. Lastly, there are no viable treatment options for this condition and only supportive care is available. <ref><pubmed>23112982</pubmed></ref>
|-
| '''Iniencephaly''' ||
* Another neural tube defect involving severe backward bending of the head (retroflexion) with subsequent spinal distortions as well. Affected infants have no neck and hence the scalp of the head is directly joined to the skin of the back (also skin of the face connected to skin of the chest). Other conditions that develop along with iniencephaly are cyclopia, cephalocele and anencephaly. The development of this condition is not solely due to one factor but from various causes (both genetic and environmental factors).
* There are specific factors that have been shown to increase the occurrence of this condition. Malnutrition, reduced folic acid intake and elevated levels of homocysteine in blood are environmental factors that increase the risk of iniencephaly <ref><pubmed> 22408660 </pubmed></ref>. Intake of certain drugs such as anti-histamines and sulphonamide/tetracycline (antibiotics) have also increases this risk <ref><pubmed> 22439066 </pubmed></ref>. Furthermore obesity has been shown to have a significant effect on the incidence of iniencephaly with 1.7-3 fold increase <ref><pubmed> 18538144 </pubmed></ref>.
* In terms of treatment, folic acid supplementation as well as avoiding certain drugs such as those outlined above significantly reduces the occurrence of this condition. <ref><pubmed>10719321</pubmed></ref>
|-
| '''Spina Bifida Cystica''' ||
* A neural tube defect which involves either the formation of a meningocele or myelomeningocele. Of the two, the meningocele, is the least debilitating in that a cyst-like structure forms when the neural tube does not close properly. The membrane (meninges) is pushed into openings of the vertebrae where spinal fluid builds up within the cyst. The myelomeningocele leads to severe problems as the portion of the nueral tube that is unfused allows the spinal cord to protrude through. As a result, neuronal tissue is highly exposed due to myeloschisis as well as infections and hence may lead to severe complications.
|-
| '''Spina Bifida Occulta''' ||
* A neural tube defect that has minimal complications in comparison to other defects. Furthermore, this defect is hidden in that a tethered spinal cord may arise as well as a thicker filum terminale and diastematomyelia (spinal cord split into two). It is also important to note that no cysts form as opposed to the other more severe spina bifida defects. <ref><pubmed>24009034</pubmed></ref>

|}

<references/>

User:Z3418981

2014-10-29T00:40:02Z

Z3418981: /* Lab Attendance */

==Lab Attendance==
Lab 1 --[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 12:45, 6 August 2014 (EST)
http://www.ncbi.nlm.nih.gov/pubmed
[http://www.ncbi.nlm.nih.gov/pubmed PubMed]
[http://www.ncbi.nlm.nih.gov/pubmed/25084016 PMID25084016]
<pubmed>25084016</pubmed>
Lab 2 --[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 12:17, 13 August 2014 (EST)
Lab 3--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 12:58, 20 August 2014 (EST)
Lab 4--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 11:48, 27 August 2014 (EST)
Lab 5--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 11:42, 3 September 2014 (EST)
Lab 6--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 11:51, 10 September 2014 (EST)
Lab 7--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 11:17, 17 September 2014 (EST)
Lab 8--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 12:30, 24 September 2014 (EST)
Lab 9--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 12:22, 8 October 2014 (EST)
Lab 10--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 12:11, 15 October 2014 (EST)
Lab 11--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 12:18, 22 October 2014 (EST)
Lab 12--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 11:39, 29 October 2014 (EST)

==Individual Assessments==
===Lab 1 Assessment===
'''Reference''': [http://www.ncbi.nlm.nih.gov/pubmed/24726222 PMID24726222]

<pubmed>24726222</pubmed>

'''Summary of the Method'''

In this study, genomic DNA was extracted from the umbilical cord blood of a total of 185 newborn females. Patients included 60 infants conceived by intracytoplasmic sperm injection (ICSI) and 73 infants conceived by in vitro fertilization (IVF) all recruited from a number of IVF centers across Canada. In addition, 52 naturally conceived patients were recruited from hospitals across the Lower Mainland in British Columbia, Canada. A karyotype or comparative genomic hybridization (CGH) analysis of the chromosomes was performed for all newborn cases. Cases were not included if congenital and/or chromosome abnormalities were present.

The X-chromosome inactivation (XCI) assay was performed to determine the XCI skewing of different tissues in different parts of the placenta by assaying allelic ratio of methylated alleles at the androgen receptor(AR), fragile X mental retardation 1 (FMR1), and DXS6673E loci. Fisher's exact test was a statistical method used to compare the frequency of mildly skewed (≥75%) and extremely skewed (≥90%) XCI in the patients. The parental nature of the skewed allele was determined by automated fluorescence analysis which was used to measure the AR alleles of the maternal decidua of the placenta.

'''Summary of the Results'''

There was no statistically significant difference between the ICSI, IVF and NC populations in the frequency of skewing ≥75% (7.0% vs. 5.7% vs. 2.0%, respectively; P=.523) or ≥ 90% (0 vs. 1.4% vs. 2.0%, respectively; P=.747). The mean level of skewing between the ICSI, IVF, and ICSI groups also was not significantly different (63.7% vs. 61.8% vs. 60.7%, respectively). Only two samples were found to have extremely skewed cases (≥90% skewing): one IVF (89.6%) and one NC (90.6%). The parental origin of the preferentially inactivated X chromosome in these extremely skewed cases was maternal for IVF and paternal for NC case.

'''Reference:''' [http://www.ncbi.nlm.nih.gov/pubmed/24399508 PMID24399508]

<pubmed>24399508</pubmed>

'''Summary of the Method'''

All of the pregnancies conceived by in vitro fertilization in Denmark from 1995 to 2005 (n = 18 787) was included in this study using the data reported to the National In Vitro Fertilisation register (IVF register). Information about the pregnancy outcomes as well as cycle-specific information on the type and date of treatment, and the occurrence of pregnancy, abortions and deliveries was also obtained from IVF.

A study published by Virkus et al. on venous thromboembolism in pregnant and puerperal women in Denmark was used as a reference (Virkus et al., 2011). This study was used as a reference since the population used in this study (727 VTE patients among the 805 464 pregnancies recorded in the Danish National Patient Registry from 1995 to 2005) is ideal and comparable to the present study. Consequently, venous thrombosis incidence rates in pregnancies conceived by in vitro fertilization were compared with venous thrombosis incidence rates in reference pregnancies, by calculating incidence rate ratios.

'''Summary of the Results'''

The venous thrombosis incidence was significantly increased in pregnancies after in vitro fertilization. The overall ratio of venous thrombosis incidence rate during in vitro fertilization pregnancies to reference pregnancies was 3.0 (95% CI 2.1–4.3). The overall venous thrombosis incidence rate was 28.6 per 10 000 pregnancy-years (95% confidence interval (CI) 20.6–39.6) for pregnancies after in vitro fertilization compared to 10.7 per 10 000 woman-years in reference pregnancies.

Reference used in the "Summary of the Method" section:

<pubmed>21713323</pubmed>

--[[User:Z8600021|Mark Hill]] These articles are well summarised and relevant. Please do not use all capitals in sub-headings and follow the site formatting. (5/5)

===Lab 2 Assessment===
[[File:An overview of the process of fertilisation in mutant C. elegans.jpeg|300px]]

Image showing the process of fertilisation in mutant C. elegans<ref><pubmed>15086962</pubmed>|[http://www.biomedcentral.com/1471-213X/4/3 BMC Developmental Biology]</ref>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 16:19, 21 August 2014 (EST) This is all correct. The image is very large (1.15 MB), perhaps a smaller image version could have been uploaded. You can adjust the resolution and size in most image editing programs. (5/5)

<references/>

===Lab 3 Assessment===

====Abnormalities associated with neural development====
<pubmed>12454899</pubmed>
<pubmed>25007063</pubmed>
<pubmed>16530991</pubmed>
<pubmed>7504639</pubmed>
<pubmed>19651588</pubmed>
<pubmed>25135350</pubmed>
<pubmed>25128525</pubmed>
<pubmed>24397701</pubmed>

--[[User:Z8600021|Mark Hill]] These are all relevant references, and a sentence description for selection would also help. (4/5)

===Lab 4 Assessment===

'''1. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.'''

<pubmed>24104453</pubmed>

The inhibitory effect of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) on the growth of C6 glioma cells was investigated in this study. Initially C6 cells were cultured with different concentrations of hUC-MSCs in order to examine whether the hUC-MSCs inhibition of glioma cell growth was mediated by soluble factors. It was found that hUCMSCs-CM exhibited a concentration-dependent inhibitory effect on C6 cell growth which in turn suggested that soluble factors in the conditioned media from hUC-MSCs were responsible for the inhibition of C6 glioma cells. Subsequently, flow cytometric analysis was used to test the effect of the soluble factors derived from hUCMSCs-CM on the cell cycle of glioma cells. Using this method, cell cycle status of C6 cells treated with different concentrations of hUCMSCs-CM was identified. It was observed that C6 cells treated with hUCMSCs-CM showed increases in the G0/G1 phase and reductions in the S phase compared to the control group (0 % hUCMSCs). These results suggested that hUC-MSCs could potentially inhibit the growth of C6 glioma cells and stop the cell cycle at the G0/G1 phase by secreting some soluble factors.

Western blot analysis was then performed and it was observed that the expression levels of β-catenin and c-Myc in C6 cells were reduced in the conditioned media derived from hUC-MSCs. These results indicated that some soluble factors secreted from hUCMSCs-CM may play a role in the inhibition of Wnt signaling pathway in C6 cells. Further investigations demonstrated that the secretion levels of dickkopf-1 (DKK1) were positively correlated with the concentrations of hUCMSCs-CM. Subsequently, the hypothesis that stem cells secreted Wnt inhibitors, such as DKK1, which could inhibit the Wnt signaling in tumor cells, was made.

Neutralizing antibody against DKK1 was then added to the hUCMSCs-CM in order to further confirm that DKK1 is a key factor in the inhibitory effect of hUCMSCs on C6 cell proliferation. It was observed that the inhibitory effect of hUC-MSCs on C6 cells was decreased when DKK1 was neutralized by anti-DKK1 antibody. Moreover, it was found that conditioned media from hUC-MSCs transfection with siRNA targeting DKK1 mRNA altered the regulation of the Wnt signaling in C6 cells. Therefore, it was concluded that hUC-MSCs inhibited C6 glioma cell growth by secreting DKK1, an inhibitor of Wnt pathway.

'''2.There are a number of developmental vascular "shunts" present in the embryo, that are closed postnatally. Identify these shunts and their anatomical location.'''

There are three developmental vascular "shunts" present in the embryo that are closed postnatally:

Foramen ovale (Foramen Botalli)

Foramen ovale is an opening in the inter-atrial septum which allows blood from the right atrium to enter the left atrium during foetal development. Foramen ovale allows blood to bypass the non-functional foetal lungs while the foetus obtains its oxygen from the placenta. A layer of cells exist over the foramen ovale during fetal development which acts as a valve and is known as septum primum. After birth, increased pulmonary blood flow and pulmonary venous return to left heart causes the pressure in the left atrium to be higher than the pressure in the right atrium. The increased left atrial pressure results in the closure of foramen ovale after birth.

Ductus venosus

In the foetus, the ductus venosus shunts blood from the left umbilical vein directly to the inferior vena cava and therefore allows oxygenated blood from the placenta to bypass the liver. Ductus venosus plays an important role in shunting oxygenated blood to the fetal brain.The ligamentum venosum which is usually attached to the left branch of the portal vein is the fibrous remnant of the ductus venosus

Ductus arteriosus (Ductus Botalli)

Ductus arteriosus connects the pulmonary artery to the proximal descending aorta. Ductus arteriosus prevents the output of the right ventricle from entering the unexpanded, fluid-filled and non-functional foetal lung. Therefore only enough blood reaches the foetal lungs to maintain the developing lung tissue. Ductus arteriosus becomes the ligamentum arteriosum after closing at birth.

===Lab 5 Assessment===

'''Azygos Lobe'''

Azygos lobe (also known as Adam's lobe) is a congenital malformation of the lung due to an alteration in the embryonic development of the azygos vein. Azygos lobe is a common congenital anomaly with an incidence of 1 in 100-200 of anatomical samples and 0.4-0.5% of chest radiographs. In general, azygos lobe means accessory lobe or supernumerary lobe of lung. There are three main types of azygos lobes: upper azygos lobe, lower azygos lobe and the lobe of azygos vein. The upper and lower azygos lobes are of very little clinical significance compared to the lobe of azygos vein.

During normal fetal development, the right posterior cardinal vein (precursor of the thoracic segment of the azygos vein) migrates over the apex of the right upper lung to occupy a medial mediastinal position. In the case of azygos lobe, an abnormal migration of this vein occurs and it penetrates into the right upper lobe. The right posterior cardinal vein carries the parietal and visceral layers of pleura with it and forms an accessory fissure made up of a total of four pleural layers called mesoazygos. The lung parenchyma located medial to the accessory fissure is called the azygos lobe.

Subsequently in the case of azygos lobe, the abnormal azygos vein crosses the apex of lung instead of its border and forms a fissure which separates the apex of the lung into medial and lateral parts. The medial part of the ruptured apex forms the lobe of azygos vein. Therefore the azygos lobe is a variably separated portion of the right lung and not an independent segment. Moreover, some course variability of the phrenic nerve have also been observed in the presence of an azygos lobe which is of importance when performing surgery.

'''References'''

<pubmed>16333920</pubmed>
<pubmed>23705047</pubmed>

===Lab 7 Assessment===

1. Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.

<pubmed>14561778 </pubmed>

In this study, the functional characterization of ''Arx'', a gene encoding homeodomain-containing proteins that are potentially involved in endocrine pancreas development is being investigated. To study the role of this gene in pancreas development, loss-of-function mutant mice were generated by targeting the genes in mice embryonic stem cells. Arx-deficient mice developed severe and early-onset hypoglycaemia, dehydration and weakness and died only two days after birth. Immunohistochemical analysis of Arx mutant pancreas then revealed an absence of mature endocrine α cells and an increased number of β and δ cells. However, islet morphology and the total number of endocrine cells remained intact. These results suggested a requirement of Arx transcription factor for α-cell fate acquirement and a repressive action on β-and δ-cell destiny, which is exactly the opposite of the phenotype observed in Pax4-deficient mice.

Therefore, the results of this study suggest that a mutual cross-regulatory inhibition of these factors exist so that Arx promotes α-cell cycle and prevents β- and δ-cell proliferation whereas Pax4 favours β- and δ-cell fate and inhibits α-cell proliferation. It was demonstrated using multiplex reverse transcriptase PCR (RT-PCR) that Pax4 and Arx transcripts accumulate in Arx and Pax4 mutant mice, respectively. These results further suggest that the antagonistic functions of Arx and Pax4 for proper islet cell specification are based on the pancreatic levels of the respective transcripts.

2. Identify the embryonic layers and tissues that contribute to the developing teeth.

a) Neural-crest-derived mesenchymal cells that differentiate under the influence of the enamel epithelium form odontoblasts. Odontoblasts secrete predentin which calcifies to form dentin.

b) Epithelial cells give rise to ameloblasts that produce the enamel of the tooth.

c) Periodontal ligament is a special connective tissue structure that holds the tooth in place and surrounds the tooth root coating of cementum.

===Lab 8 Assessment===

1. Provide a brief time course and overview of embryonic development of either the human testis or ovary. (2-3 paragraphs)

'''Embryonic Development of Ovaries'''

The gonads are developed from mesothelium lining the posterior abdominal wall, underlying mesenchyme and primordial germ cells. The initial stages of gonadal development are the same in males and females and occur during the fifth week with the formation of the gonadal ridge, a bulge on the medial side of the mesonephros. Finger like epithelial cords then grow into the underlying mesenchyme forming the gonadal cords. In females (XX), the cortex of the indifferent gonad differentiates into an ovary, and the medulla regresses.

Primordial germ cells are the first population of cells that migrate through the primitive streak in early gastrulation. These cells then lie at the hindgut yolk sac junctional region and subsequently migrate into the gonadal ridge in early embryonic development. The primordial germ cells enter the underlying mesenchyme during week 6 and are incorporated in the gonadal cords.

The gonads of males and females are identical before week 7 and are called indifferent gonads. Germ cells migrate into the indifferent gonads. The ovaries (females, XX) or testis (males, XY) then begin to develop and the successive structure of germ cells differentiates for each of the two sexes. In females with XX, genes on X-chromosome (such as Wnt-4 and DAX-1) along with an autosomal gene are necessary for initiation of female pathway. Ovary development is a slow process in female embryos and the ovary is not histologically identifiable until week 10.

[http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00012-6--s0095&isbn=978-1-4377-2002-0&uniqId=466385578-2 Moore: The Developing Human, 9th ed. Chapter 12]

2. Include an image from the historic genital embryology section of the online notes in your description.

[[File:Bailey330.jpg|500px]]

'''Image showing a section through the ovary of a human foetus of 4 months.'''

===Lab 9 Assessment===

'''Group 1 (Respiratory System)'''

The introduction is written well and it provides sufficient background information on the anatomy and development of respiratory system. It is also well-divided into the two conducting and respiratory zones. However it lacks to provide information on what is included in the page such as current research and abnormalities. In addition, this assignment is aimed to describe the fetal development but fetal period does not seem to be the focus in this project. I understand that it is difficult to focus on fetal period, especially for the respiratory system but if that is the case, you can mention why you’re also including information on embryonic and postnatal periods in your introduction. There are also a few spelling errors within the text that should be corrected (such as ‘id’ instead of ‘is’). The images of the histological sections are relevant but there is no caption for any of the photos and it is difficult to understand what they are trying to show. There is no information provided on the summary of the image either and one of the images is missing copyright information. In addition, the text as well as the images in the introduction needs to be referenced on the page.
The table of lung development stages is simple and very well summarised. The content of this section relates to the learning objectives of embryology however there is not enough explanation considering that this section is the main part of the project. In order to aid with understanding of the development of lungs, simple diagrams could be drawn that show different developmental stages. You can then explain more on what happens in each stage.

The first paragraph of the current research and findings about the conducting system and functional unit is already discussed in the introduction and therefore there is no need to include it again in this section. Try to include more precise information on the findings of each study and also talk about the new models that have aided in understanding of the development of this system. For example you can elaborate more on the three geometrical models that are proposed in the review study in 2013(there is no information under the “current models” subheading at the moment- you can put this information there). Also it is a good idea to organise the research findings in chronological order so that new advancements are found in more recent studies (2011 must come before 2013).The two alveolar cell types under current research is irrelevant – I would put them under introduction. Also I don’t understand why the image of lung diseases is under current research (maybe put that image under abnormalities?)

The historic findings section is very informative, especially the “surfactant” section. You can also tabulate the data to make it look neater. However from my understanding, in this section we also need to provide information on the history and stages of fetal lung development. I know it is hard to find this information but maybe try looking for review articles that summarise the findings of past studies in this area. The abnormality section is well written and thorough with so many abnormalities named and described. The only suggestion is to include more images.

Overall, this web page shows a very effective team work and it is clear that work has been allocated with each person working on a different subheading. You only need to pay attention to minor issues mentioned above. Also in terms of referencing, there are many in-text references missing in different sections. It is very important to format these references correctly under one ‘references’ subheading at the end of the page (instead of having a separate reference list for each section).

'''Group 2 (Renal System)'''

Introduction is very well-written with a precise background on the renal system anatomy and function. There is also a brief introduction on the development of renal system in both embryonic and fetal period as well as the abnormalities that can be associated with the development of this system. Therefore the reader can gain an expectation of what is going to be included in the wiki-page by reading the introduction first. In-cite referencing is also used to support the information provided. I suggest including an image of the anatomy of organs in the renal system to make the introduction even more perfect.

The developmental timeline is a very good way to start the development section; however your timeline is missing some of the important features such as when the ureter and urethra develop. I would also recommend tabulating the data so that it looks neater. I also recommend placing the “current research models” section after the sections describing the development of different organs so that the timeline is located right before the section explaining the development of “kidney”. Dividing the development into different organs and the subheadings used (especially under the heading of “kidney”) are very appropriate and are evidence of significant research that has been done for this project. The information provided is very comprehensive; however it is all formatted in paragraphs. I would suggest using dot points or adding your own diagrams and figures to summarise the text and make it more interesting to the readers. For example the diagram used to illustrate the anatomical position is very helpful and effectively summarises the information to readers. You should also make sure that you remove the image used for the development of kidney since it cannot be used due to copyright. In addition, most images are missing the ‘student template’ so make sure the template is added.
There isn’t any information under the heading ‘historic findings’. I understand that this section is a bit more difficult than the rest. A suggestion I can make is to search for old articles in PubMed (by adjusting the year) which can include key historical events. Review articles that summarise historic findings related to renal development may also be helpful.

The content under “current research” is very interesting and relevant. A minor spelling error exists (“buy” instead of “by”). To further improve this section, I suggest searching for recent models that aid in better understanding of kidney development. The abnormalities section is very informative. Each disease is explained thoroughly and concisely. The images are also very helpful with the understanding of clinical manifestations. To improve this section, I suggest using dot-points and using more images. Make sure you include information for “Horseshoe Kidney” as well.

Overall, the content used in this project was very relevant and showed extensive research and understanding. The use of headings and subheadings was very appropriate which showed that the work has been well-divided among members. The use of in-cite referencing is also very good and references are all listed under one subheading; however, some references are used more than once, this can be fixed and they can be all combined under one number.

'''Group 3 (GIT)'''

Introduction is good with brief background information on the anatomy of the GIT which is an appropriate starting point for the readers. Fetal development is also described in the introduction, however I suggest including more information on embryonic period and how that leads to fetal development so that the rest of the page can focus more on the fetal stages. I also suggest including parts of each of the major subheadings in the introduction such as the common abnormalities and the recent finding. An image illustrating different organs of GIT can also help with better understanding of the anatomy. There is no referencing in the introduction to support the information provided.
Regarding the timeline section, the information needs to be tabulated in order to make it easier to compare between organs. Another alternative is to include a small timeline for each of the organs at the beginning of each section. It is very good that each stage of the timeline has been separately referenced; this shows the extensive research that has been conducted.

The recent finding section focuses on only one study in 2006 on hedge-hog signalling pathway. There are a lot of interesting and more recent studies that can be included in this section. As a starting point, you can search for recent models that help in better understanding of GIT development.
The information under each of the foregut, midgut and hindgut is very detailed and comprehensive; however the structure does not flow through the whole page with mid-gut including different subheadings and diagrams. In my opinion you should break up the foregut and hindgut sections into smaller subheadings and use diagrams like the ones used for midgut. Potential images can also be used in these sections. Additionally, the anorectal deformities under the ‘hindgut’ section can be placed under the deformities section. The “Midgut” section includes very good information and the drawings are helpful in understanding the concept however they need to be captioned.

This project does not include historic findings. I understand that this section is a bit more difficult as it is hard to find information on it. A suggestion I can make is to search for old articles in PubMed (by adjusting the year) which can include key historical events. Review articles that summarise historic findings related to GIT development may also be helpful. The abnormalities are precisely discussed and are relevant to the topic but as mentioned before, I suggest putting all the abnormalities under one subheading to make it easier for the viewers to navigate.

Overall, the main key points are addressed in this project and the content demonstrates extensive research and a good understanding of the concept. In order to facilitate learning and to make it more interesting and understandable for viewers, some of the text can be summarised in diagrams. Dot -points can also be used in some parts instead of paragraphs. The use of hand written drawings was creative and aided in understanding however I would suggest stating that the drawing is handwritten in your page. If the drawing is copied from another image, then the source of that image needs to be included as well. Also a more complete description of the image will make it easier to understand.

'''Group 4 (Genital System)'''

An introduction is recommended as it is usually a good starting point. I suggest starting by giving background information on the anatomy of male and female genital systems. You can then talk about the embryonic period and give a brief summary of how this period is different to fetal period. You can then briefly mention the significant events that occur during fetal period and the sections you are including in your project (including abnormalities and research findings).

The table in the system development is a good summary however it looks a bit messy at this stage. I suggest having two different tables for male and female, avoid using all capital letters and bold texts in the table. I also suggest starting the development section with a brief paragraph on early stages of development. The image included under ‘system development” is a very good summary but it needs to be captioned and referenced. I also recommend re-uploading the image in a smaller size to improve the quality. The use of the video is also very creative. Well done for finding this helpful video!! It would be perfect if you could reference the video and maybe include a few sentences on what it is showing. Overall, the development section is very good with the use of different methods to help in learning. To make this section perfect, you can add some details in paragraphs to explain more on different stages of development.

There is a lot of information under “current models” which shows extensive research, however I find this section hard to follow. Using paragraphs instead of dot points will result in a more coherent flow. Also the studies need to be referenced appropriately; it would be a good idea to include the name and year of the article in the text. The division into “current research” and “current models” is a smart thing to do however in both sections the amount of information provided for male is much more than female therefore more research needs to be done for female. I like how a self-drawn image is used; it would be a good idea to include a description for the image (rather than “alt text”). Also make sure that all the references are listed at the end under one reference subheading instead of having different references for each section. Also, great job for historic findings! This is the most difficult section but you have managed to include detailed information. Similar to current research section however, most of the information found is for the development of male system. Try to add to historic findings on female system if possible.

Abnormalities section includes a significant number of abnormalities with causes and treatment of each abnormality addressed precisely. I also like how you divided this section into female, male and both. Information is well referenced and helpful images are included. Make sure that your images are referenced. If self-drawn images are used, then you can briefly mention that in your text. I would also recommend adding more images for other diseases to illustrate the clinical manifestations of each disease. Overall this group has done an extensive research and the methods used (such as drawings and videos) are very creative and helpful. Well done!

'''Group 5 (Integumentary System)'''

The presentation of this page is very well with multiple images being used and text organised into tables and dot points. The introduction is short however includes necessary information regarding what is being included in the project. I recommend adding background information on anatomy of the skin (explaining on different layers) and other structures as well as a brief summary on the embryonic development of the system so that fetal development can be further expanded throughout the project.

The development overview section is done very well and is divided into different sections each explaining the development of a different structure. The use of table, images and bullet points has made the page look very interesting. The table of the timeline in the ‘Development Overview’ is done very well and the use of histological images is excellent as it helps in visualising the anatomy at each stage. There is however no proper referencing, copyright information or student template for any of the images. The table under “teeth” is also a very good summary of events during fetal period. I recommend including self-drawn diagram as well, since this is the only feature missing from your project. You can include a drawing of the different layers of skin (possibly in the introduction section). I also suggest putting all the references under one reference list at the end of the page instead of having references at the end of each section.

The “some research finding” section is presented well with a different background colour to other sections (it is similar to recent findings in mark’s wiki pages). This makes the page look very visually appealing! You have elaborated on two out of four research papers which is very good. However I recommend describing the other two papers as well and even including more papers (It would be perfect if you could provide research papers for different structures). I like how the “more research papers” can be expanded for anyone interested.

Historic findings section is very well researched considering it is difficult to find information for this section. The ‘Abnormalities’ section is also perfect and complete with all four diseases having sufficient information and appropriate references. The images are also relevant and illustrate the clinical manifestations well. Overall this page is very well-organised and only minor issues mentioned above need to be fixed.

'''Group 6 (Endocrine System)'''

The endocrine system is made up of different glands and there is so much information that could be provided regarding the the anatomy and development of each gland so very well done for working on the difficult system! I like how you have divided the page into different glands; I can imagine having the four major headings (development, historic findings, current research and abnormalities) and then subdividing it into different organs would be more confusing. Just try to follow the same structure for each organ; I recommend doing a brief introduction, anatomy, function, timeline, development, historic findings, current research and abnormalities for each organ. It is important that your page has a coherent flow by following the same structure for each subheading. An overall introduction on endocrine system might also be very useful. You can then include in the introduction how you are planning to structure your page.

The content and number of references show that extensive research has been conducted. It would be great if you could use in-text referencing and place all the references under one subheading at the end of the page. Arranging the information into tables is a great idea but you need to complete your tables for pineal gland, hypothalamus and placenta. You also need to include more images in your page (you can include at least one image for the abnormality associated with each organ). There are a few images included at the moment and they are well done and appropriately referenced. You can also try to draw your own diagrams. In my opinion, a timeline showing the development of all the systems would be a great way to compare the different stages in development of different endocrine glands. Maybe think about including this in a table after you finished all the sections; it is a good way to connect the information provided separately for each organ. Overall the content of this page is very good but it needs to be formatted so that it can have a coherent flow. Also there is no information for introduction, historic findings and development of placenta, make sure you include those.

'''Group 8 (Musculoskeletal System)'''

In this project the development section is well-researched however introduction, historical findings, current models and abnormalities still need some work. The development section is very informative with appropriate use of in-text referencing. However, to prevent having bulks of text, you can create diagrams and flow charts or use bullet points. It would also be great if you could provide a timeline under “muscle development general timeline” section. Background embryonic development section is very helpful but we do not need this much information on embryonic period for this project. You can summarise this information in introduction, so that it provides a starting point and fetal development can be further expanded through the project. The rest of the information regarding system development seems to cover the important points; however it still needs work (for e.g. “second trimester muscular development” section is clearly missing some bits).

The abnormality section only includes one abnormality (Duchenne Muscular Dystrophy). This abnormality is well described but it needs to be referenced. An image of the clinical manifestation of the disease can clearly help with understanding. There are lots of other abnormalities that you can include in this section (We learnt from the musculoskeletal development lecture that musculoskeletal conditions form 20% of all abnormalities at birth). You can also refer to “limb development lecture” to find information on musculoskeletal abnormalities.

Finding information on historic findings might be a little challenging. A suggestion I can make is to search for old articles in PubMed (by adjusting the year). These articles can include key historical events. Review articles that summarise historic findings related to musculoskeletal development may also be helpful. You also need to find information on current research.

Finally, you should add an introduction to your project. It seems like you are more focused on muscular development rather than “musculoskeletal” so you can mention that in your introduction. You can also show creativity by drawing your own diagrams, adding images, and tabulating timeline data. You should also fix the references by putting all the references under one subheading in the bottom of the page.

===Lab 10 Assessment===

'''Research article- The Involvement of Neural Retina Pax6 in Lens Fiber Differentiation'''

<pubmed>15855760</pubmed>

Specific interactions that occur between neural and ectodermal tissues as a result of regulated gene expression and controlled signalling events are necessary for proper eye formation. The homeobox gene Pax6 is proved to be essential for eye development in both vertebrates and invertebrates. Pax6 expression for the retina anlage has been revealed to be crucial in the development of different retinal cells. In this study, lab techniques such as plasmid construction, in ovo microelectroporation, in situ hybridization and section immunostaining were performed to examine the expression of several transcription factors in the lens of Pax6-negative optic vesicle eye in chick embryos. Initially, it was shown that the expression of a negative version of Pax6 isoform in developing optic vesicles of chick embryos prevents proper lens development at the lens vesicle stage as well as resulting in optic cup deformation. Following this finding, the molecular events underlying deformed lens formation were further explored.

A Pax6-EnR gene which effectively repressed endogenous Pax6 activity in neurons was used to examine the role of Pax6 in optic cup formation and lens differentiation. It was observed that overexpression of Pax6-EnR in optic vesicle results in abnormal optic cup formation. In addition, a severely deformed lens was formed in the Pax6-negative optic vesicle eye. The development of the lens was significantly delayed at stage 24 and the lens was dramatically smaller than the control lens. It was concluded from these findings that Pax6 expression plays an important role in lens development.

The remaining part of this study was focused on determining the molecular pathways underlying the previous findings. Initially, the expression of L-Maf (a transcription factor that has a crucial role in lens differentiation) was investigated. There was almost no reactivity for L-Maf in the deformed lens while the contralateral lens showed normal L-Maf expression. The expression of c-Maf was investigated afterwards. C-Maf is a transcription factor that is strongly expressed in both epithelial and fiber cells. Unlike L-Maf, C-Maf transcripts were normally expressed in both control and malformed lens. This result suggests that the function of Pax6 is not required for c-Maf expression in the lens at stage 24.

Finally, to illustrate how the Pax6-EnR effect is coupled to the down-regulation of L-Maf, the expression of fibroblast growth factor FGF8, a diffusible factor that was shown to activate L-Maf in non-lens cells was investigated. It was found that FGF8 is down-regulated in the neural tissue. This finding suggests that Pax6 in neural retina regulates FGF8 expression, which may maintain L-Maf expression in the lens to be essential for subsequent lens fiber differentiation.

[https://embryology.med.unsw.edu.au/embryology/index.php/Sensory_-_Vision_Development#Lens Sensory-Vision development Wiki page]

2014 Group Project 7

2014-10-24T06:46:53Z

Z3418981: /* Development during fetal period */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, receiving and integration of information from all parts of the human body, serving as the processing center of the body's nervous system. The CNS controls all of the body functions (sensory and motor) and consists of 2 main organs: The Brain and Spinal Cord.

The brain is the body's control center consisting of 3 main components; forebrain, midbrain and hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures such as hypothalamus and thalamus, which are responsible in motor control, autonomic function control and relaying sensory information. The midbrain along with the hindbrain together forms the brain-stem which has many important functions such as regulating the cardiac and respiratory systems.

The spinal cord is a cylindrical-shaped structure composed of nerve fiber bundles and is connected to the brain via the brain-stalk formed from the midbrain and hindbrain. The spinal cord is running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. It plays the important role of transmitting information from body organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into ascending bundles, which transmits sensory information from the body to the brain, and descending bundles which transmits motor function information from the brain to the body.

Neurulation occurs in the embryonic period during which ectoderm forms initial structures of the CNS and folds upon itself to form the neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the prosencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon further divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.
During the fetal period, there is ongoing growth in the size, weight and surface area of the brain and spinal cord. Microscopically, the cellular processes during this period can be divided into: cell proliferation, cell migration, cell differentiation and cell death. Neural development will continue after birth with substantial growth, death and reorganization of the cells.

In this website, the fetal development of CNS is being discussed with the focus being on cellular processes of brain development. Some current research models and findings as well as historic findings will be mentioned as well. In addition, the major abnormalities associated with CNS during fetal period and neural tube defects that occur during embryonic period but will further carry on to fetal development will be discussed too.

==Development during fetal period==

===Cellular process===

In the developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. There are a cascade of events in which the earlier occurring processes may influence the subsequent occurring ones, but a late-occurring event cannot influence the earlier ones.

[[File:Schematic_representation_of_the_timeline_of_human_neural_development.jpg|700px]]

A simplified timeline of human neural development (modified) <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

This simplified graph shows a timeline for major events of neural development that occur during fetal and postnatal periods. These events, which are summarized in the following table, are broadly classified by cell multiplication, cell migration, growth and differentiation and angiogenesis:

{| class="wikitable"
|-
! Major Events !! Descriptions
|-
| Cell multiplication ||
* Neurons are proliferated and generated from neural stem cells and progenitor cells (precursor cells) in a process known as neurogenesis in 2nd trimester.
* Cell death and Gliogenesis (glial cells (such as astrocytes) deriving from multipotent neural stem cells) occur in the 3rd trimester.
* Local gliogenesis continues postnatally.
|-
| Cell migration ||
* Neuronal migration is maximised during 2nd trimester while glial migration is maximised during 3rd trimester
|-
| Growth and differentiation ||
* Axonal and dendritic arborisation (fine branching structures at the end of nerve fibers) appear by the end of fetal period.
* Synaptogenesis (formation of synapses) and electrical activity is maximised in 3rd trimester (and continued postnatally).
* Cell death due to over-innervation can be observed in late fetal and postnatal period.
* Myelination occurs in late fetal and postnatal period (vast majority of postnatal growth in brain is due to myelination).
|-
| Angiogenesis ||
* Oxidative metabolism can be seen in late fetal period.
* Capillary networks develop postnatally.
|}

'''1. cell proliferation'''

[[Image:Somatosensory cortex of E20 rat.jpeg|frame|500x500px|Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) <ref name="PMID22272298"><pubmed>22272298</pubmed></ref>]]

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref name="PMID4203033"><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that is comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref name="PMID5414696"><pubmed>5414696</pubmed></ref>. In some parts of the developing CNS, this is the only proliferative zone and therefore it is assumed that the ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref name="PMID7204662"><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref name="PMID12764033"><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia of most parts of the brain are produced in this zone, therefore it is important to the adult brain <ref name="PMID8523077"><pubmed>8523077</pubmed></ref>. In some parts of the brain, production of a significant number of neurons is seen in this zone <ref name="PMID9712307"><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes to large number of cells in the neocortex, which is the youngest structure in the brain <ref name="PMID1713238"><pubmed>1713238</pubmed></ref>. Unlike the ventricular zone, the proliferating cells do not move through the cell cycle.

'''2. cell migration'''
[[Image:CNS_passive.jpg|frame|200x150px|Passive cell displacement and outside-to-inside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]
[[Image:CNS_active.jpg|frame|350x250px|Active cell migration and inside-to-outside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]

* This is the process that influences the final cell position. In this process, cells produced from the two ventricular zones migrate.

* The postmitotic young neurons migrate from the proliferation site into their ultimate position in two different ways:

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus <ref name="PMID489804"><pubmed>489804</pubmed></ref>, hypothalamus <ref name="PMID5029133"><pubmed>5029133</pubmed></ref>, spinal cord <ref name="PMID4407392"><pubmed>4407392</pubmed></ref>, dentate gyrus of the hippocampal formation <ref name="PMID17533671"><pubmed>17533671</pubmed></ref> and many regions of the brainstem.
# Active migration: Active participation of the moving cell is required for the cell displacement. Neurons move at a greater distance than passive migration, and the migrating young neurons bypass the previously generated cells (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structures including cerebral cortex and several subcortical areas <ref name="PMID17533671"><pubmed>17533671</pubmed></ref>.

{| style="width:20%; height:170px" align="center"
|-
| [[Image:Internurons migration in cerebral cortex.jpg|frame|200x400px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex <ref name="PMID17726524"><pubmed>17726524</pubmed></ref>]]
|}

'''3. cell differentiation'''<ref name="PMID10532616"><pubmed>10532616</pubmed></ref>

* This is the process which begins after the migration of neuronal and glial cells to their final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, the axon and dendrites of each neuron grow out.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways which cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: One neuron innervates many cells. These connections will be eliminated after the reduction of the projection area.
#Convergent transient connections: Several neurons innervate one target neuron. Only one of these neuronal connections is found in the adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs. Two mechanisms: axonal retraction and neuronal pruning <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death. Neurons die because they fail to establish projections.

* Critical for appropriate brain development

 

=== Brain Development ===

* The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells. By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

* The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

[[Image:Brain ventricles and ganglia development 03.jpg|frame|200x200px|Increase in size of of brain and ventricles <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]
[[Image:Brain fissure development 02.jpg|frame|200x200px|Increase in size of brain fissure <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]

* The gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding.

* The brain development begins rostral in GW8, proceeding caudally until it is complete at GW22 <ref><pubmed>560818</pubmed></ref>

* The formation of Secondary Sulci is between GW30-35, while the formation of of Tertiary Sulci begins during GW36 and into the postnatal period.

* Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

* Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

* The major fibre pathways make up the brain white matter

* AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Neuron Production'''

* The human brain contains billions of neurons which are produced by mid-gestation during fetal development <ref><pubmed>8361683</pubmed></ref>

* Processes of Neuronal production is initiated by first increasing the size of the neural progenitor cell population within the body, these cells are mitotic in nature and are capable of forming new cells.

* Initially (from the end of gastrulation through to embryonic day 42), the neural progenitor cell population is increased greatly when the progenitor cells divide through 'symmetrical' mode of cell division. Multiple repeats of the cell division occurs throughout this period. This 'symmetrical' division method brings about the formation of 2 new identical neural progenitor cells

* Mode of cell division changes from a symmetrical cell division type to an 'asymmetrical' cell division from the beginning of E42. This asymmetrical cell division forms 2 different cell types; one Neural progenitor & one Neuron <ref><pubmed>12764028 </pubmed></ref>

* Newly formed Neural progenitor cells remains to undergo more processes of cell division whereas the newly formed neuron moves into position in the developing neocortex

'''Neuron Migration''' <ref name="PMID21042938"><pubmed>21042938</pubmed></ref>

Outlined above was a broad summary on neuron migration. Neuron migration in the cortex will be covered below in more detail.

* The ventricular zone (VZ) is where the majority of neurons migrate radially out and into the neocortex. The type of migration utilised here is referred to as somal translocation where the neuron cell body translocates out of the VZ and into the outer brain region with the nucleus moving across the cytoplasm and into the outer brain region.

* With increasing brain size, somal translocation is no longer efficient for neuronal migration out of VZ. Since greater distances are evident, radial glial guides are adopted to allow the migration of neurons to continue. Similar to somal translocation, these cell populations establish a scaffolding system where neurons can attach to (basal process occurs) and then move into the developing cortical plate. These cell populations are comprised of neural progenitor cells and are therefore able to support mass neuron migration.

* Another mode of transport utilised by neurons situated within a second zone of the ventral telencephalon is referred to as tangential migration. The neurons here migrate tangentially to the cortical mantle whilst adopting different signalling pathways (guidance molecules) as opposed to radial migration. As a result of neuronal migration, a 6-layered structure forms within the developing neocortex.

* Once completion of the pre-plate has occurred, two regions are formed which are the subplate (SP) and the marginal zone (MZ).In between these two regions, the cortical plate arises as well. Earliest neuron arrival forms the deepest layer of the cortex: cortical layer 6. More superficial layers of the cortex will develop with continuous cell migration. It is important to note that a specific cell class is located within the MZ in which the Cajal-Retzius cells (CR) reside. CR's are important for correct neuron positioning within the cortical layers as well as having an inhibitory effect on neuron migration. Rheelin, a molecular signal produced by the CR's is important here as it stops neurons from migrating and signals them to up their corresponding positions.

'''Folding: sulcation and gyration'''

[[Image:Dev anat 01.jpg|frame|200x200px|Simplified external lateral (left) view of the brain growth]]

* During the fifth and sixth month of gestation, the smooth cortex begins to fold by sulcation and gyration. <ref name=PMID21571694><pubmed>21571694</pubmed></ref>

# Sulcation: This is the development of sulci, including primary and secondary. The formation of primary sulci involves the appearance of shallow grooves on the surface of the brain, which then becomes more deeply infolded, while the formation of secondary sulci is due to the development of side branches of the primary ones <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.
# Gyration: This is the development of gyrus that occurs during late fetal development until the end of the pregnancy or after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>. This process is the formation of tertiary sulci, which is the formation of other side branches of the secondary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

{| class="wikitable"
|-
! Weeks of gestation !! Visible anatomical details
|-
| 20-21 || smooth, with the impression of "lissencephalic" brain; wide Sylvian fissures; visible interhemispheric fissure and parieto-occipital fissure
|-
| 22-23 || beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || smooth cerebral cortex surface; visible shallow grooves in the central sulci, interparietal sulci and superior temporal sulci; start of opercularization of Sylvian fissures; presence of calcarine fissures and cingular sulci
|-
| 26 || presence of central and collateral sulci
|-
| 27 || presence of marginal and precentral sulci
|-
| 28 || presence of postcentral and intraparietal sulci
|-
| 29 || presence of superior and inferior frontal sulci; narrower Sylvian fissure; clear corpus callosum; bright white matter; dark cortical ribbon
|-
| 30-31 || beginning of infolding of cortex which is first apparent in the occipital lobe; narrower ventricular system and subarachnoid spaces
|-
| 32 || presence of superior and inferior temporal sulci
|-
| 33 || presence of external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration; compactly and extensively folded cortex
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table of the process of sulcation and gyration <ref name=PMID20608424><pubmed>20608424</pubmed></ref>

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations <ref><pubmed>7472570</pubmed></ref>

|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.
{|
|-bgcolor="ECCEF5"
|

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.
|}

{|
|-bgcolor="CED8F6"
|The following recent studies use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

** Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

** The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

** The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.

'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.
|}

{|
|-bgcolor="ECCEF5"
|
In the following studies new models and imaging techniques have been employed to gain a better understanding of the changes in brains of patients with schizophrenia

'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

Moreover, in the following study, a neuroimaging technique known as Proton Magnetic Resonance Spectroscopy (1H-MRS) is used to examine the brain of patients with schizophrenia.

'''Multimodal neuroimaging of frontal white matter microstructure in early phase schizophrenia: the impact of early adolescent cannabis use'''
<ref><pubmed> 3852698 </pubmed></ref>

[[Image:Online_placement_of_the_1H-MRS_volume_of_interest_.jpg|400x400px|frame|Proton magnetic resonance spectroscopy (1H-MRS) is used to examine the white matter tissue in brain of patients with schizophrenia. The image shows online placement of the 1H-MRS volume of interest.The 1H-MRS volume of interest is placed parallel to the AC-PC line (AC =anterior commissure, PC = posterior commissure). <ref><pubmed> 3852698 </pubmed></ref> ]]

* The neurochemical used in this technique is N-acetylaspartate (NAA), a free amino acid that has a peak resonance at 2.02 ppm on the spectral profile in the 1H-MRS of human brain.
* In vivo concentration levels of NAA are higher in white matter compared to gray matter.
* Post-mortem studies have demonstrated that NAA is produced in neurons, transported into white matter and broken down into aspartate and acetate in oligodendrocytes. <ref><pubmed>17275978</pubmed></ref> NAA catabolism is thus closely related to the metabolism of myelin, since it provides a crucial source of acetate which is necessary for the formation of myelin from lipid.
* Therefore due to abnormal myelin biosynthesis in schizophrenia, brain tissues can be examined by 1H-MRS studies as long as the targeted brain region involves a single tissue type (white matter) that provides the necessary information regarding the catabolic cycle of NAA.

|}

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]

Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.

* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period).

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation. <ref><pubmed>15806441</pubmed></ref>

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.<ref><pubmed>21215908</pubmed></ref>

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.<ref><pubmed>1400921</pubmed></ref>

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.<ref><pubmed>25283616</pubmed></ref>

===Fetal Alcohol Syndrome===

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status. <ref><pubmed> 24904907 </pubmed></ref>

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.<ref><pubmed> 23809349 </pubmed></ref>

{| class="wikitable"
|-
| [[File:Fetal alcohol syndrome.jpg|500px]] || [[File:Ethanol fetal neural.jpg|400px]]
|-
| The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref>|| A mechanism of the effect of ethanol on neural stem cells (NSCs). Ethanol promotes asymmetrical cell division, the formation of radial glial-like cells, leading to the premature depletion of the VZ and its NSCs, and the thickening and cell proliferation in SVZ. The increased migration during early differentiation of ethanol-treated NSCs also leads to the appearance of subpial heterotopias<ref name="PMID22623924"><pubmed>22623924</pubmed></ref>
|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

* All degrees of iodine deficiency (mild: 50-99 μg/day, moderate: 20-49 μg/day and severe≤20 μg/day) affect thyroid function of both mother and the neonate as well as mental development of the child. The damage increases with the degree of deficiency; overt endemic cretinism is the most severe consequence.

* Iodine deficiency disorders refer to complications that arise when the recommended dietary allowance of iodine is not met. These complications include thyroid function abnormalities and when iodine deficiency is severe, endemic goitre and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality.

* Iodine deficiency represents the world’s greatest cause of preventable brain damage and mental retardation, resulting of a loss of 10-15 IQ points globally. Therefore it is essential that the recommended dietary requirement for iodine is met, especially during pregnancy and lactation (200–300 μg/day). <ref><pubmed>10750030</pubmed></ref>

* Clinical manifestations of hypothyroidism include: Myxedematous facies (condition characterized by thickening of the skin, blunting of the senses and intellect, and laboured speech), jaundice, a puffy face and a wide posterior fontanelle with open sutures. The nasal bridge is flat. The mouth may be slightly open revealing macroglossia. Further examination would reveal bradycardia and a protuberant abdomen with a large umbilical hernia. Neurologic examination findings include hypotonia with delayed reflexes. Skin may be cool to touch and mottled in appearance due to circulatory compromise.<ref><pubmed>2903524</pubmed></ref>

===Abnormalities associated with apoptosis and migration of cells in the fetal CNS===

* The migration of cells and cell death are critically important to fetal brain and CNS development. Abnormalities in each of these processes, programmed cell death (apoptosis) in particular, have been shown to result in severe developmental abnormalities in experimental animals. Apoptosis is critically important for appropriate brain development; certain areas in brain may experience up to 50% cell death. <ref><pubmed> 11589424 </pubmed></ref>

* In an experiment conducted by kuida et. al 1996, it was observed that mice that were deficient for CPP32 (a protease responsible for apoptosis), were born at a lower frequency than expected, were smaller in size compared to the normal mice and died at an early age. Brain development is significantly affected in CPP32-deficient mice resulting in a variety of hyperplasia and disorganised cell development. <ref><pubmed>8934524</pubmed></ref>

* On the other hand, disrupted neuronal migration can lead to an abnormality in cell position. When this happens, the neurons are said to be heterotopic. Abnormalities in neuronal migration have been studied extensively in human cerebral cortex where these defects are associated with a variety of syndromes and diseases, ranging from behavioural disorders (including some forms of schizophrenia, dyslexia and autism) to extremely severe mental retardation and failure to thrive. <ref><pubmed>10532616</pubmed></ref>

===Neural Tube Defects===

Defects which affect the either the brain or the spinal cord in which openings remain. Grastulation occurs in week 3 of embryonic development where specialized cells (dorsal side) structurally change shape leading to the formation of the neural tube. If the neural tube does not close or fuse together properly, then openings remain which lead to various neural tube defects such as Spina bifida cystica and Spina bifida occulta.

'''Anencephaly''' <ref><pubmed> 8286034 </pubmed></ref>

* A neural tube defect involving abnormal development of the brain and incomplete skull formation leading to high infant mortality rates with infants being stillborn or dying within a few hours after birth.

* The failure of the neural tube to close around the 23rd and 26th day into embryonic development is characteristic of this condition. As a result, the forebrain is severely affected where the cerebrum does not grow and hence partial growth occurs only. The cerebrum has a key importance in maintaining thought, consciousness and coordination whilst having no intact cerebrum rules out the probability of the affected fetus gaining consciousness .

* Increasing one's dietary intake of folic acid notably reduces the incidence of neural tube defects. Consuming 0.4mg of folic acid is sufficient to induce these results.

* Since incomplete skull formation occurs, brain tissue becomes exposed due to the absence of bone covering and therefore leading to further complications.

'''Encephaloceles''' <ref><pubmed> 11151720 </pubmed></ref>

* Another neural tube defect in which a sac-like projections (including membrane covering) that occurs around the 3-4 week of embryonic development in which neural tube closure has not successfully occurred. The location of these protrusions varies but can be naso-frontal (nose and head), naso-ethmoidal (nose and ethmoid bone), naso-orbital (nose and eyes), meningocele (cerebrospinal fluid and membrane covering) and encephalomeningocele (meningocele with brain tissue as well).

* These sac-like protrusions lead to a variety of abnormal effects which include cerebro-spinal fluid build-up in brain, microcephaly, hydrocephaly, mental retardation, developmental problems, uncoordinated muscle movement and seizures. Consumption of folic acid again has been shown to significantly reduce the occurrence of encephaloceles in infants.

'''Hydranencephaly''' <ref><pubmed> 23112982 </pubmed></ref>

* A very rare neural tube defect in which the cerebral hemispheres are destroyed (necrotic tissue) with the occupied space being replaced by cerebro-spinal fluid, cortex and white matter remnants within a membranous sac. Interestingly, this condition can also develop in the postnatal peroid due to viral infections or traumatic brain injury. The brain stem may remain intact and functioning in hydranencephalic infants.

* Accompanied with this condition are many effects in which include seizures, hydrocephalus, increases in head circumference,impairment in vision/ body temperature regulation and cerebral palsy. Infants affected by hydranencephaly live typically short lives being no longer than 1 year of age. Lastly, there are no viable treatment options for this condition and only supportive care is available.

'''Iniencephaly''' <ref><pubmed> 10719321 </pubmed></ref>

* Another neural tube defect involving severe backward bending of the head (retroflexion) with subsequent spinal distortions as well. Affected infants have no neck and hence the scalp of the head is directly joined to the skin of the back (also skin of the face connected to skin of the chest). Other conditions that develop along with iniencephaly are cyclopia, cephalocele and anencephaly. The development of this condition is not solely due to one factor but from various causes (both genetic and environmental factors).

* There are specific factors that have been shown to increase the occurrence of this condition. Malnutrition, reduced folic acid intake and elevated levels of homocysteine in blood are environmental factors that increase the risk of iniencephaly <ref><pubmed> 22408660 </pubmed></ref>. Intake of certain drugs such as anti-histamines and sulphonamide/tetracycline (antibiotics) have also increases this risk <ref><pubmed> 22439066 </pubmed></ref>. Furthermore obesity has been shown to have a significant effect on the incidence of iniencephaly with 1.7-3 fold increase <ref><pubmed> 18538144 </pubmed></ref>.

* In terms of treatment, folic acid supplementation as well as avoiding certain drugs such as those outlined above significantly reduces the occurrence of this condition.

'''Spina Bifida Cystica'''

* A neural tube defect in which involves either the formation of a meningocele or myelomeningocele. Of the two, the meningocele, is the least debilitating in that a cyst-like structure forms when the neural tube does not close properly. The membrane (meninges) is pushed into openings of the vertebrae where spinal fluid builds up within the cyst. The myelomeningocele leads to severe problems as the portion of the nueral tube that is unfused allows the spinal cord to protrude through. As a result, neuronal tissue is highly exposed due to myeloschisis as well as infections and hence may lead to severe complications.

'''Spina Bifida Occulta'''

* A neural tube defect that has minimal complications in comparison to other defects. Furthermore, this defect is hidden in that a tethered spinal cord may arise as well as a thicker filum terminale and diastematomyelia (spinal cord split into two). It is also important to note that no cysts form as opposed to the other more severe spina bifida defects.

==References==

<references/>

2014 Group Project 7

2014-10-24T05:48:54Z

Z3418981: /* Introduction */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, receiving and integration of information from all parts of the human body, serving as the processing center of the body's nervous system. The CNS controls all of the body functions (sensory and motor) and consists of 2 main organs: The Brain and Spinal Cord.

The brain is the body's control center consisting of 3 main components; forebrain, midbrain and hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures such as hypothalamus and thalamus, which are responsible in motor control, autonomic function control and relaying sensory information. The midbrain along with the hindbrain together forms the brain-stem which has many important functions such as regulating the cardiac and respiratory systems.

The spinal cord is a cylindrical-shaped structure composed of nerve fiber bundles and is connected to the brain via the brain-stalk formed from the midbrain and hindbrain. The spinal cord is running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. It plays the important role of transmitting information from body organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into ascending bundles, which transmits sensory information from the body to the brain, and descending bundles which transmits motor function information from the brain to the body.

Neurulation occurs in the embryonic period during which ectoderm forms initial structures of the CNS and folds upon itself to form the neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the prosencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon further divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.
During the fetal period, there is ongoing growth in the size, weight and surface area of the brain and spinal cord. Microscopically, the cellular processes during this period can be divided into: cell proliferation, cell migration, cell differentiation and cell death. Neural development will continue after birth with substantial growth, death and reorganization of the cells.

In this website, the fetal development of CNS is being discussed with the focus being on cellular processes of brain development. Some current research models and findings as well as historic findings will be mentioned as well. In addition, the major abnormalities associated with CNS during fetal period and neural tube defects that occur during embryonic period but will further carry on to fetal development will be discussed too.

==Development during fetal period==

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

[[File:Schematic_representation_of_the_timeline_of_human_neural_development.jpg|700px]]

A simplified timeline of human neural development (modified) <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

This simplified graph shows a timeline for major events of neural development that occur during fetal and postnatal periods. These events, which are summarized in the following table, are broadly classified by cell multiplication, cell migration, growth and differentiation and angiogenesis:

{| class="wikitable"
|-
! Major Events !! Descriptions
|-
| Cell multiplication ||
* Neurons are proliferated and generated from neural stem cells and progenitor cells (precursor cells) in a process known as neurogenesis in 2nd trimester.
* Cell death and Gliogenesis (glial cells (such as astrocytes) deriving from multipotent neural stem cells) occur in the 3rd trimester.
* Local gliogenesis continues postnatally.
|-
| Cell migration ||
* Neuronal migration is maximised during 2nd trimester while glial migration is maximised during 3rd trimester
|-
| Growth and differentiation ||
* Axonal and dendritic arborisation (fine branching structures at the end of nerve fibers) appear by the end of fetal period.
* Synaptogenesis (formation of synapses) and electrical activity is maximised in 3rd trimester (and continued postnatally).
* Cell death due to over-innervation can be observed in late fetal and postnatal period.
* Myelination occurs in late fetal and postnatal period (vast majority of postnatal growth in brain is due to myelination).
|-
| Angiogenesis ||
* Oxidative metabolism can be seen in late fetal period.
* Capillary networks develop postnatally.
|}

'''1. cell proliferation'''

[[Image:Somatosensory cortex of E20 rat.jpeg|frame|500x500px|Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) <ref name="PMID22272298"><pubmed>22272298</pubmed></ref>]]

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref name="PMID4203033"><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref name="PMID5414696"><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref name="PMID7204662"><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref name="PMID12764033"><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref name="PMID8523077"><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref name="PMID9712307"><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref name="PMID1713238"><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

'''2. cell migration'''
[[Image:CNS_passive.jpg|frame|200x150px|Passive cell displacement and outside-to-inside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]
[[Image:CNS_active.jpg|frame|350x250px|Active cell migration and inside-to-outside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways.

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus <ref name="PMID489804"><pubmed>489804</pubmed></ref>, hypothalamus <ref name="PMID5029133"><pubmed>5029133</pubmed></ref>, spinal cord <ref name="PMID4407392"><pubmed>4407392</pubmed></ref>, dentate gyrus of the hippocampal formation <ref name="PMID17533671"><pubmed>17533671</pubmed></ref> and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas <ref name="PMID17533671"><pubmed>17533671</pubmed></ref>.

{| style="width:20%; height:170px" align="center"
|-
| [[Image:Internurons migration in cerebral cortex.jpg|frame|200x400px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex <ref name="PMID17726524"><pubmed>17726524</pubmed></ref>]]
|}

'''3. cell differentiation'''<ref name="PMID10532616"><pubmed>10532616</pubmed></ref>

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

=== Brain Development ===

* The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells. By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

* The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

[[Image:Brain ventricles and ganglia development 03.jpg|frame|200x200px|Increase in size of of brain and ventricles <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]
[[Image:Brain fissure development 02.jpg|frame|200x200px|Increase in size of brain fissure <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]

* The gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding.

* The brain development begins rostral in GW8, proceeding caudally until it is complete at GW22 <ref><pubmed>560818</pubmed></ref>

* The formation of Secondary Sulci is between GW30-35, while the formation of of Tertiary Sulci begins during GW36 and into the postnatal period.

* Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

* Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

* The major fibre pathways make up the brain white matter

* AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Neuron Production'''

* The human brain contains billions of neurons which are produced by mid-gestation; during fetal development <ref><pubmed>8361683</pubmed></ref>

* Processes of Neuronal production is initiated by first increasing the size of the Neural progenitor cell population within the body, these cells are mitotic in nature and are capable of forming new cells.

* Initially (from the end of gastrulation through to embryonic day 42), the neural progenitor cell population is increased greatly when the progenitor cells divide through 'symmetrical' mode of cell division. Multiple repeats of the cell division occurs throughout this period. This 'symmetrical' division method brings about the formation of 2 new identical neural progenitor cells

* Mode of cell division changes from a symmetrical cell division type to an 'asymmetrical' cell division from the beginning of E42. This asymmetrical cell division forms 2 different cell types; one Neural progenitor & one Neuron <ref><pubmed>12764028 </pubmed></ref>

* Newly formed Neural progenitor cells remains to undergo more processes of cell division whereas the newly formed neuron moves into position in the developing neocortex

'''Neuron Migration''' <ref name="PMID21042938"><pubmed>21042938</pubmed></ref>

Outlined above was a broad summary on neuron migration. Neuron migration in the cortex will be covered below in more detail.

* The ventricular zone (VZ) is where the majority of neurons migrate radially out and into the neocortex. The type of migration utilised here is referred to as somal translocation where the neuron cell body translocates out of the VZ and into the outer brain region with the nucleus moving across the cytoplasm and into the outer brain region.

* With increasing brain size, somal translocation is no longer efficient for neuronal migration out of VZ. Since greater distances are evident, radial glial guides are adopted to allow the migration of neurons to continue. Similar to somal translocation, these cell populations establish a scaffolding system where neurons can attach to (basal process occurs) and then move into the developing cortical plate. These cell populations are comprised of neural progenitor cells and are therefore able to support mass neuron migration.

* Another mode of transport utilised by neurons situated within a second zone of the ventral telencephalon is referred to as tangential migration. The neurons here migrate tangentially to the cortical mantle whilst adopting different signalling pathways (guidance molecules) as opposed to radial migration. As a result of neuronal migration, a 6-layered structure forms within the developing neocortex.

* Once completion of the pre-plate has occurred, two regions are formed and which are the subplate (SP) and th marginal zone (MZ).In between these two regions, the cortical plate arises as well. Earliest neuron arrival forms the deepest layer of the cortex; cortical layer 6. More superficial layers of the cortex will develop with continuous cell migration. It is important to note that a specific cell class is located within the MZ in which are the Cajal-Retzius cells (CR). CR's are important for correct neuron positioning within the cortical layers as well as having an inhibitory effect on neuron migration. Rheelin, a molecular signal produced by the CR's is important here as it stops neurons from migrating and signals them to up their corresponding positions.

'''Folding: sulcation and gyration'''

[[Image:Dev anat 01.jpg|frame|200x200px|Simplified external lateral (left) view of the brain growth]]

* During the fifth and sixth month of gestation, the smooth cortex begins to fold by sulcation and gyration. <ref name=PMID21571694><pubmed>21571694</pubmed></ref>

# Sulcation: This is the development of sulci, including primary and secondary. The formation of primary sulci involve the appearance of shallow grooves on the surface of the brain, which then become more deeply infolded, while the formation of secondary sulci is due to the development of side branches of the primary ones <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.
# Gyration: This is the development of gyrus that occurs during late during fetal development until the end of the pregnancy or after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>. This process is the formation of tertiary sulci, which is the formation of other side branches of the secondary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

{| class="wikitable"
|-
! Weeks of gestation !! Visible anatomical details
|-
| 20-21 || smooth, with the impression of "lissencephalic" brain; wide Sylvian fissures; visible interhemispheric fissure and parieto-occipital fissure
|-
| 22-23 || beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || smooth cerebral cortex surface; visible shallow grooves in the central sulci, interparietal sulci and superior temporal sulci; start of opercularization of Sylvian fissures; presence of calcarine fissures and cingular sulci
|-
| 26 || presence of central and collateral sulci
|-
| 27 || presence of marginal and precentral sulci
|-
| 28 || presence of postcentral and intraparietal sulci
|-
| 29 || presence of superior and inferior frontal sulci; narrower Sylvian fissure; clear corpus callosum; bright white matter; dark cortical ribbon
|-
| 30-31 || beginning of infolding of cortex which is first apparent in the occipital lobe; narrower ventricular system and subarachnoid spaces
|-
| 32 || presence of superior and inferior temporal sulci
|-
| 33 || presence of external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration; compactly and extensively folded cortex
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table of the process of sulcation and gyration <ref name=PMID20608424><pubmed>20608424</pubmed></ref>

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations <ref><pubmed>7472570</pubmed></ref>

|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.
{|
|-bgcolor="ECCEF5"
|

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.
|}

{|
|-bgcolor="CED8F6"
|The following recent studies use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

** Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

** The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

** The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.

'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.
|}

{|
|-bgcolor="ECCEF5"
|
In the following studies new models and imaging techniques have been employed to gain a better understanding of the changes in brains of patients with schizophrenia

'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

Moreover, in the following study, a neuroimaging technique known as Proton Magnetic Resonance Spectroscopy (1H-MRS) is used to examine the brain of patients with schizophrenia.

'''Multimodal neuroimaging of frontal white matter microstructure in early phase schizophrenia: the impact of early adolescent cannabis use'''
<ref><pubmed> 3852698 </pubmed></ref>

[[Image:Online_placement_of_the_1H-MRS_volume_of_interest_.jpg|400x400px|frame|Proton magnetic resonance spectroscopy (1H-MRS) is used to examine the white matter tissue in brain of patients with schizophrenia. The image shows online placement of the 1H-MRS volume of interest.The 1H-MRS volume of interest is placed parallel to the AC-PC line (AC =anterior commissure, PC = posterior commissure). <ref><pubmed> 3852698 </pubmed></ref> ]]

* The neurochemical used in this technique is N-acetylaspartate (NAA), a free amino acid that has a peak resonance at 2.02 ppm on the spectral profile in the 1H-MRS of human brain.
* In vivo concentration levels of NAA are higher in white matter compared to gray matter.
* Post-mortem studies have demonstrated that NAA is produced in neurons, transported into white matter and broken down into aspartate and acetate in oligodendrocytes. <ref><pubmed>17275978</pubmed></ref> NAA catabolism is thus closely related to the metabolism of myelin, since it provides a crucial source of acetate which is necessary for the formation of myelin from lipid.
* Therefore due to abnormal myelin biosynthesis in schizophrenia, brain tissues can be examined by 1H-MRS studies as long as the targeted brain region involves a single tissue type (white matter) that provides the necessary information regarding the catabolic cycle of NAA.

|}

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]

Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.

* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period).

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation. <ref><pubmed>15806441</pubmed></ref>

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.<ref><pubmed>21215908</pubmed></ref>

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.<ref><pubmed>1400921</pubmed></ref>

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.<ref><pubmed>25283616</pubmed></ref>

===Fetal Alcohol Syndrome===

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status. <ref><pubmed> 24904907 </pubmed></ref>

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.<ref><pubmed> 23809349 </pubmed></ref>

{| class="wikitable"
|-
| [[File:Fetal alcohol syndrome.jpg|500px]] || [[File:Ethanol fetal neural.jpg|400px]]
|-
| The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref>|| A mechanism of the effect of ethanol on neural stem cells (NSCs). Ethanol promotes asymmetrical cell division, the formation of radial glial-like cells, leading to the premature depletion of the VZ and its NSCs, and the thickening and cell proliferation in SVZ. The increased migration during early differentiation of ethanol-treated NSCs also leads to the appearance of subpial heterotopias<ref name="PMID22623924"><pubmed>22623924</pubmed></ref>
|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

* All degrees of iodine deficiency (mild: 50-99 μg/day, moderate: 20-49 μg/day and severe≤20 μg/day) affect thyroid function of both mother and the neonate as well as mental development of the child. The damage increases with the degree of deficiency; overt endemic cretinism is the most severe consequence.

* Iodine deficiency disorders refer to complications that arise when the recommended dietary allowance of iodine is not met. These complications include thyroid function abnormalities and when iodine deficiency is severe, endemic goitre and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality.

* Iodine deficiency represents the world’s greatest cause of preventable brain damage and mental retardation, resulting of a loss of 10-15 IQ points globally. Therefore it is essential that the recommended dietary requirement for iodine is met, especially during pregnancy and lactation (200–300 μg/day). <ref><pubmed>10750030</pubmed></ref>

* Clinical manifestations of hypothyroidism include: Myxedematous facies (condition characterized by thickening of the skin, blunting of the senses and intellect, and laboured speech), jaundice, a puffy face and a wide posterior fontanelle with open sutures. The nasal bridge is flat. The mouth may be slightly open revealing macroglossia. Further examination would reveal bradycardia and a protuberant abdomen with a large umbilical hernia. Neurologic examination findings include hypotonia with delayed reflexes. Skin may be cool to touch and mottled in appearance due to circulatory compromise.<ref><pubmed>2903524</pubmed></ref>

===Abnormalities associated with apoptosis and migration of cells in the fetal CNS===

* The migration of cells and cell death are critically important to fetal brain and CNS development. Abnormalities in each of these processes, programmed cell death (apoptosis) in particular, have been shown to result in severe developmental abnormalities in experimental animals. Apoptosis is critically important for appropriate brain development; certain areas in brain may experience up to 50% cell death. <ref><pubmed> 11589424 </pubmed></ref>

* In an experiment conducted by kuida et. al 1996, it was observed that mice that were deficient for CPP32 (a protease responsible for apoptosis), were born at a lower frequency than expected, were smaller in size compared to the normal mice and died at an early age. Brain development is significantly affected in CPP32-deficient mice resulting in a variety of hyperplasia and disorganised cell development. <ref><pubmed>8934524</pubmed></ref>

* On the other hand, disrupted neuronal migration can lead to an abnormality in cell position. When this happens, the neurons are said to be heterotopic. Abnormalities in neuronal migration have been studied extensively in human cerebral cortex where these defects are associated with a variety of syndromes and diseases, ranging from behavioural disorders (including some forms of schizophrenia, dyslexia and autism) to extremely severe mental retardation and failure to thrive. <ref><pubmed>10532616</pubmed></ref>

===Neural Tube Defects===

Defects which affect the either the brain or the spinal cord in which openings remain. Grastulation occurs in week 3 of embryonic development where specialized cells (dorsal side) structurally change shape leading to the formation of the neural tube. If the neural tube does not close or fuse together properly, then openings remain which lead to various neural tube defects such as Spina bifida cystica and Spina bifida occulta.

'''Anencephaly''' <ref><pubmed> 8286034 </pubmed></ref>

* A neural tube defect involving abnormal development of the brain and incomplete skull formation leading to high infant mortality rates with infants being stillborn or dying within a few hours after birth.

* The failure of the neural tube to close around the 23rd and 26th day into embryonic development is characteristic of this condition. As a result, the forebrain is severely affected where the cerebrum does not grow and hence partial growth occurs only. The cerebrum has a key importance in maintaining thought, consciousness and coordination whilst having no intact cerebrum rules out the probability of the affected fetus gaining consciousness .

* Increasing one's dietary intake of folic acid notably reduces the incidence of neural tube defects. Consuming 0.4mg of folic acid is sufficient to induce these results.

* Since incomplete skull formation occurs, brain tissue becomes exposed due to the absence of bone covering and therefore leading to further complications.

'''Encephaloceles''' <ref><pubmed> 11151720 </pubmed></ref>

* Another neural tube defect in which a sac-like projections (including membrane covering) that occurs around the 3-4 week of embryonic development in which neural tube closure has not successfully occurred. The location of these protrusions varies but can be naso-frontal (nose and head), naso-ethmoidal (nose and ethmoid bone), naso-orbital (nose and eyes), meningocele (cerebrospinal fluid and membrane covering) and encephalomeningocele (meningocele with brain tissue as well).

* These sac-like protrusions lead to a variety of abnormal effects which include cerebro-spinal fluid build-up in brain, microcephaly, hydrocephaly, mental retardation, developmental problems, uncoordinated muscle movement and seizures. Consumption of folic acid again has been shown to significantly reduce the occurrence of encephaloceles in infants.

'''Hydranencephaly''' <ref><pubmed> 23112982 </pubmed></ref>

* A very rare neural tube defect in which the cerebral hemispheres are destroyed (necrotic tissue) with the occupied space being replaced by cerebro-spinal fluid, cortex and white matter remnants within a membranous sac. Interestingly, this condition can also develop in the postnatal peroid due to viral infections or traumatic brain injury. The brain stem may remain intact and functioning in hydranencephalic infants.

* Accompanied with this condition are many effects in which include seizures, hydrocephalus, increases in head circumference,impairment in vision/ body temperature regulation and cerebral palsy. Infants affected by hydranencephaly live typically short lives being no longer than 1 year of age. Lastly, there are no viable treatment options for this condition and only supportive care is available.

'''Iniencephaly''' <ref><pubmed> 10719321 </pubmed></ref>

* Another neural tube defect involving severe backward bending of the head (retroflexion) with subsequent spinal distortions as well. Affected infants have no neck and hence the scalp of the head is directly joined to the skin of the back (also skin of the face connected to skin of the chest). Other conditions that develop along with iniencephaly are cyclopia, cephalocele and anencephaly. The development of this condition is not solely due to one factor but from various causes (both genetic and environmental factors).

* There are specific factors that have been shown to increase the occurrence of this condition. Malnutrition, reduced folic acid intake and elevated levels of homocysteine in blood are environmental factors that increase the risk of iniencephaly <ref><pubmed> 22408660 </pubmed></ref>. Intake of certain drugs such as anti-histamines and sulphonamide/tetracycline (antibiotics) have also increases this risk <ref><pubmed> 22439066 </pubmed></ref>. Furthermore obesity has been shown to have a significant effect on the incidence of iniencephaly with 1.7-3 fold increase <ref><pubmed> 18538144 </pubmed></ref>.

* In terms of treatment, folic acid supplementation as well as avoiding certain drugs such as those outlined above significantly reduces the occurrence of this condition.

'''Spina Bifida Cystica'''

* A neural tube defect in which involves either the formation of a meningocele or myelomeningocele. Of the two, the meningocele, is the least debilitating in that a cyst-like structure forms when the neural tube does not close properly. The membrane (meninges) is pushed into openings of the vertebrae where spinal fluid builds up within the cyst. The myelomeningocele leads to severe problems as the portion of the nueral tube that is unfused allows the spinal cord to protrude through. As a result, neuronal tissue is highly exposed due to myeloschisis as well as infections and hence may lead to severe complications.

'''Spina Bifida Occulta'''

* A neural tube defect that has minimal complications in comparison to other defects. Furthermore, this defect is hidden in that a tethered spinal cord may arise as well as a thicker filum terminale and diastematomyelia (spinal cord split into two). It is also important to note that no cysts form as opposed to the other more severe spina bifida defects.

==References==

<references/>

2014 Group Project 7

2014-10-24T05:30:30Z

Z3418981: /* Introduction */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, receiving and integration of information from all parts of the human body, serving as the processing center of the body's nervous system. The CNS controls all of the body functions (sensory and motor) and consists of 2 main organs: The Brain and Spinal Cord.

The brain is the body's control center consisting of 3 main components; forebrain, midbrain and hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures such as hypothalamus and thalamus, which are responsible in motor control, autonomic function control and relaying sensory information. The midbrain along with the hindbrain together forms the brain-stem which has many important functions such as regulating the cardiac and respiratory systems.

The spinal cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into ascending bundles, which transmits sensory information from the body to the brain, and descending bundle, which transmits motor function information from the brain to the body.

Before fetal period, neurulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, including cellular processes and brain development will be discussed. Current research models and findings, and historic findings will be stated. The abnormalities associated to CNS during fetal period, and neural defects that occur during embryonic period and contribute in fetal development will be discussed.

==Development during fetal period==

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

[[File:Schematic_representation_of_the_timeline_of_human_neural_development.jpg|700px]]

A simplified timeline of human neural development (modified) <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

This simplified graph shows a timeline for major events of neural development that occur during fetal and postnatal periods. These events, which are summarized in the following table, are broadly classified by cell multiplication, cell migration, growth and differentiation and angiogenesis:

{| class="wikitable"
|-
! Major Events !! Descriptions
|-
| Cell multiplication ||
* Neurons are proliferated and generated from neural stem cells and progenitor cells (precursor cells) in a process known as neurogenesis in 2nd trimester.
* Cell death and Gliogenesis (glial cells (such as astrocytes) deriving from multipotent neural stem cells) occur in the 3rd trimester.
* Local gliogenesis continues postnatally.
|-
| Cell migration ||
* Neuronal migration is maximised during 2nd trimester while glial migration is maximised during 3rd trimester
|-
| Growth and differentiation ||
* Axonal and dendritic arborisation (fine branching structures at the end of nerve fibers) appear by the end of fetal period.
* Synaptogenesis (formation of synapses) and electrical activity is maximised in 3rd trimester (and continued postnatally).
* Cell death due to over-innervation can be observed in late fetal and postnatal period.
* Myelination occurs in late fetal and postnatal period (vast majority of postnatal growth in brain is due to myelination).
|-
| Angiogenesis ||
* Oxidative metabolism can be seen in late fetal period.
* Capillary networks develop postnatally.
|}

'''1. cell proliferation'''

[[Image:Somatosensory cortex of E20 rat.jpeg|frame|500x500px|Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) <ref name="PMID22272298"><pubmed>22272298</pubmed></ref>]]

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref name="PMID4203033"><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref name="PMID5414696"><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref name="PMID7204662"><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref name="PMID12764033"><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref name="PMID8523077"><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref name="PMID9712307"><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref name="PMID1713238"><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

'''2. cell migration'''
[[Image:CNS_passive.jpg|frame|200x150px|Passive cell displacement and outside-to-inside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]
[[Image:CNS_active.jpg|frame|350x250px|Active cell migration and inside-to-outside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways.

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus <ref name="PMID489804"><pubmed>489804</pubmed></ref>, hypothalamus <ref name="PMID5029133"><pubmed>5029133</pubmed></ref>, spinal cord <ref name="PMID4407392"><pubmed>4407392</pubmed></ref>, dentate gyrus of the hippocampal formation <ref name="PMID17533671"><pubmed>17533671</pubmed></ref> and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas <ref name="PMID17533671"><pubmed>17533671</pubmed></ref>.

{| style="width:20%; height:170px" align="center"
|-
| [[Image:Internurons migration in cerebral cortex.jpg|frame|200x400px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex <ref name="PMID17726524"><pubmed>17726524</pubmed></ref>]]
|}

'''3. cell differentiation'''<ref name="PMID10532616"><pubmed>10532616</pubmed></ref>

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

=== Brain Development ===

* The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells. By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

* The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

[[Image:Brain ventricles and ganglia development 03.jpg|frame|200x200px|Increase in size of of brain and ventricles <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]
[[Image:Brain fissure development 02.jpg|frame|200x200px|Increase in size of brain fissure <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]

* The gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding.

* The brain development begins rostral in GW8, proceeding caudally until it is complete at GW22 <ref><pubmed>560818</pubmed></ref>

* The formation of Secondary Sulci is between GW30-35, while the formation of of Tertiary Sulci begins during GW36 and into the postnatal period.

* Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

* Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

* The major fibre pathways make up the brain white matter

* AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Neuron Production'''

* The human brain contains billions of neurons which are produced by mid-gestation; during fetal development <ref><pubmed>8361683</pubmed></ref>

* Processes of Neuronal production is initiated by first increasing the size of the Neural progenitor cell population within the body, these cells are mitotic in nature and are capable of forming new cells.

* Initially (from the end of gastrulation through to embryonic day 42), the neural progenitor cell population is increased greatly when the progenitor cells divide through 'symmetrical' mode of cell division. Multiple repeats of the cell division occurs throughout this period. This 'symmetrical' division method brings about the formation of 2 new identical neural progenitor cells

* Mode of cell division changes from a symmetrical cell division type to an 'asymmetrical' cell division from the beginning of E42. This asymmetrical cell division forms 2 different cell types; one Neural progenitor & one Neuron <ref><pubmed>12764028 </pubmed></ref>

* Newly formed Neural progenitor cells remains to undergo more processes of cell division whereas the newly formed neuron moves into position in the developing neocortex

'''Neuron Migration''' <ref name="PMID21042938"><pubmed>21042938</pubmed></ref>

Outlined above was a broad summary on neuron migration. Neuron migration in the cortex will be covered below in more detail.

* The ventricular zone (VZ) is where the majority of neurons migrate radially out and into the neocortex. The type of migration utilised here is referred to as somal translocation where the neuron cell body translocates out of the VZ and into the outer brain region with the nucleus moving across the cytoplasm and into the outer brain region.

* With increasing brain size, somal translocation is no longer efficient for neuronal migration out of VZ. Since greater distances are evident, radial glial guides are adopted to allow the migration of neurons to continue. Similar to somal translocation, these cell populations establish a scaffolding system where neurons can attach to (basal process occurs) and then move into the developing cortical plate. These cell populations are comprised of neural progenitor cells and are therefore able to support mass neuron migration.

* Another mode of transport utilised by neurons situated within a second zone of the ventral telencephalon is referred to as tangential migration. The neurons here migrate tangentially to the cortical mantle whilst adopting different signalling pathways (guidance molecules) as opposed to radial migration. As a result of neuronal migration, a 6-layered structure forms within the developing neocortex.

* Once completion of the pre-plate has occurred, two regions are formed and which are the subplate (SP) and th marginal zone (MZ).In between these two regions, the cortical plate arises as well. Earliest neuron arrival forms the deepest layer of the cortex; cortical layer 6. More superficial layers of the cortex will develop with continuous cell migration. It is important to note that a specific cell class is located within the MZ in which are the Cajal-Retzius cells (CR). CR's are important for correct neuron positioning within the cortical layers as well as having an inhibitory effect on neuron migration. Rheelin, a molecular signal produced by the CR's is important here as it stops neurons from migrating and signals them to up their corresponding positions.

'''Folding: sulcation and gyration'''

[[Image:Dev anat 01.jpg|frame|200x200px|Simplified external lateral (left) view of the brain growth]]

* During the fifth and sixth month of gestation, the smooth cortex begins to fold by sulcation and gyration. <ref name=PMID21571694><pubmed>21571694</pubmed></ref>

# Sulcation: This is the development of sulci, including primary and secondary. The formation of primary sulci involve the appearance of shallow grooves on the surface of the brain, which then become more deeply infolded, while the formation of secondary sulci is due to the development of side branches of the primary ones <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.
# Gyration: This is the development of gyrus that occurs during late during fetal development until the end of the pregnancy or after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>. This process is the formation of tertiary sulci, which is the formation of other side branches of the secondary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

{| class="wikitable"
|-
! Weeks of gestation !! Visible anatomical details
|-
| 20-21 || smooth, with the impression of "lissencephalic" brain; wide Sylvian fissures; visible interhemispheric fissure and parieto-occipital fissure
|-
| 22-23 || beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || smooth cerebral cortex surface; visible shallow grooves in the central sulci, interparietal sulci and superior temporal sulci; start of opercularization of Sylvian fissures; presence of calcarine fissures and cingular sulci
|-
| 26 || presence of central and collateral sulci
|-
| 27 || presence of marginal and precentral sulci
|-
| 28 || presence of postcentral and intraparietal sulci
|-
| 29 || presence of superior and inferior frontal sulci; narrower Sylvian fissure; clear corpus callosum; bright white matter; dark cortical ribbon
|-
| 30-31 || beginning of infolding of cortex which is first apparent in the occipital lobe; narrower ventricular system and subarachnoid spaces
|-
| 32 || presence of superior and inferior temporal sulci
|-
| 33 || presence of external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration; compactly and extensively folded cortex
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table of the process of sulcation and gyration <ref name=PMID20608424><pubmed>20608424</pubmed></ref>

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations <ref><pubmed>7472570</pubmed></ref>

|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.
{|
|-bgcolor="ECCEF5"
|

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.
|}

{|
|-bgcolor="CED8F6"
|The following recent studies use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

** Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

** The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

** The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.

'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.
|}

{|
|-bgcolor="ECCEF5"
|
In the following studies new models and imaging techniques have been employed to gain a better understanding of the changes in brains of patients with schizophrenia

'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

Moreover, in the following study, a neuroimaging technique known as Proton Magnetic Resonance Spectroscopy (1H-MRS) is used to examine the brain of patients with schizophrenia.

'''Multimodal neuroimaging of frontal white matter microstructure in early phase schizophrenia: the impact of early adolescent cannabis use'''
<ref><pubmed> 3852698 </pubmed></ref>

[[Image:Online_placement_of_the_1H-MRS_volume_of_interest_.jpg|400x400px|frame|Proton magnetic resonance spectroscopy (1H-MRS) is used to examine the white matter tissue in brain of patients with schizophrenia. The image shows online placement of the 1H-MRS volume of interest.The 1H-MRS volume of interest is placed parallel to the AC-PC line (AC =anterior commissure, PC = posterior commissure). <ref><pubmed> 3852698 </pubmed></ref> ]]

* The neurochemical used in this technique is N-acetylaspartate (NAA), a free amino acid that has a peak resonance at 2.02 ppm on the spectral profile in the 1H-MRS of human brain.
* In vivo concentration levels of NAA are higher in white matter compared to gray matter.
* Post-mortem studies have demonstrated that NAA is produced in neurons, transported into white matter and broken down into aspartate and acetate in oligodendrocytes. <ref><pubmed>17275978</pubmed></ref> NAA catabolism is thus closely related to the metabolism of myelin, since it provides a crucial source of acetate which is necessary for the formation of myelin from lipid.
* Therefore due to abnormal myelin biosynthesis in schizophrenia, brain tissues can be examined by 1H-MRS studies as long as the targeted brain region involves a single tissue type (white matter) that provides the necessary information regarding the catabolic cycle of NAA.

|}

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]

Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.

* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period).

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation. <ref><pubmed>15806441</pubmed></ref>

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.<ref><pubmed>21215908</pubmed></ref>

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.<ref><pubmed>1400921</pubmed></ref>

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.<ref><pubmed>25283616</pubmed></ref>

===Fetal Alcohol Syndrome===

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status. <ref><pubmed> 24904907 </pubmed></ref>

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.<ref><pubmed> 23809349 </pubmed></ref>

{| class="wikitable"
|-
| [[File:Fetal alcohol syndrome.jpg|500px]] || [[File:Ethanol fetal neural.jpg|400px]]
|-
| The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref>|| A mechanism of the effect of ethanol on neural stem cells (NSCs). Ethanol promotes asymmetrical cell division, the formation of radial glial-like cells, leading to the premature depletion of the VZ and its NSCs, and the thickening and cell proliferation in SVZ. The increased migration during early differentiation of ethanol-treated NSCs also leads to the appearance of subpial heterotopias<ref name="PMID22623924"><pubmed>22623924</pubmed></ref>
|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

* All degrees of iodine deficiency (mild: 50-99 μg/day, moderate: 20-49 μg/day and severe≤20 μg/day) affect thyroid function of both mother and the neonate as well as mental development of the child. The damage increases with the degree of deficiency; overt endemic cretinism is the most severe consequence.

* Iodine deficiency disorders refer to complications that arise when the recommended dietary allowance of iodine is not met. These complications include thyroid function abnormalities and when iodine deficiency is severe, endemic goitre and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality.

* Iodine deficiency represents the world’s greatest cause of preventable brain damage and mental retardation, resulting of a loss of 10-15 IQ points globally. Therefore it is essential that the recommended dietary requirement for iodine is met, especially during pregnancy and lactation (200–300 μg/day). <ref><pubmed>10750030</pubmed></ref>

* Clinical manifestations of hypothyroidism include: Myxedematous facies (condition characterized by thickening of the skin, blunting of the senses and intellect, and laboured speech), jaundice, a puffy face and a wide posterior fontanelle with open sutures. The nasal bridge is flat. The mouth may be slightly open revealing macroglossia. Further examination would reveal bradycardia and a protuberant abdomen with a large umbilical hernia. Neurologic examination findings include hypotonia with delayed reflexes. Skin may be cool to touch and mottled in appearance due to circulatory compromise.<ref><pubmed>2903524</pubmed></ref>

===Abnormalities associated with apoptosis and migration of cells in the fetal CNS===

* The migration of cells and cell death are critically important to fetal brain and CNS development. Abnormalities in each of these processes, programmed cell death (apoptosis) in particular, have been shown to result in severe developmental abnormalities in experimental animals. Apoptosis is critically important for appropriate brain development; certain areas in brain may experience up to 50% cell death. <ref><pubmed> 11589424 </pubmed></ref>

* In an experiment conducted by kuida et. al 1996, it was observed that mice that were deficient for CPP32 (a protease responsible for apoptosis), were born at a lower frequency than expected, were smaller in size compared to the normal mice and died at an early age. Brain development is significantly affected in CPP32-deficient mice resulting in a variety of hyperplasia and disorganised cell development. <ref><pubmed>8934524</pubmed></ref>

* On the other hand, disrupted neuronal migration can lead to an abnormality in cell position. When this happens, the neurons are said to be heterotopic. Abnormalities in neuronal migration have been studied extensively in human cerebral cortex where these defects are associated with a variety of syndromes and diseases, ranging from behavioural disorders (including some forms of schizophrenia, dyslexia and autism) to extremely severe mental retardation and failure to thrive. <ref><pubmed>10532616</pubmed></ref>

===Neural Tube Defects===

Defects which affect the either the brain or the spinal cord in which openings remain. Grastulation occurs in week 3 of embryonic development where specialized cells (dorsal side) structurally change shape leading to the formation of the neural tube. If the neural tube does not close or fuse together properly, then openings remain which lead to various neural tube defects such as Spina bifida cystica and Spina bifida occulta.

'''Anencephaly''' <ref><pubmed> 8286034 </pubmed></ref>

* A neural tube defect involving abnormal development of the brain and incomplete skull formation leading to high infant mortality rates with infants being stillborn or dying within a few hours after birth.

* The failure of the neural tube to close around the 23rd and 26th day into embryonic development is characteristic of this condition. As a result, the forebrain is severely affected where the cerebrum does not grow and hence partial growth occurs only. The cerebrum has a key importance in maintaining thought, consciousness and coordination whilst having no intact cerebrum rules out the probability of the affected fetus gaining consciousness .

* Increasing one's dietary intake of folic acid notably reduces the incidence of neural tube defects. Consuming 0.4mg of folic acid is sufficient to induce these results.

* Since incomplete skull formation occurs, brain tissue becomes exposed due to the absence of bone covering and therefore leading to further complications.

'''Encephaloceles''' <ref><pubmed> 11151720 </pubmed></ref>

* Another neural tube defect in which a sac-like projections (including membrane covering) that occurs around the 3-4 week of embryonic development in which neural tube closure has not successfully occurred. The location of these protrusions varies but can be naso-frontal (nose and head), naso-ethmoidal (nose and ethmoid bone), naso-orbital (nose and eyes), meningocele (cerebrospinal fluid and membrane covering) and encephalomeningocele (meningocele with brain tissue as well).

* These sac-like protrusions lead to a variety of abnormal effects which include cerebro-spinal fluid build-up in brain, microcephaly, hydrocephaly, mental retardation, developmental problems, uncoordinated muscle movement and seizures. Consumption of folic acid again has been shown to significantly reduce the occurrence of encephaloceles in infants.

'''Hydranencephaly''' <ref><pubmed> 23112982 </pubmed></ref>

* A very rare neural tube defect in which the cerebral hemispheres are destroyed (necrotic tissue) with the occupied space being replaced by cerebro-spinal fluid, cortex and white matter remnants within a membranous sac. Interestingly, this condition can also develop in the postnatal peroid due to viral infections or traumatic brain injury. The brain stem may remain intact and functioning in hydranencephalic infants.

* Accompanied with this condition are many effects in which include seizures, hydrocephalus, increases in head circumference,impairment in vision/ body temperature regulation and cerebral palsy. Infants affected by hydranencephaly live typically short lives being no longer than 1 year of age. Lastly, there are no viable treatment options for this condition and only supportive care is available.

'''Iniencephaly''' <ref><pubmed> 10719321 </pubmed></ref>

* Another neural tube defect involving severe backward bending of the head (retroflexion) with subsequent spinal distortions as well. Affected infants have no neck and hence the scalp of the head is directly joined to the skin of the back (also skin of the face connected to skin of the chest). Other conditions that develop along with iniencephaly are cyclopia, cephalocele and anencephaly. The development of this condition is not solely due to one factor but from various causes (both genetic and environmental factors).

* There are specific factors that have been shown to increase the occurrence of this condition. Malnutrition, reduced folic acid intake and elevated levels of homocysteine in blood are environmental factors that increase the risk of iniencephaly <ref><pubmed> 22408660 </pubmed></ref>. Intake of certain drugs such as anti-histamines and sulphonamide/tetracycline (antibiotics) have also increases this risk <ref><pubmed> 22439066 </pubmed></ref>. Furthermore obesity has been shown to have a significant effect on the incidence of iniencephaly with 1.7-3 fold increase <ref><pubmed> 18538144 </pubmed></ref>.

* In terms of treatment, folic acid supplementation as well as avoiding certain drugs such as those outlined above significantly reduces the occurrence of this condition.

'''Spina Bifida Cystica'''

* A neural tube defect in which involves either the formation of a meningocele or myelomeningocele. Of the two, the meningocele, is the least debilitating in that a cyst-like structure forms when the neural tube does not close properly. The membrane (meninges) is pushed into openings of the vertebrae where spinal fluid builds up within the cyst. The myelomeningocele leads to severe problems as the portion of the nueral tube that is unfused allows the spinal cord to protrude through. As a result, neuronal tissue is highly exposed due to myeloschisis as well as infections and hence may lead to severe complications.

'''Spina Bifida Occulta'''

* A neural tube defect that has minimal complications in comparison to other defects. Furthermore, this defect is hidden in that a tethered spinal cord may arise as well as a thicker filum terminale and diastematomyelia (spinal cord split into two). It is also important to note that no cysts form as opposed to the other more severe spina bifida defects.

==References==

<references/>

2014 Group Project 7

2014-10-24T05:18:45Z

Z3418981: /* Introduction */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, receiving and integration of information from all parts of the human body, serving as the processing center of the body's nervous system. The CNS controls all of the body functions (sensory and motor) and consists of 2 main organs: The Brain and Spinal Cord.

The brain is the body's control center consisting of 3 main components; forebrain, midbrain and hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures such as hypothalamus and thalamus, which are responsible in motor control, autonomic function control and relaying sensory information. The midbrain along with the hindbrain together forms the brain-stem which has many important functions such as regulating the cardiac and respiratory systems.

The brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

The spinal cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into ascending bundles, which transmits sensory information from the body to the brain, and descending bundle, which transmits motor function information from the brain to the body.

Before fetal period, neurulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, including cellular processes and brain development will be discussed. Current research models and findings, and historic findings will be stated. The abnormalities associated to CNS during fetal period, and neural defects that occur during embryonic period and contribute in fetal development will be discussed.

==Development during fetal period==

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

[[File:Schematic_representation_of_the_timeline_of_human_neural_development.jpg|700px]]

A simplified timeline of human neural development (modified) <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

This simplified graph shows a timeline for major events of neural development that occur during fetal and postnatal periods. These events, which are summarized in the following table, are broadly classified by cell multiplication, cell migration, growth and differentiation and angiogenesis:

{| class="wikitable"
|-
! Major Events !! Descriptions
|-
| Cell multiplication ||
* Neurons are proliferated and generated from neural stem cells and progenitor cells (precursor cells) in a process known as neurogenesis in 2nd trimester.
* Cell death and Gliogenesis (glial cells (such as astrocytes) deriving from multipotent neural stem cells) occur in the 3rd trimester.
* Local gliogenesis continues postnatally.
|-
| Cell migration ||
* Neuronal migration is maximised during 2nd trimester while glial migration is maximised during 3rd trimester
|-
| Growth and differentiation ||
* Axonal and dendritic arborisation (fine branching structures at the end of nerve fibers) appear by the end of fetal period.
* Synaptogenesis (formation of synapses) and electrical activity is maximised in 3rd trimester (and continued postnatally).
* Cell death due to over-innervation can be observed in late fetal and postnatal period.
* Myelination occurs in late fetal and postnatal period (vast majority of postnatal growth in brain is due to myelination).
|-
| Angiogenesis ||
* Oxidative metabolism can be seen in late fetal period.
* Capillary networks develop postnatally.
|}

'''1. cell proliferation'''

[[Image:Somatosensory cortex of E20 rat.jpeg|frame|500x500px|Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) <ref name="PMID22272298"><pubmed>22272298</pubmed></ref>]]

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref name="PMID4203033"><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref name="PMID5414696"><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref name="PMID7204662"><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref name="PMID12764033"><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref name="PMID8523077"><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref name="PMID9712307"><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref name="PMID1713238"><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

'''2. cell migration'''
[[Image:CNS_passive.jpg|frame|200x150px|Passive cell displacement and outside-to-inside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]
[[Image:CNS_active.jpg|frame|350x250px|Active cell migration and inside-to-outside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways.

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus <ref name="PMID489804"><pubmed>489804</pubmed></ref>, hypothalamus <ref name="PMID5029133"><pubmed>5029133</pubmed></ref>, spinal cord <ref name="PMID4407392"><pubmed>4407392</pubmed></ref>, dentate gyrus of the hippocampal formation <ref name="PMID17533671"><pubmed>17533671</pubmed></ref> and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas <ref name="PMID17533671"><pubmed>17533671</pubmed></ref>.

{| style="width:20%; height:170px" align="center"
|-
| [[Image:Internurons migration in cerebral cortex.jpg|frame|200x400px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex <ref name="PMID17726524"><pubmed>17726524</pubmed></ref>]]
|}

'''3. cell differentiation'''<ref name="PMID10532616"><pubmed>10532616</pubmed></ref>

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

=== Brain Development ===

* The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells. By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

* The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

[[Image:Brain ventricles and ganglia development 03.jpg|frame|200x200px|Increase in size of of brain and ventricles <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]
[[Image:Brain fissure development 02.jpg|frame|200x200px|Increase in size of brain fissure <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]

* The gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding.

* The brain development begins rostral in GW8, proceeding caudally until it is complete at GW22 <ref><pubmed>560818</pubmed></ref>

* The formation of Secondary Sulci is between GW30-35, while the formation of of Tertiary Sulci begins during GW36 and into the postnatal period.

* Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

* Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

* The major fibre pathways make up the brain white matter

* AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Neuron Production'''

* The human brain contains billions of neurons which are produced by mid-gestation; during fetal development <ref><pubmed>8361683</pubmed></ref>

* Processes of Neuronal production is initiated by first increasing the size of the Neural progenitor cell population within the body, these cells are mitotic in nature and are capable of forming new cells.

* Initially (from the end of gastrulation through to embryonic day 42), the neural progenitor cell population is increased greatly when the progenitor cells divide through 'symmetrical' mode of cell division. Multiple repeats of the cell division occurs throughout this period. This 'symmetrical' division method brings about the formation of 2 new identical neural progenitor cells

* Mode of cell division changes from a symmetrical cell division type to an 'asymmetrical' cell division from the beginning of E42. This asymmetrical cell division forms 2 different cell types; one Neural progenitor & one Neuron <ref><pubmed>12764028 </pubmed></ref>

* Newly formed Neural progenitor cells remains to undergo more processes of cell division whereas the newly formed neuron moves into position in the developing neocortex

'''Neuron Migration''' <ref name="PMID21042938"><pubmed>21042938</pubmed></ref>

Outlined above was a broad summary on neuron migration. Neuron migration in the cortex will be covered below in more detail.

* The ventricular zone (VZ) is where the majority of neurons migrate radially out and into the neocortex. The type of migration utilised here is referred to as somal translocation where the neuron cell body translocates out of the VZ and into the outer brain region with the nucleus moving across the cytoplasm and into the outer brain region.

* With increasing brain size, somal translocation is no longer efficient for neuronal migration out of VZ. Since greater distances are evident, radial glial guides are adopted to allow the migration of neurons to continue. Similar to somal translocation, these cell populations establish a scaffolding system where neurons can attach to (basal process occurs) and then move into the developing cortical plate. These cell populations are comprised of neural progenitor cells and are therefore able to support mass neuron migration.

* Another mode of transport utilised by neurons situated within a second zone of the ventral telencephalon is referred to as tangential migration. The neurons here migrate tangentially to the cortical mantle whilst adopting different signalling pathways (guidance molecules) as opposed to radial migration. As a result of neuronal migration, a 6-layered structure forms within the developing neocortex.

* Once completion of the pre-plate has occurred, two regions are formed and which are the subplate (SP) and th marginal zone (MZ).In between these two regions, the cortical plate arises as well. Earliest neuron arrival forms the deepest layer of the cortex; cortical layer 6. More superficial layers of the cortex will develop with continuous cell migration. It is important to note that a specific cell class is located within the MZ in which are the Cajal-Retzius cells (CR). CR's are important for correct neuron positioning within the cortical layers as well as having an inhibitory effect on neuron migration. Rheelin, a molecular signal produced by the CR's is important here as it stops neurons from migrating and signals them to up their corresponding positions.

'''Folding: sulcation and gyration'''

[[Image:Dev anat 01.jpg|frame|200x200px|Simplified external lateral (left) view of the brain growth]]

* During the fifth and sixth month of gestation, the smooth cortex begins to fold by sulcation and gyration. <ref name=PMID21571694><pubmed>21571694</pubmed></ref>

# Sulcation: This is the development of sulci, including primary and secondary. The formation of primary sulci involve the appearance of shallow grooves on the surface of the brain, which then become more deeply infolded, while the formation of secondary sulci is due to the development of side branches of the primary ones <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.
# Gyration: This is the development of gyrus that occurs during late during fetal development until the end of the pregnancy or after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>. This process is the formation of tertiary sulci, which is the formation of other side branches of the secondary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

{| class="wikitable"
|-
! Weeks of gestation !! Visible anatomical details
|-
| 20-21 || smooth, with the impression of "lissencephalic" brain; wide Sylvian fissures; visible interhemispheric fissure and parieto-occipital fissure
|-
| 22-23 || beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || smooth cerebral cortex surface; visible shallow grooves in the central sulci, interparietal sulci and superior temporal sulci; start of opercularization of Sylvian fissures; presence of calcarine fissures and cingular sulci
|-
| 26 || presence of central and collateral sulci
|-
| 27 || presence of marginal and precentral sulci
|-
| 28 || presence of postcentral and intraparietal sulci
|-
| 29 || presence of superior and inferior frontal sulci; narrower Sylvian fissure; clear corpus callosum; bright white matter; dark cortical ribbon
|-
| 30-31 || beginning of infolding of cortex which is first apparent in the occipital lobe; narrower ventricular system and subarachnoid spaces
|-
| 32 || presence of superior and inferior temporal sulci
|-
| 33 || presence of external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration; compactly and extensively folded cortex
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table of the process of sulcation and gyration <ref name=PMID20608424><pubmed>20608424</pubmed></ref>

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations <ref><pubmed>7472570</pubmed></ref>

|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.
{|
|-bgcolor="ECCEF5"
|

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.
|}

{|
|-bgcolor="CED8F6"
|The following recent studies use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

** Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

** The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

** The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.

'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.
|}

{|
|-bgcolor="ECCEF5"
|
In the following studies new models and imaging techniques have been employed to gain a better understanding of the changes in brains of patients with schizophrenia

'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

Moreover, in the following study, a neuroimaging technique known as Proton Magnetic Resonance Spectroscopy (1H-MRS) is used to examine the brain of patients with schizophrenia.

'''Multimodal neuroimaging of frontal white matter microstructure in early phase schizophrenia: the impact of early adolescent cannabis use'''
<ref><pubmed> 3852698 </pubmed></ref>

[[Image:Online_placement_of_the_1H-MRS_volume_of_interest_.jpg|400x400px|frame|Proton magnetic resonance spectroscopy (1H-MRS) is used to examine the white matter tissue in brain of patients with schizophrenia. The image shows online placement of the 1H-MRS volume of interest.The 1H-MRS volume of interest is placed parallel to the AC-PC line (AC =anterior commissure, PC = posterior commissure). <ref><pubmed> 3852698 </pubmed></ref> ]]

* The neurochemical used in this technique is N-acetylaspartate (NAA), a free amino acid that has a peak resonance at 2.02 ppm on the spectral profile in the 1H-MRS of human brain.
* In vivo concentration levels of NAA are higher in white matter compared to gray matter.
* Post-mortem studies have demonstrated that NAA is produced in neurons, transported into white matter and broken down into aspartate and acetate in oligodendrocytes. <ref><pubmed>17275978</pubmed></ref> NAA catabolism is thus closely related to the metabolism of myelin, since it provides a crucial source of acetate which is necessary for the formation of myelin from lipid.
* Therefore due to abnormal myelin biosynthesis in schizophrenia, brain tissues can be examined by 1H-MRS studies as long as the targeted brain region involves a single tissue type (white matter) that provides the necessary information regarding the catabolic cycle of NAA.

|}

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]

Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.

* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period).

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation. <ref><pubmed>15806441</pubmed></ref>

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.<ref><pubmed>21215908</pubmed></ref>

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.<ref><pubmed>1400921</pubmed></ref>

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.<ref><pubmed>25283616</pubmed></ref>

===Fetal Alcohol Syndrome===

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status. <ref><pubmed> 24904907 </pubmed></ref>

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.<ref><pubmed> 23809349 </pubmed></ref>

{| class="wikitable"
|-
| [[File:Fetal alcohol syndrome.jpg|500px]] || [[File:Ethanol fetal neural.jpg|400px]]
|-
| The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref>|| A mechanism of the effect of ethanol on neural stem cells (NSCs). Ethanol promotes asymmetrical cell division, the formation of radial glial-like cells, leading to the premature depletion of the VZ and its NSCs, and the thickening and cell proliferation in SVZ. The increased migration during early differentiation of ethanol-treated NSCs also leads to the appearance of subpial heterotopias<ref name="PMID22623924"><pubmed>22623924</pubmed></ref>
|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

* All degrees of iodine deficiency (mild: 50-99 μg/day, moderate: 20-49 μg/day and severe≤20 μg/day) affect thyroid function of both mother and the neonate as well as mental development of the child. The damage increases with the degree of deficiency; overt endemic cretinism is the most severe consequence.

* Iodine deficiency disorders refer to complications that arise when the recommended dietary allowance of iodine is not met. These complications include thyroid function abnormalities and when iodine deficiency is severe, endemic goitre and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality.

* Iodine deficiency represents the world’s greatest cause of preventable brain damage and mental retardation, resulting of a loss of 10-15 IQ points globally. Therefore it is essential that the recommended dietary requirement for iodine is met, especially during pregnancy and lactation (200–300 μg/day). <ref><pubmed>10750030</pubmed></ref>

* Clinical manifestations of hypothyroidism include: Myxedematous facies (condition characterized by thickening of the skin, blunting of the senses and intellect, and laboured speech), jaundice, a puffy face and a wide posterior fontanelle with open sutures. The nasal bridge is flat. The mouth may be slightly open revealing macroglossia. Further examination would reveal bradycardia and a protuberant abdomen with a large umbilical hernia. Neurologic examination findings include hypotonia with delayed reflexes. Skin may be cool to touch and mottled in appearance due to circulatory compromise.<ref><pubmed>2903524</pubmed></ref>

===Abnormalities associated with apoptosis and migration of cells in the fetal CNS===

* The migration of cells and cell death are critically important to fetal brain and CNS development. Abnormalities in each of these processes, programmed cell death (apoptosis) in particular, have been shown to result in severe developmental abnormalities in experimental animals. Apoptosis is critically important for appropriate brain development; certain areas in brain may experience up to 50% cell death. <ref><pubmed> 11589424 </pubmed></ref>

* In an experiment conducted by kuida et. al 1996, it was observed that mice that were deficient for CPP32 (a protease responsible for apoptosis), were born at a lower frequency than expected, were smaller in size compared to the normal mice and died at an early age. Brain development is significantly affected in CPP32-deficient mice resulting in a variety of hyperplasia and disorganised cell development. <ref><pubmed>8934524</pubmed></ref>

* On the other hand, disrupted neuronal migration can lead to an abnormality in cell position. When this happens, the neurons are said to be heterotopic. Abnormalities in neuronal migration have been studied extensively in human cerebral cortex where these defects are associated with a variety of syndromes and diseases, ranging from behavioural disorders (including some forms of schizophrenia, dyslexia and autism) to extremely severe mental retardation and failure to thrive. <ref><pubmed>10532616</pubmed></ref>

===Neural Tube Defects===

Defects which affect the either the brain or the spinal cord in which openings remain. Grastulation occurs in week 3 of embryonic development where specialized cells (dorsal side) structurally change shape leading to the formation of the neural tube. If the neural tube does not close or fuse together properly, then openings remain which lead to various neural tube defects such as Spina bifida cystica and Spina bifida occulta.

'''Anencephaly''' <ref><pubmed> 8286034 </pubmed></ref>

* A neural tube defect involving abnormal development of the brain and incomplete skull formation leading to high infant mortality rates with infants being stillborn or dying within a few hours after birth.

* The failure of the neural tube to close around the 23rd and 26th day into embryonic development is characteristic of this condition. As a result, the forebrain is severely affected where the cerebrum does not grow and hence partial growth occurs only. The cerebrum has a key importance in maintaining thought, consciousness and coordination whilst having no intact cerebrum rules out the probability of the affected fetus gaining consciousness .

* Increasing one's dietary intake of folic acid notably reduces the incidence of neural tube defects. Consuming 0.4mg of folic acid is sufficient to induce these results.

* Since incomplete skull formation occurs, brain tissue becomes exposed due to the absence of bone covering and therefore leading to further complications.

'''Encephaloceles''' <ref><pubmed> 11151720 </pubmed></ref>

* Another neural tube defect in which a sac-like projections (including membrane covering) that occurs around the 3-4 week of embryonic development in which neural tube closure has not successfully occurred. The location of these protrusions varies but can be naso-frontal (nose and head), naso-ethmoidal (nose and ethmoid bone), naso-orbital (nose and eyes), meningocele (cerebrospinal fluid and membrane covering) and encephalomeningocele (meningocele with brain tissue as well).

* These sac-like protrusions lead to a variety of abnormal effects which include cerebro-spinal fluid build-up in brain, microcephaly, hydrocephaly, mental retardation, developmental problems, uncoordinated muscle movement and seizures. Consumption of folic acid again has been shown to significantly reduce the occurrence of encephaloceles in infants.

'''Hydranencephaly''' <ref><pubmed> 23112982 </pubmed></ref>

* A very rare neural tube defect in which the cerebral hemispheres are destroyed (necrotic tissue) with the occupied space being replaced by cerebro-spinal fluid, cortex and white matter remnants within a membranous sac. Interestingly, this condition can also develop in the postnatal peroid due to viral infections or traumatic brain injury. The brain stem may remain intact and functioning in hydranencephalic infants.

* Accompanied with this condition are many effects in which include seizures, hydrocephalus, increases in head circumference,impairment in vision/ body temperature regulation and cerebral palsy. Infants affected by hydranencephaly live typically short lives being no longer than 1 year of age. Lastly, there are no viable treatment options for this condition and only supportive care is available.

'''Iniencephaly''' <ref><pubmed> 10719321 </pubmed></ref>

* Another neural tube defect involving severe backward bending of the head (retroflexion) with subsequent spinal distortions as well. Affected infants have no neck and hence the scalp of the head is directly joined to the skin of the back (also skin of the face connected to skin of the chest). Other conditions that develop along with iniencephaly are cyclopia, cephalocele and anencephaly. The development of this condition is not solely due to one factor but from various causes (both genetic and environmental factors).

* There are specific factors that have been shown to increase the occurrence of this condition. Malnutrition, reduced folic acid intake and elevated levels of homocysteine in blood are environmental factors that increase the risk of iniencephaly <ref><pubmed> 22408660 </pubmed></ref>. Intake of certain drugs such as anti-histamines and sulphonamide/tetracycline (antibiotics) have also increases this risk <ref><pubmed> 22439066 </pubmed></ref>. Furthermore obesity has been shown to have a significant effect on the incidence of iniencephaly with 1.7-3 fold increase <ref><pubmed> 18538144 </pubmed></ref>.

* In terms of treatment, folic acid supplementation as well as avoiding certain drugs such as those outlined above significantly reduces the occurrence of this condition.

'''Spina Bifida Cystica'''

* A neural tube defect in which involves either the formation of a meningocele or myelomeningocele. Of the two, the meningocele, is the least debilitating in that a cyst-like structure forms when the neural tube does not close properly. The membrane (meninges) is pushed into openings of the vertebrae where spinal fluid builds up within the cyst. The myelomeningocele leads to severe problems as the portion of the nueral tube that is unfused allows the spinal cord to protrude through. As a result, neuronal tissue is highly exposed due to myeloschisis as well as infections and hence may lead to severe complications.

'''Spina Bifida Occulta'''

* A neural tube defect that has minimal complications in comparison to other defects. Furthermore, this defect is hidden in that a tethered spinal cord may arise as well as a thicker filum terminale and diastematomyelia (spinal cord split into two). It is also important to note that no cysts form as opposed to the other more severe spina bifida defects.

==References==

<references/>

2014 Group Project 7

2014-10-24T03:54:25Z

Z3418981: /* Abnormalities */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, recieving and integration of information from all parts of the body, serving as the processing center of the bodies nervous system. The CNS controls all bodily functions (sensory and motor), consisting of 2 main organs; The Brain and Spinal Cord.

The brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

The spinal cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into ascending bundles, which transmits sensory information from the body to the brain, and descending bundle, which transmits motor function information from the brain to the body.

Before fetal period, neurulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, including cellular processes and brain development will be discussed. Current research models and findings, and historic findings will be stated. The abnormalities associated to CNS during fetal period, and neural defects that occur during embryonic period and contribute in fetal development will be discussed.

==Development during fetal period==

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

[[File:Schematic_representation_of_the_timeline_of_human_neural_development.jpg|700px]]

A simplified timeline of human neural development (modified) <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

This simplified graph shows a timeline for major events of neural development that occur during fetal and postnatal periods. These events, which are summarized in the following table, are broadly classified by cell multiplication, cell migration, growth and differentiation and angiogenesis:

{| class="wikitable"
|-
! Major Events !! Descriptions
|-
| Cell multiplication ||
* Neurons are proliferated and generated from neural stem cells and progenitor cells (precursor cells) in a process known as neurogenesis in 2nd trimester.
* Cell death and Gliogenesis (glial cells (such as astrocytes) deriving from multipotent neural stem cells) occur in the 3rd trimester.
* Local gliogenesis continues postnatally.
|-
| Cell migration ||
* Neuronal migration is maximised during 2nd trimester while glial migration is maximised during 3rd trimester
|-
| Growth and differentiation ||
* Axonal and dendritic arborisation (fine branching structures at the end of nerve fibers) appear by the end of fetal period.
* Synaptogenesis (formation of synapses) and electrical activity is maximised in 3rd trimester (and continued postnatally).
* Cell death due to over-innervation can be observed in late fetal and postnatal period.
* Myelination occurs in late fetal and postnatal period (vast majority of postnatal growth in brain is due to myelination).
|-
| Angiogenesis ||
* Oxidative metabolism can be seen in late fetal period.
* Capillary networks develop postnatally.
|}

'''1. cell proliferation'''

[[Image:Somatosensory cortex of E20 rat.jpeg|frame|500x500px|Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) <ref name="PMID22272298"><pubmed>22272298</pubmed></ref>]]

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref name="PMID4203033"><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref name="PMID5414696"><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref name="PMID7204662"><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref name="PMID12764033"><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref name="PMID8523077"><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref name="PMID9712307"><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref name="PMID1713238"><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

'''2. cell migration'''
[[Image:CNS_passive.jpg|frame|200x150px|Passive cell displacement and outside-to-inside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]
[[Image:CNS_active.jpg|frame|350x250px|Active cell migration and inside-to-outside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways.

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus <ref name="PMID489804"><pubmed>489804</pubmed></ref>, hypothalamus <ref name="PMID5029133"><pubmed>5029133</pubmed></ref>, spinal cord <ref name="PMID4407392"><pubmed>4407392</pubmed></ref>, dentate gyrus of the hippocampal formation <ref name="PMID17533671"><pubmed>17533671</pubmed></ref> and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas <ref name="PMID17533671"><pubmed>17533671</pubmed></ref>.

{| style="width:20%; height:170px" align="center"
|-
| [[Image:Internurons migration in cerebral cortex.jpg|frame|200x400px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex <ref name="PMID17726524"><pubmed>17726524</pubmed></ref>]]
|}

'''3. cell differentiation'''<ref name="PMID10532616"><pubmed>10532616</pubmed></ref>

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

=== Brain Development ===

* The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells. By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

* The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

[[Image:Brain ventricles and ganglia development 03.jpg|frame|200x200px|Increase in size of of brain and ventricles <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]
[[Image:Brain fissure development 02.jpg|frame|200x200px|Increase in size of brain fissure <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]

* The gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding.

* The brain development begins rostral in GW8, proceeding caudally until it is complete at GW22 <ref><pubmed>560818</pubmed></ref>

* The formation of Secondary Sulci is between GW30-35, while the formation of of Tertiary Sulci begins during GW36 and into the postnatal period.

* Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

* Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

* The major fibre pathways make up the brain white matter

* AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Neuron Production'''

* The human brain contains billions of neurons which are produced by mid-gestation; during fetal development <ref><pubmed>8361683</pubmed></ref>

* Processes of Neuronal production is initiated by first increasing the size of the Neural progenitor cell population within the body, these cells are mitotic in nature and are capable of forming new cells.

* Initially (from the end of gastrulation through to embryonic day 42), the neural progenitor cell population is increased greatly when the progenitor cells divide through 'symmetrical' mode of cell division. Multiple repeats of the cell division occurs throughout this period. This 'symmetrical' division method brings about the formation of 2 new identical neural progenitor cells

* Mode of cell division changes from a symmetrical cell division type to an 'asymmetrical' cell division from the beginning of E42. This asymmetrical cell division forms 2 different cell types; one Neural progenitor & one Neuron <ref><pubmed>12764028 </pubmed></ref>

* Newly formed Neural progenitor cells remains to undergo more processes of cell division whereas the newly formed neuron moves into position in the developing neocortex

'''Neuron Migration''' <ref name="PMID21042938"><pubmed>21042938</pubmed></ref>

Outlined above was a broad summary on neuron migration. Neuron migration in the cortex will be covered below in more detail.

* The ventricular zone (VZ) is where the majority of neurons migrate radially out and into the neocortex. The type of migration utilised here is referred to as somal translocation where the neuron cell body translocates out of the VZ and into the outer brain region with the nucleus moving across the cytoplasm and into the outer brain region.

* With increasing brain size, somal translocation is no longer efficient for neuronal migration out of VZ. Since greater distances are evident, radial glial guides are adopted to allow the migration of neurons to continue. Similar to somal translocation, these cell populations establish a scaffolding system where neurons can attach to (basal process occurs) and then move into the developing cortical plate. These cell populations are comprised of neural progenitor cells and are therefore able to support mass neuron migration.

* Another mode of transport utilised by neurons situated within a second zone of the ventral telencephalon is referred to as tangential migration. The neurons here migrate tangentially to the cortical mantle whilst adopting different signalling pathways (guidance molecules) as opposed to radial migration. As a result of neuronal migration, a 6-layered structure forms within the developing neocortex.

* Once completion of the pre-plate has occurred, two regions are formed and which are the subplate (SP) and th marginal zone (MZ).In between these two regions, the cortical plate arises as well. Earliest neuron arrival forms the deepest layer of the cortex; cortical layer 6. More superficial layers of the cortex will develop with continuous cell migration. It is important to note that a specific cell class is located within the MZ in which are the Cajal-Retzius cells (CR). CR's are important for correct neuron positioning within the cortical layers as well as having an inhibitory effect on neuron migration. Rheelin, a molecular signal produced by the CR's is important here as it stops neurons from migrating and signals them to up their corresponding positions.

'''Folding: sulcation and gyration'''

[[Image:Dev anat 01.jpg|frame|200x200px|Simplified external lateral (left) view of the brain growth]]

* During the fifth and sixth month of gestation, the smooth cortex begins to fold by sulcation and gyration. <ref name=PMID21571694><pubmed>21571694</pubmed></ref>

# Sulcation: This is the development of sulci, including primary and secondary. The formation of primary sulci involve the appearance of shallow grooves on the surface of the brain, which then become more deeply infolded, while the formation of secondary sulci is due to the development of side branches of the primary ones <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.
# Gyration: This is the development of gyrus that occurs during late during fetal development until the end of the pregnancy or after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>. This process is the formation of tertiary sulci, which is the formation of other side branches of the secondary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

{| class="wikitable"
|-
! Weeks of gestation !! Visible anatomical details
|-
| 20-21 || smooth, with the impression of "lissencephalic" brain; wide Sylvian fissures; visible interhemispheric fissure and parieto-occipital fissure
|-
| 22-23 || beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || smooth cerebral cortex surface; visible shallow grooves in the central sulci, interparietal sulci and superior temporal sulci; start of opercularization of Sylvian fissures; presence of calcarine fissures and cingular sulci
|-
| 26 || presence of central and collateral sulci
|-
| 27 || presence of marginal and precentral sulci
|-
| 28 || presence of postcentral and intraparietal sulci
|-
| 29 || presence of superior and inferior frontal sulci; narrower Sylvian fissure; clear corpus callosum; bright white matter; dark cortical ribbon
|-
| 30-31 || beginning of infolding of cortex which is first apparent in the occipital lobe; narrower ventricular system and subarachnoid spaces
|-
| 32 || presence of superior and inferior temporal sulci
|-
| 33 || presence of external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration; compactly and extensively folded cortex
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table of the process of sulcation and gyration <ref name=PMID20608424><pubmed>20608424</pubmed></ref>

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations <ref><pubmed>7472570</pubmed></ref>

|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.
{|
|-bgcolor="ECCEF5"
|

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.
|}

{|
|-bgcolor="CED8F6"
|The following recent studies use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

** Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

** The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

** The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.

'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.
|}

{|
|-bgcolor="ECCEF5"
|
In the following studies new models and imaging techniques have been employed to gain a better understanding of the changes in brains of patients with schizophrenia

'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

Moreover, in the following study, a neuroimaging technique known as Proton Magnetic Resonance Spectroscopy (1H-MRS) is used to examine the brain of patients with schizophrenia.

'''Multimodal neuroimaging of frontal white matter microstructure in early phase schizophrenia: the impact of early adolescent cannabis use'''
<ref><pubmed> 3852698 </pubmed></ref>

[[Image:Online_placement_of_the_1H-MRS_volume_of_interest_.jpg|400x400px|frame|Proton magnetic resonance spectroscopy (1H-MRS) is used to examine the white matter tissue in brain of patients with schizophrenia. The image shows online placement of the 1H-MRS volume of interest.The 1H-MRS volume of interest is placed parallel to the AC-PC line (AC =anterior commissure, PC = posterior commissure). <ref><pubmed> 3852698 </pubmed></ref> ]]

* The neurochemical used in this technique is N-acetylaspartate (NAA), a free amino acid that has a peak resonance at 2.02 ppm on the spectral profile in the 1H-MRS of human brain.
* In vivo concentration levels of NAA are higher in white matter compared to gray matter.
* Post-mortem studies have demonstrated that NAA is produced in neurons, transported into white matter and broken down into aspartate and acetate in oligodendrocytes. <ref><pubmed>17275978</pubmed></ref> NAA catabolism is thus closely related to the metabolism of myelin, since it provides a crucial source of acetate which is necessary for the formation of myelin from lipid.
* Therefore due to abnormal myelin biosynthesis in schizophrenia, brain tissues can be examined by 1H-MRS studies as long as the targeted brain region involves a single tissue type (white matter) that provides the necessary information regarding the catabolic cycle of NAA.

|}

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]

Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.

* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period).

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation. <ref><pubmed>15806441</pubmed></ref>

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.<ref><pubmed>21215908</pubmed></ref>

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.<ref><pubmed>1400921</pubmed></ref>

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.<ref><pubmed>25283616</pubmed></ref>

===Fetal Alcohol Syndrome===

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status. <ref><pubmed> 24904907 </pubmed></ref>

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.<ref><pubmed> 23809349 </pubmed></ref>

{| class="wikitable"
|-
| [[File:Fetal alcohol syndrome.jpg|500px]] || [[File:Ethanol fetal neural.jpg|400px]]
|-
| The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref>|| A mechanism of the effect of ethanol on neural stem cells (NSCs). Ethanol promotes asymmetrical cell division, the formation of radial glial-like cells, leading to the premature depletion of the VZ and its NSCs, and the thickening and cell proliferation in SVZ. The increased migration during early differentiation of ethanol-treated NSCs also leads to the appearance of subpial heterotopias<ref name="PMID22623924"><pubmed>22623924</pubmed></ref>
|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

* All degrees of iodine deficiency (mild: 50-99 μg/day, moderate: 20-49 μg/day and severe≤20 μg/day) affect thyroid function of both mother and the neonate as well as mental development of the child. The damage increases with the degree of deficiency; overt endemic cretinism is the most severe consequence.

* Iodine deficiency disorders refer to complications that arise when the recommended dietary allowance of iodine is not met. These complications include thyroid function abnormalities and when iodine deficiency is severe, endemic goitre and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality.

* Iodine deficiency represents the world’s greatest cause of preventable brain damage and mental retardation, resulting of a loss of 10-15 IQ points globally. Therefore it is essential that the recommended dietary requirement for iodine is met, especially during pregnancy and lactation (200–300 μg/day). <ref><pubmed>10750030</pubmed></ref>

* Clinical manifestations of hypothyroidism include: Myxedematous facies (condition characterized by thickening of the skin, blunting of the senses and intellect, and laboured speech), jaundice, a puffy face and a wide posterior fontanelle with open sutures. The nasal bridge is flat. The mouth may be slightly open revealing macroglossia. Further examination would reveal bradycardia and a protuberant abdomen with a large umbilical hernia. Neurologic examination findings include hypotonia with delayed reflexes. Skin may be cool to touch and mottled in appearance due to circulatory compromise.<ref><pubmed>2903524</pubmed></ref>

===Abnormalities associated with apoptosis and migration of cells in the fetal CNS===

* The migration of cells and cell death are critically important to fetal brain and CNS development. Abnormalities in each of these processes, programmed cell death (apoptosis) in particular, have been shown to result in severe developmental abnormalities in experimental animals. Apoptosis is critically important for appropriate brain development; certain areas in brain may experience up to 50% cell death. <ref><pubmed> 11589424 </pubmed></ref>

* In an experiment conducted by kuida et. al 1996, it was observed that mice that were deficient for CPP32 (a protease responsible for apoptosis), were born at a lower frequency than expected, were smaller in size compared to the normal mice and died at an early age. Brain development is significantly affected in CPP32-deficient mice resulting in a variety of hyperplasia and disorganised cell development. <ref><pubmed>8934524</pubmed></ref>

* On the other hand, disrupted neuronal migration can lead to an abnormality in cell position. When this happens, the neurons are said to be heterotopic. Abnormalities in neuronal migration have been studied extensively in human cerebral cortex where these defects are associated with a variety of syndromes and diseases, ranging from behavioural disorders (including some forms of schizophrenia, dyslexia and autism) to extremely severe mental retardation and failure to thrive. <ref><pubmed>10532616</pubmed></ref>

===Neural Tube Defects===

Defects which affect the either the brain or the spinal cord in which openings remain. Grastulation occurs in week 3 of embryonic development where specialized cells (dorsal side) structurally change shape leading to the formation of the neural tube. If the neural tube does not close or fuse together properly, then openings remain which lead to various neural tube defects such as Spina bifida cystica and Spina bifida occulta.

'''Anencephaly'''

* A neural tube defect involving abnormal development of the brain and incomplete skull formation leading to high infant mortality rates with infants being stillborn or dying within a few hours after birth.

* The failure of the neural tube to close around the 23rd and 26th day into embryonic development is characteristic of this condition. As a result, the forebrain is severely affected where the cerebrum does not grow and hence partial growth occurs only. The cerebrum has a key importance in maintaining thought, consciousness and coordination whilst having no intact cerebrum rules out the probability of the affected fetus gaining consciousness .

* Increasing one's dietary intake of folic acid notably reduces the incidence of neural tube defects. Consuming 0.4mg of folic acid is sufficient to induce these results.

* Since incomplete skull formation occurs, brain tissue becomes exposed due to the absence of bone covering and therefore leading to further complications.

'''Encephaloceles'''

* Another neural tube defect in which a sac-like projections (including membrane covering) that occurs around the 3-4 week of embryonic development in which neural tube closure has not successfully occurred. The location of these protrusions varies but can be naso-frontal (nose and head), naso-ethmoidal (nose and ethmoid bone), naso-orbital (nose and eyes), meningocele (cerebrospinal fluid and membrane covering) and encephalomeningocele (meningocele with brain tissue as well).

* These sac-like protrusions lead to a variety of abnormal effects which include cerebro-spinal fluid build-up in brain, microcephaly, hydrocephaly, mental retardation, developmental problems, uncoordinated muscle movement and seizures. Consumption of folic acid again has been shown to significantly reduce the occurrence of encephaloceles in infants.

'''Hydranencephaly'''

* A very rare neural tube defect in which the cerebral hemispheres are destroyed (necrotic tissue) with the occupied space being replaced by cerebro-spinal fluid, cortex and white matter remnants within a membranous sac. Interestingly, this condition can also develop in the postnatal peroid due to viral infections or traumatic brain injury. The brain stem may remain intact and functioning in hydranencephalic infants.

* Accompanied with this condition are many effects in which include seizures, hydrocephalus, increases in head circumference,impairment in vision/ body temperature regulation and cerebral palsy. Infants affected by hydranencephaly live typically short lives being no longer than 1 year of age. Lastly, there are no viable treatment options for this condition and only supportive care is available.

'''Iniencephaly'''

* Another neural tube defect involving severe backward bending of the head (retroflexion) with subsequent spinal distortions as well. Affected infants have no neck and hence the scalp of the head is directly joined to the skin of the back (also skin of the face connected to skin of the chest). Other conditions that develop along with iniencephaly are cyclopia, cephalocele and anencephaly. The development of this condition is not solely due to one factor but from various causes (both genetic and environmental factors).

* There are specific factors that have been shown to increase the occurrence of this condition. Malnutrition, reduced folic acid intake and elevated levels of homocysteine in blood are environmental factors that increase the risk of iniencephaly <ref><pubmed> 22408660 </pubmed></ref>. Intake of certain drugs such as anti-histamines and sulphonamide/tetracycline (antibiotics) have also increases this risk <ref><pubmed> 22439066 </pubmed></ref>. Furthermore obesity has been shown to have a significant effect on the incidence of iniencephaly with 1.7-3 fold increase <ref><pubmed> 18538144 </pubmed></ref>.

* In terms of treatment, folic acid supplementation as well as avoiding certain drugs such as those outlined above significantly reduces the occurrence of this condition.

'''Spina Bifida Cystica'''

* A neural tube defect in which involves either the formation of a meningocele or myelomeningocele. Of the two, the meningocele, is the least debilitating in that a cyst-like structure forms when the neural tube does not close properly. The membrane (meninges) is pushed into openings of the vertebrae where spinal fluid builds up within the cyst. The myelomeningocele leads to severe problems as the portion of the nueral tube that is unfused allows the spinal cord to protrude through. As a result, neuronal tissue is highly exposed due to myeloschisis as well as infections and hence may lead to severe complications.

'''Spina Bifida Occulta'''

* A neural tube defect that has minimal complications in comparison to other defects. Furthermore, this defect is hidden in that a tethered spinal cord may arise as well as a thicker filum terminale and diastematomyelia (spinal cord split into two). It is also important to note that no cysts form as opposed to the other more severe spina bifida defects.

==References==

<references/>

2014 Group Project 7

2014-10-24T03:47:41Z

Z3418981: /* Current Research */

2014 Group Project 7

2014-10-24T03:42:11Z

Z3418981: /* Abnormalities associated with apoptosis and migration of cells in the fetal CNS */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, recieving and integration of information from all parts of the body, serving as the processing center of the bodies nervous system. The CNS controls all bodily functions (sensory and motor), consisting of 2 main organs; The Brain and Spinal Cord.

The brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

The spinal cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into ascending bundles, which transmits sensory information from the body to the brain, and descending bundle, which transmits motor function information from the brain to the body.

Before fetal period, neurulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, including cellular processes and brain development will be discussed. Current research models and findings, and historic findings will be stated. The abnormalities associated to CNS during fetal period, and neural defects that occur during embryonic period and contribute in fetal development will be discussed.

==Development during fetal period==

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

[[File:Schematic_representation_of_the_timeline_of_human_neural_development.jpg|700px]]

A simplified timeline of human neural development (modified) <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

This simplified graph shows a timeline for major events of neural development that occur during fetal and postnatal periods. These events, which are summarized in the following table, are broadly classified by cell multiplication, cell migration, growth and differentiation and angiogenesis:

{| class="wikitable"
|-
! Major Events !! Descriptions
|-
| Cell multiplication ||
* Neurons are proliferated and generated from neural stem cells and progenitor cells (precursor cells) in a process known as neurogenesis in 2nd trimester.
* Cell death and Gliogenesis (glial cells (such as astrocytes) deriving from multipotent neural stem cells) occur in the 3rd trimester.
* Local gliogenesis continues postnatally.
|-
| Cell migration ||
* Neuronal migration is maximised during 2nd trimester while glial migration is maximised during 3rd trimester
|-
| Growth and differentiation ||
* Axonal and dendritic arborisation (fine branching structures at the end of nerve fibers) appear by the end of fetal period.
* Synaptogenesis (formation of synapses) and electrical activity is maximised in 3rd trimester (and continued postnatally).
* Cell death due to over-innervation can be observed in late fetal and postnatal period.
* Myelination occurs in late fetal and postnatal period (vast majority of postnatal growth in brain is due to myelination).
|-
| Angiogenesis ||
* Oxidative metabolism can be seen in late fetal period.
* Capillary networks develop postnatally.
|}

'''1. cell proliferation'''

[[Image:Somatosensory cortex of E20 rat.jpeg|frame|500x500px|Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) <ref name="PMID22272298"><pubmed>22272298</pubmed></ref>]]

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref name="PMID4203033"><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref name="PMID5414696"><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref name="PMID7204662"><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref name="PMID12764033"><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref name="PMID8523077"><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref name="PMID9712307"><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref name="PMID1713238"><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

'''2. cell migration'''
[[Image:CNS_passive.jpg|frame|200x150px|Passive cell displacement and outside-to-inside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]
[[Image:CNS_active.jpg|frame|350x250px|Active cell migration and inside-to-outside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways.

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus <ref name="PMID489804"><pubmed>489804</pubmed></ref>, hypothalamus <ref name="PMID5029133"><pubmed>5029133</pubmed></ref>, spinal cord <ref name="PMID4407392"><pubmed>4407392</pubmed></ref>, dentate gyrus of the hippocampal formation <ref name="PMID17533671"><pubmed>17533671</pubmed></ref> and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas <ref name="PMID17533671"><pubmed>17533671</pubmed></ref>.

{| style="width:20%; height:170px" align="center"
|-
| [[Image:Internurons migration in cerebral cortex.jpg|frame|200x400px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex <ref name="PMID17726524"><pubmed>17726524</pubmed></ref>]]
|}

'''3. cell differentiation'''<ref name="PMID10532616"><pubmed>10532616</pubmed></ref>

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

=== Brain Development ===

* The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells. By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

* The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

[[Image:Brain ventricles and ganglia development 03.jpg|frame|200x200px|Increase in size of of brain and ventricles <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]
[[Image:Brain fissure development 02.jpg|frame|200x200px|Increase in size of brain fissure <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]

* The gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding.

* The brain development begins rostral in GW8, proceeding caudally until it is complete at GW22 <ref><pubmed>560818</pubmed></ref>

* The formation of Secondary Sulci is between GW30-35, while the formation of of Tertiary Sulci begins during GW36 and into the postnatal period.

* Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

* Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

* The major fibre pathways make up the brain white matter

* AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Neuron Production'''

* The human brain contains billions of neurons which are produced by mid-gestation; during fetal development <ref><pubmed>8361683</pubmed></ref>

* Processes of Neuronal production is initiated by first increasing the size of the Neural progenitor cell population within the body, these cells are mitotic in nature and are capable of forming new cells.

* Initially (from the end of gastrulation through to embryonic day 42), the neural progenitor cell population is increased greatly when the progenitor cells divide through 'symmetrical' mode of cell division. Multiple repeats of the cell division occurs throughout this period. This 'symmetrical' division method brings about the formation of 2 new identical neural progenitor cells

* Mode of cell division changes from a symmetrical cell division type to an 'asymmetrical' cell division from the beginning of E42. This asymmetrical cell division forms 2 different cell types; one Neural progenitor & one Neuron <ref><pubmed>12764028 </pubmed></ref>

* Newly formed Neural progenitor cells remains to undergo more processes of cell division whereas the newly formed neuron moves into position in the developing neocortex

'''Neuron Migration''' <ref name="PMID21042938"><pubmed>21042938</pubmed></ref>

Outlined above was a broad summary on neuron migration. Neuron migration in the cortex will be covered below in more detail.

* The ventricular zone (VZ) is where the majority of neurons migrate radially out and into the neocortex. The type of migration utilised here is referred to as somal translocation where the neuron cell body translocates out of the VZ and into the outer brain region with the nucleus moving across the cytoplasm and into the outer brain region.

* With increasing brain size, somal translocation is no longer efficient for neuronal migration out of VZ. Since greater distances are evident, radial glial guides are adopted to allow the migration of neurons to continue. Similar to somal translocation, these cell populations establish a scaffolding system where neurons can attach to (basal process occurs) and then move into the developing cortical plate. These cell populations are comprised of neural progenitor cells and are therefore able to support mass neuron migration.

* Another mode of transport utilised by neurons situated within a second zone of the ventral telencephalon is referred to as tangential migration. The neurons here migrate tangentially to the cortical mantle whilst adopting different signalling pathways (guidance molecules) as opposed to radial migration. As a result of neuronal migration, a 6-layered structure forms within the developing neocortex.

* Once completion of the pre-plate has occurred, two regions are formed and which are the subplate (SP) and th marginal zone (MZ).In between these two regions, the cortical plate arises as well. Earliest neuron arrival forms the deepest layer of the cortex; cortical layer 6. More superficial layers of the cortex will develop with continuous cell migration. It is important to note that a specific cell class is located within the MZ in which are the Cajal-Retzius cells (CR). CR's are important for correct neuron positioning within the cortical layers as well as having an inhibitory effect on neuron migration. Rheelin, a molecular signal produced by the CR's is important here as it stops neurons from migrating and signals them to up their corresponding positions.

'''Folding: sulcation and gyration'''

[[Image:Dev anat 01.jpg|frame|200x200px|Simplified external lateral (left) view of the brain growth]]

* During the fifth and sixth month of gestation, the smooth cortex begins to fold by sulcation and gyration. <ref name=PMID21571694><pubmed>21571694</pubmed></ref>

# Sulcation: This is the development of sulci, including primary and secondary. The formation of primary sulci involve the appearance of shallow grooves on the surface of the brain, which then become more deeply infolded, while the formation of secondary sulci is due to the development of side branches of the primary ones <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.
# Gyration: This is the development of gyrus that occurs during late during fetal development until the end of the pregnancy or after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>. This process is the formation of tertiary sulci, which is the formation of other side branches of the secondary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

{| class="wikitable"
|-
! Weeks of gestation !! Visible anatomical details
|-
| 20-21 || smooth, with the impression of "lissencephalic" brain; wide Sylvian fissures; visible interhemispheric fissure and parieto-occipital fissure
|-
| 22-23 || beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || smooth cerebral cortex surface; visible shallow grooves in the central sulci, interparietal sulci and superior temporal sulci; start of opercularization of Sylvian fissures; presence of calcarine fissures and cingular sulci
|-
| 26 || presence of central and collateral sulci
|-
| 27 || presence of marginal and precentral sulci
|-
| 28 || presence of postcentral and intraparietal sulci
|-
| 29 || presence of superior and inferior frontal sulci; narrower Sylvian fissure; clear corpus callosum; bright white matter; dark cortical ribbon
|-
| 30-31 || beginning of infolding of cortex which is first apparent in the occipital lobe; narrower ventricular system and subarachnoid spaces
|-
| 32 || presence of superior and inferior temporal sulci
|-
| 33 || presence of external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration; compactly and extensively folded cortex
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table of the process of sulcation and gyration <ref name=PMID20608424><pubmed>20608424</pubmed></ref>

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations <ref><pubmed>7472570</pubmed></ref>

|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.
{|
|-bgcolor="ECCEF5"
|

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.
|}

{|
|-bgcolor="CED8F6"
|The following recent studies use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

** Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

** The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

** The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.
|}

{|
|-bgcolor="CED8F6"
|
'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.
|}

{|
|-bgcolor="ECCEF5"
|
In the following studies new models and imaging techniques have been employed to gain a better understanding of the changes in brains of patients with schizophrenia

'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

Moreover, in the following study, a neuroimaging technique known as Proton Magnetic Resonance Spectroscopy (1H-MRS) is used to examine the brain of patients with schizophrenia.

'''Multimodal neuroimaging of frontal white matter microstructure in early phase schizophrenia: the impact of early adolescent cannabis use'''
<ref><pubmed> 3852698 </pubmed></ref>

[[Image:Online_placement_of_the_1H-MRS_volume_of_interest_.jpg|400x400px|frame|Proton magnetic resonance spectroscopy (1H-MRS) is used to examine the white matter tissue in brain of patients with schizophrenia. The image shows online placement of the 1H-MRS volume of interest.The 1H-MRS volume of interest is placed parallel to the AC-PC line (AC =anterior commissure, PC = posterior commissure). <ref><pubmed> 3852698 </pubmed></ref> ]]

* The neurochemical used in this technique is N-acetylaspartate (NAA), a free amino acid that has a peak resonance at 2.02 ppm on the spectral profile in the 1H-MRS of human brain.
* In vivo concentration levels of NAA are higher in white matter compared to gray matter.
* Post-mortem studies have demonstrated that NAA is produced in neurons, transported into white matter and broken down into aspartate and acetate in oligodendrocytes. <ref><pubmed>17275978</pubmed></ref> NAA catabolism is thus closely related to the metabolism of myelin, since it provides a crucial source of acetate which is necessary for the formation of myelin from lipid.
* Therefore due to abnormal myelin biosynthesis in schizophrenia, brain tissues can be examined by 1H-MRS studies as long as the targeted brain region involves a single tissue type (white matter) that provides the necessary information regarding the catabolic cycle of NAA.

|}

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]

Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.

* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period).

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation. <ref><pubmed>15806441</pubmed></ref>

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.<ref><pubmed>21215908</pubmed></ref>

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.<ref><pubmed>1400921</pubmed></ref>

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.<ref><pubmed>25283616</pubmed></ref>

===Fetal Alcohol Syndrome===

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status. <ref><pubmed> 24904907 </pubmed></ref>

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.<ref><pubmed> 23809349 </pubmed></ref>

{| class="wikitable"

−
|-

−
| [[File:Fetal alcohol syndrome.jpg|500px]] || [[File:Ethanol fetal neural.jpg|400px]]

−
|-

−
| The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref>|| A mechanism of the effect of ethanol on neural stem cells (NSCs). Ethanol promotes asymmetrical cell division, the formation of radial glial-like cells, leading to the premature depletion of the VZ and its NSCs, and the thickening and cell proliferation in SVZ. The increased migration during early differentiation of ethanol-treated NSCs also leads to the appearance of subpial heterotopias<ref name="PMID22623924"><pubmed>22623924</pubmed></ref>

|}

|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

* All degrees of iodine deficiency (mild: 50-99 μg/day, moderate: 20-49 μg/day and severe≤20 μg/day) affect thyroid function of both mother and the neonate as well as mental development of the child. The damage increases with the degree of deficiency; overt endemic cretinism is the most severe consequence.

* Iodine deficiency disorders refer to complications that arise when the recommended dietary allowance of iodine is not met. These complications include thyroid function abnormalities and when iodine deficiency is severe, endemic goitre and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality.

* Iodine deficiency represents the world’s greatest cause of preventable brain damage and mental retardation, resulting of a loss of 10-15 IQ points globally. Therefore it is essential that the recommended dietary requirement for iodine is met, especially during pregnancy and lactation (200–300 μg/day). <ref><pubmed>10750030</pubmed></ref>

* Clinical manifestations of hypothyroidism include: Myxedematous facies (condition characterized by thickening of the skin, blunting of the senses and intellect, and laboured speech), jaundice, a puffy face and a wide posterior fontanelle with open sutures. The nasal bridge is flat. The mouth may be slightly open revealing macroglossia. Further examination would reveal bradycardia and a protuberant abdomen with a large umbilical hernia. Neurologic examination findings include hypotonia with delayed reflexes. Skin may be cool to touch and mottled in appearance due to circulatory compromise.<ref><pubmed>2903524</pubmed></ref>

===Abnormalities associated with apoptosis and migration of cells in the fetal CNS===

* The migration of cells and cell death are critically important to fetal brain and CNS development. Abnormalities in each of these processes, programmed cell death (apoptosis) in particular, have been shown to result in severe developmental abnormalities in experimental animals. Apoptosis is critically important for appropriate brain development; certain areas in brain may experience up to 50% cell death. <ref><pubmed> 11589424 </pubmed></ref>

* In an experiment conducted by kuida et. al 1996, it was observed that mice that were deficient for CPP32 (a protease responsible for apoptosis), were born at a lower frequency than expected, were smaller in size compared to the normal mice and died at an early age. Brain development is significantly affected in CPP32-deficient mice resulting in a variety of hyperplasia and disorganised cell development. <ref><pubmed>8934524</pubmed></ref>

* On the other hand, disrupted neuronal migration can lead to an abnormality in cell position. When this happens, the neurons are said to be heterotopic. Abnormalities in neuronal migration have been studied extensively in human cerebral cortex where these defects are associated with a variety of syndromes and diseases, ranging from behavioural disorders (including some forms of schizophrenia, dyslexia and autism) to extremely severe mental retardation and failure to thrive. <ref><pubmed>10532616</pubmed></ref>

==References==

<references/>

2014 Group Project 7

2014-10-24T03:39:52Z

Z3418981: /* Iodine deficiency */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, recieving and integration of information from all parts of the body, serving as the processing center of the bodies nervous system. The CNS controls all bodily functions (sensory and motor), consisting of 2 main organs; The Brain and Spinal Cord.

The brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

The spinal cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into ascending bundles, which transmits sensory information from the body to the brain, and descending bundle, which transmits motor function information from the brain to the body.

Before fetal period, neurulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, including cellular processes and brain development will be discussed. Current research models and findings, and historic findings will be stated. The abnormalities associated to CNS during fetal period, and neural defects that occur during embryonic period and contribute in fetal development will be discussed.

==Development during fetal period==

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

[[File:Schematic_representation_of_the_timeline_of_human_neural_development.jpg|700px]]

A simplified timeline of human neural development (modified) <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

This simplified graph shows a timeline for major events of neural development that occur during fetal and postnatal periods. These events, which are summarized in the following table, are broadly classified by cell multiplication, cell migration, growth and differentiation and angiogenesis:

{| class="wikitable"
|-
! Major Events !! Descriptions
|-
| Cell multiplication ||
* Neurons are proliferated and generated from neural stem cells and progenitor cells (precursor cells) in a process known as neurogenesis in 2nd trimester.
* Cell death and Gliogenesis (glial cells (such as astrocytes) deriving from multipotent neural stem cells) occur in the 3rd trimester.
* Local gliogenesis continues postnatally.
|-
| Cell migration ||
* Neuronal migration is maximised during 2nd trimester while glial migration is maximised during 3rd trimester
|-
| Growth and differentiation ||
* Axonal and dendritic arborisation (fine branching structures at the end of nerve fibers) appear by the end of fetal period.
* Synaptogenesis (formation of synapses) and electrical activity is maximised in 3rd trimester (and continued postnatally).
* Cell death due to over-innervation can be observed in late fetal and postnatal period.
* Myelination occurs in late fetal and postnatal period (vast majority of postnatal growth in brain is due to myelination).
|-
| Angiogenesis ||
* Oxidative metabolism can be seen in late fetal period.
* Capillary networks develop postnatally.
|}

'''1. cell proliferation'''

[[Image:Somatosensory cortex of E20 rat.jpeg|frame|500x500px|Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) <ref name="PMID22272298"><pubmed>22272298</pubmed></ref>]]

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref name="PMID4203033"><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref name="PMID5414696"><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref name="PMID7204662"><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref name="PMID12764033"><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref name="PMID8523077"><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref name="PMID9712307"><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref name="PMID1713238"><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

'''2. cell migration'''
[[Image:CNS_passive.jpg|frame|200x150px|Passive cell displacement and outside-to-inside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]
[[Image:CNS_active.jpg|frame|350x250px|Active cell migration and inside-to-outside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways.

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus <ref name="PMID489804"><pubmed>489804</pubmed></ref>, hypothalamus <ref name="PMID5029133"><pubmed>5029133</pubmed></ref>, spinal cord <ref name="PMID4407392"><pubmed>4407392</pubmed></ref>, dentate gyrus of the hippocampal formation <ref name="PMID17533671"><pubmed>17533671</pubmed></ref> and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas <ref name="PMID17533671"><pubmed>17533671</pubmed></ref>.

{| style="width:20%; height:170px" align="center"
|-
| [[Image:Internurons migration in cerebral cortex.jpg|frame|200x400px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex <ref name="PMID17726524"><pubmed>17726524</pubmed></ref>]]
|}

'''3. cell differentiation'''<ref name="PMID10532616"><pubmed>10532616</pubmed></ref>

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

=== Brain Development ===

* The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells. By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

* The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

[[Image:Brain ventricles and ganglia development 03.jpg|frame|200x200px|Increase in size of of brain and ventricles <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]
[[Image:Brain fissure development 02.jpg|frame|200x200px|Increase in size of brain fissure <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]

* The gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding.

* The brain development begins rostral in GW8, proceeding caudally until it is complete at GW22 <ref><pubmed>560818</pubmed></ref>

* The formation of Secondary Sulci is between GW30-35, while the formation of of Tertiary Sulci begins during GW36 and into the postnatal period.

* Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

* Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

* The major fibre pathways make up the brain white matter

* AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Neuron Production'''

* The human brain contains billions of neurons which are produced by mid-gestation; during fetal development <ref><pubmed>8361683</pubmed></ref>

* Processes of Neuronal production is initiated by first increasing the size of the Neural progenitor cell population within the body, these cells are mitotic in nature and are capable of forming new cells.

* Initially (from the end of gastrulation through to embryonic day 42), the neural progenitor cell population is increased greatly when the progenitor cells divide through 'symmetrical' mode of cell division. Multiple repeats of the cell division occurs throughout this period. This 'symmetrical' division method brings about the formation of 2 new identical neural progenitor cells

* Mode of cell division changes from a symmetrical cell division type to an 'asymmetrical' cell division from the beginning of E42. This asymmetrical cell division forms 2 different cell types; one Neural progenitor & one Neuron <ref><pubmed>12764028 </pubmed></ref>

* Newly formed Neural progenitor cells remains to undergo more processes of cell division whereas the newly formed neuron moves into position in the developing neocortex

'''Neuron Migration''' <ref name="PMID21042938"><pubmed>21042938</pubmed></ref>

Outlined above was a broad summary on neuron migration. Neuron migration in the cortex will be covered below in more detail.

* The ventricular zone (VZ) is where the majority of neurons migrate radially out and into the neocortex. The type of migration utilised here is referred to as somal translocation where the neuron cell body translocates out of the VZ and into the outer brain region with the nucleus moving across the cytoplasm and into the outer brain region.

* With increasing brain size, somal translocation is no longer efficient for neuronal migration out of VZ. Since greater distances are evident, radial glial guides are adopted to allow the migration of neurons to continue. Similar to somal translocation, these cell populations establish a scaffolding system where neurons can attach to (basal process occurs) and then move into the developing cortical plate. These cell populations are comprised of neural progenitor cells and are therefore able to support mass neuron migration.

* Another mode of transport utilised by neurons situated within a second zone of the ventral telencephalon is referred to as tangential migration. The neurons here migrate tangentially to the cortical mantle whilst adopting different signalling pathways (guidance molecules) as opposed to radial migration. As a result of neuronal migration, a 6-layered structure forms within the developing neocortex.

* Once completion of the pre-plate has occurred, two regions are formed and which are the subplate (SP) and th marginal zone (MZ).In between these two regions, the cortical plate arises as well. Earliest neuron arrival forms the deepest layer of the cortex; cortical layer 6. More superficial layers of the cortex will develop with continuous cell migration. It is important to note that a specific cell class is located within the MZ in which are the Cajal-Retzius cells (CR). CR's are important for correct neuron positioning within the cortical layers as well as having an inhibitory effect on neuron migration. Rheelin, a molecular signal produced by the CR's is important here as it stops neurons from migrating and signals them to up their corresponding positions.

'''Folding: sulcation and gyration'''

[[Image:Dev anat 01.jpg|frame|200x200px|Simplified external lateral (left) view of the brain growth]]

* During the fifth and sixth month of gestation, the smooth cortex begins to fold by sulcation and gyration. <ref name=PMID21571694><pubmed>21571694</pubmed></ref>

# Sulcation: This is the development of sulci, including primary and secondary. The formation of primary sulci involve the appearance of shallow grooves on the surface of the brain, which then become more deeply infolded, while the formation of secondary sulci is due to the development of side branches of the primary ones <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.
# Gyration: This is the development of gyrus that occurs during late during fetal development until the end of the pregnancy or after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>. This process is the formation of tertiary sulci, which is the formation of other side branches of the secondary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

{| class="wikitable"
|-
! Weeks of gestation !! Visible anatomical details
|-
| 20-21 || smooth, with the impression of "lissencephalic" brain; wide Sylvian fissures; visible interhemispheric fissure and parieto-occipital fissure
|-
| 22-23 || beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || smooth cerebral cortex surface; visible shallow grooves in the central sulci, interparietal sulci and superior temporal sulci; start of opercularization of Sylvian fissures; presence of calcarine fissures and cingular sulci
|-
| 26 || presence of central and collateral sulci
|-
| 27 || presence of marginal and precentral sulci
|-
| 28 || presence of postcentral and intraparietal sulci
|-
| 29 || presence of superior and inferior frontal sulci; narrower Sylvian fissure; clear corpus callosum; bright white matter; dark cortical ribbon
|-
| 30-31 || beginning of infolding of cortex which is first apparent in the occipital lobe; narrower ventricular system and subarachnoid spaces
|-
| 32 || presence of superior and inferior temporal sulci
|-
| 33 || presence of external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration; compactly and extensively folded cortex
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table of the process of sulcation and gyration <ref name=PMID20608424><pubmed>20608424</pubmed></ref>

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations <ref><pubmed>7472570</pubmed></ref>

|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.
{|
|-bgcolor="ECCEF5"
|

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.
|}

{|
|-bgcolor="CED8F6"
|The following recent studies use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

** Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

** The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

** The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.
|}

{|
|-bgcolor="CED8F6"
|
'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.
|}

{|
|-bgcolor="ECCEF5"
|
In the following studies new models and imaging techniques have been employed to gain a better understanding of the changes in brains of patients with schizophrenia

'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

Moreover, in the following study, a neuroimaging technique known as Proton Magnetic Resonance Spectroscopy (1H-MRS) is used to examine the brain of patients with schizophrenia.

'''Multimodal neuroimaging of frontal white matter microstructure in early phase schizophrenia: the impact of early adolescent cannabis use'''
<ref><pubmed> 3852698 </pubmed></ref>

[[Image:Online_placement_of_the_1H-MRS_volume_of_interest_.jpg|400x400px|frame|Proton magnetic resonance spectroscopy (1H-MRS) is used to examine the white matter tissue in brain of patients with schizophrenia. The image shows online placement of the 1H-MRS volume of interest.The 1H-MRS volume of interest is placed parallel to the AC-PC line (AC =anterior commissure, PC = posterior commissure). <ref><pubmed> 3852698 </pubmed></ref> ]]

* The neurochemical used in this technique is N-acetylaspartate (NAA), a free amino acid that has a peak resonance at 2.02 ppm on the spectral profile in the 1H-MRS of human brain.
* In vivo concentration levels of NAA are higher in white matter compared to gray matter.
* Post-mortem studies have demonstrated that NAA is produced in neurons, transported into white matter and broken down into aspartate and acetate in oligodendrocytes. <ref><pubmed>17275978</pubmed></ref> NAA catabolism is thus closely related to the metabolism of myelin, since it provides a crucial source of acetate which is necessary for the formation of myelin from lipid.
* Therefore due to abnormal myelin biosynthesis in schizophrenia, brain tissues can be examined by 1H-MRS studies as long as the targeted brain region involves a single tissue type (white matter) that provides the necessary information regarding the catabolic cycle of NAA.

|}

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]

Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.

* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period).

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation. <ref><pubmed>15806441</pubmed></ref>

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.<ref><pubmed>21215908</pubmed></ref>

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.<ref><pubmed>1400921</pubmed></ref>

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.<ref><pubmed>25283616</pubmed></ref>

===Fetal Alcohol Syndrome===

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status. <ref><pubmed> 24904907 </pubmed></ref>

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.<ref><pubmed> 23809349 </pubmed></ref>

{| class="wikitable"

−
|-

−
| [[File:Fetal alcohol syndrome.jpg|500px]] || [[File:Ethanol fetal neural.jpg|400px]]

−
|-

−
| The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref>|| A mechanism of the effect of ethanol on neural stem cells (NSCs). Ethanol promotes asymmetrical cell division, the formation of radial glial-like cells, leading to the premature depletion of the VZ and its NSCs, and the thickening and cell proliferation in SVZ. The increased migration during early differentiation of ethanol-treated NSCs also leads to the appearance of subpial heterotopias<ref name="PMID22623924"><pubmed>22623924</pubmed></ref>

|}

|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

* All degrees of iodine deficiency (mild: 50-99 μg/day, moderate: 20-49 μg/day and severe≤20 μg/day) affect thyroid function of both mother and the neonate as well as mental development of the child. The damage increases with the degree of deficiency; overt endemic cretinism is the most severe consequence.

* Iodine deficiency disorders refer to complications that arise when the recommended dietary allowance of iodine is not met. These complications include thyroid function abnormalities and when iodine deficiency is severe, endemic goitre and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality.

* Iodine deficiency represents the world’s greatest cause of preventable brain damage and mental retardation, resulting of a loss of 10-15 IQ points globally. Therefore it is essential that the recommended dietary requirement for iodine is met, especially during pregnancy and lactation (200–300 μg/day). <ref><pubmed>10750030</pubmed></ref>

* Clinical manifestations of hypothyroidism include: Myxedematous facies (condition characterized by thickening of the skin, blunting of the senses and intellect, and laboured speech), jaundice, a puffy face and a wide posterior fontanelle with open sutures. The nasal bridge is flat. The mouth may be slightly open revealing macroglossia. Further examination would reveal bradycardia and a protuberant abdomen with a large umbilical hernia. Neurologic examination findings include hypotonia with delayed reflexes. Skin may be cool to touch and mottled in appearance due to circulatory compromise.<ref><pubmed>2903524</pubmed></ref>

===Abnormalities associated with apoptosis and migration of cells in the fetal CNS===

* The migration of cells and cell death are critically important to fetal brain and CNS development. Abnormalities in each of these processes, programmed cell death (apoptosis) in particular, have been shown to result in severe developmental abnormalities in experimental animals. Apoptosis is critically important for appropriate brain development; certain areas in brain may experience up to 50% cell death. <ref><pubmed> 11589424 </pubmed></ref>

In an experiment conducted by kuida et. al 1996, it was observed that mice that were deficient for CPP32 (a protease responsible for apoptosis), were born at a lower frequency than expected, were smaller in size compared to the normal mice and died at an early age. Brain development is significantly affected in CPP32-deficient mice resulting in a variety of hyperplasia and disorganised cell development. <ref><pubmed>8934524</pubmed></ref>

On the other hand, disrupted neuronal migration can lead to an abnormality in cell position. When this happens, the neurons are said to be heterotopic. Abnormalities in neuronal migration have been studied extensively in human cerebral cortex where these defects are associated with a variety of syndromes and diseases, ranging from behavioural disorders (including some forms of schizophrenia, dyslexia and autism) to extremely severe mental retardation and failure to thrive. <ref><pubmed>10532616</pubmed></ref>

==References==

<references/>

2014 Group Project 7

2014-10-24T03:36:43Z

Z3418981: /* Iodine deficiency */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, recieving and integration of information from all parts of the body, serving as the processing center of the bodies nervous system. The CNS controls all bodily functions (sensory and motor), consisting of 2 main organs; The Brain and Spinal Cord.

The brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

The spinal cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into ascending bundles, which transmits sensory information from the body to the brain, and descending bundle, which transmits motor function information from the brain to the body.

Before fetal period, neurulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, including cellular processes and brain development will be discussed. Current research models and findings, and historic findings will be stated. The abnormalities associated to CNS during fetal period, and neural defects that occur during embryonic period and contribute in fetal development will be discussed.

==Development during fetal period==

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

[[File:Schematic_representation_of_the_timeline_of_human_neural_development.jpg|700px]]

A simplified timeline of human neural development (modified) <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

This simplified graph shows a timeline for major events of neural development that occur during fetal and postnatal periods. These events, which are summarized in the following table, are broadly classified by cell multiplication, cell migration, growth and differentiation and angiogenesis:

{| class="wikitable"
|-
! Major Events !! Descriptions
|-
| Cell multiplication ||
* Neurons are proliferated and generated from neural stem cells and progenitor cells (precursor cells) in a process known as neurogenesis in 2nd trimester.
* Cell death and Gliogenesis (glial cells (such as astrocytes) deriving from multipotent neural stem cells) occur in the 3rd trimester.
* Local gliogenesis continues postnatally.
|-
| Cell migration ||
* Neuronal migration is maximised during 2nd trimester while glial migration is maximised during 3rd trimester
|-
| Growth and differentiation ||
* Axonal and dendritic arborisation (fine branching structures at the end of nerve fibers) appear by the end of fetal period.
* Synaptogenesis (formation of synapses) and electrical activity is maximised in 3rd trimester (and continued postnatally).
* Cell death due to over-innervation can be observed in late fetal and postnatal period.
* Myelination occurs in late fetal and postnatal period (vast majority of postnatal growth in brain is due to myelination).
|-
| Angiogenesis ||
* Oxidative metabolism can be seen in late fetal period.
* Capillary networks develop postnatally.
|}

'''1. cell proliferation'''

[[Image:Somatosensory cortex of E20 rat.jpeg|frame|500x500px|Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) <ref name="PMID22272298"><pubmed>22272298</pubmed></ref>]]

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref name="PMID4203033"><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref name="PMID5414696"><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref name="PMID7204662"><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref name="PMID12764033"><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref name="PMID8523077"><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref name="PMID9712307"><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref name="PMID1713238"><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

'''2. cell migration'''
[[Image:CNS_passive.jpg|frame|200x150px|Passive cell displacement and outside-to-inside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]
[[Image:CNS_active.jpg|frame|350x250px|Active cell migration and inside-to-outside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways.

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus <ref name="PMID489804"><pubmed>489804</pubmed></ref>, hypothalamus <ref name="PMID5029133"><pubmed>5029133</pubmed></ref>, spinal cord <ref name="PMID4407392"><pubmed>4407392</pubmed></ref>, dentate gyrus of the hippocampal formation <ref name="PMID17533671"><pubmed>17533671</pubmed></ref> and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas <ref name="PMID17533671"><pubmed>17533671</pubmed></ref>.

{| style="width:20%; height:170px" align="center"
|-
| [[Image:Internurons migration in cerebral cortex.jpg|frame|200x400px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex <ref name="PMID17726524"><pubmed>17726524</pubmed></ref>]]
|}

'''3. cell differentiation'''<ref name="PMID10532616"><pubmed>10532616</pubmed></ref>

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

=== Brain Development ===

* The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells. By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

* The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

[[Image:Brain ventricles and ganglia development 03.jpg|frame|200x200px|Increase in size of of brain and ventricles <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]
[[Image:Brain fissure development 02.jpg|frame|200x200px|Increase in size of brain fissure <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]

* The gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding.

* The brain development begins rostral in GW8, proceeding caudally until it is complete at GW22 <ref><pubmed>560818</pubmed></ref>

* The formation of Secondary Sulci is between GW30-35, while the formation of of Tertiary Sulci begins during GW36 and into the postnatal period.

* Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

* Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

* The major fibre pathways make up the brain white matter

* AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Neuron Production'''

* The human brain contains billions of neurons which are produced by mid-gestation; during fetal development <ref><pubmed>8361683</pubmed></ref>

* Processes of Neuronal production is initiated by first increasing the size of the Neural progenitor cell population within the body, these cells are mitotic in nature and are capable of forming new cells.

* Initially (from the end of gastrulation through to embryonic day 42), the neural progenitor cell population is increased greatly when the progenitor cells divide through 'symmetrical' mode of cell division. Multiple repeats of the cell division occurs throughout this period. This 'symmetrical' division method brings about the formation of 2 new identical neural progenitor cells

* Mode of cell division changes from a symmetrical cell division type to an 'asymmetrical' cell division from the beginning of E42. This asymmetrical cell division forms 2 different cell types; one Neural progenitor & one Neuron <ref><pubmed>12764028 </pubmed></ref>

* Newly formed Neural progenitor cells remains to undergo more processes of cell division whereas the newly formed neuron moves into position in the developing neocortex

'''Neuron Migration''' <ref name="PMID21042938"><pubmed>21042938</pubmed></ref>

Outlined above was a broad summary on neuron migration. Neuron migration in the cortex will be covered below in more detail.

* The ventricular zone (VZ) is where the majority of neurons migrate radially out and into the neocortex. The type of migration utilised here is referred to as somal translocation where the neuron cell body translocates out of the VZ and into the outer brain region with the nucleus moving across the cytoplasm and into the outer brain region.

* With increasing brain size, somal translocation is no longer efficient for neuronal migration out of VZ. Since greater distances are evident, radial glial guides are adopted to allow the migration of neurons to continue. Similar to somal translocation, these cell populations establish a scaffolding system where neurons can attach to (basal process occurs) and then move into the developing cortical plate. These cell populations are comprised of neural progenitor cells and are therefore able to support mass neuron migration.

* Another mode of transport utilised by neurons situated within a second zone of the ventral telencephalon is referred to as tangential migration. The neurons here migrate tangentially to the cortical mantle whilst adopting different signalling pathways (guidance molecules) as opposed to radial migration. As a result of neuronal migration, a 6-layered structure forms within the developing neocortex.

* Once completion of the pre-plate has occurred, two regions are formed and which are the subplate (SP) and th marginal zone (MZ).In between these two regions, the cortical plate arises as well. Earliest neuron arrival forms the deepest layer of the cortex; cortical layer 6. More superficial layers of the cortex will develop with continuous cell migration. It is important to note that a specific cell class is located within the MZ in which are the Cajal-Retzius cells (CR). CR's are important for correct neuron positioning within the cortical layers as well as having an inhibitory effect on neuron migration. Rheelin, a molecular signal produced by the CR's is important here as it stops neurons from migrating and signals them to up their corresponding positions.

'''Folding: sulcation and gyration'''

[[Image:Dev anat 01.jpg|frame|200x200px|Simplified external lateral (left) view of the brain growth]]

* During the fifth and sixth month of gestation, the smooth cortex begins to fold by sulcation and gyration. <ref name=PMID21571694><pubmed>21571694</pubmed></ref>

# Sulcation: This is the development of sulci, including primary and secondary. The formation of primary sulci involve the appearance of shallow grooves on the surface of the brain, which then become more deeply infolded, while the formation of secondary sulci is due to the development of side branches of the primary ones <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.
# Gyration: This is the development of gyrus that occurs during late during fetal development until the end of the pregnancy or after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>. This process is the formation of tertiary sulci, which is the formation of other side branches of the secondary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

{| class="wikitable"
|-
! Weeks of gestation !! Visible anatomical details
|-
| 20-21 || smooth, with the impression of "lissencephalic" brain; wide Sylvian fissures; visible interhemispheric fissure and parieto-occipital fissure
|-
| 22-23 || beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || smooth cerebral cortex surface; visible shallow grooves in the central sulci, interparietal sulci and superior temporal sulci; start of opercularization of Sylvian fissures; presence of calcarine fissures and cingular sulci
|-
| 26 || presence of central and collateral sulci
|-
| 27 || presence of marginal and precentral sulci
|-
| 28 || presence of postcentral and intraparietal sulci
|-
| 29 || presence of superior and inferior frontal sulci; narrower Sylvian fissure; clear corpus callosum; bright white matter; dark cortical ribbon
|-
| 30-31 || beginning of infolding of cortex which is first apparent in the occipital lobe; narrower ventricular system and subarachnoid spaces
|-
| 32 || presence of superior and inferior temporal sulci
|-
| 33 || presence of external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration; compactly and extensively folded cortex
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table of the process of sulcation and gyration <ref name=PMID20608424><pubmed>20608424</pubmed></ref>

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations <ref><pubmed>7472570</pubmed></ref>

|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.
{|
|-bgcolor="ECCEF5"
|

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.
|}

{|
|-bgcolor="CED8F6"
|The following recent studies use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

** Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

** The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

** The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.
|}

{|
|-bgcolor="CED8F6"
|
'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.
|}

{|
|-bgcolor="ECCEF5"
|
In the following studies new models and imaging techniques have been employed to gain a better understanding of the changes in brains of patients with schizophrenia

'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

Moreover, in the following study, a neuroimaging technique known as Proton Magnetic Resonance Spectroscopy (1H-MRS) is used to examine the brain of patients with schizophrenia.

'''Multimodal neuroimaging of frontal white matter microstructure in early phase schizophrenia: the impact of early adolescent cannabis use'''
<ref><pubmed> 3852698 </pubmed></ref>

[[Image:Online_placement_of_the_1H-MRS_volume_of_interest_.jpg|400x400px|frame|Proton magnetic resonance spectroscopy (1H-MRS) is used to examine the white matter tissue in brain of patients with schizophrenia. The image shows online placement of the 1H-MRS volume of interest.The 1H-MRS volume of interest is placed parallel to the AC-PC line (AC =anterior commissure, PC = posterior commissure). <ref><pubmed> 3852698 </pubmed></ref> ]]

* The neurochemical used in this technique is N-acetylaspartate (NAA), a free amino acid that has a peak resonance at 2.02 ppm on the spectral profile in the 1H-MRS of human brain.
* In vivo concentration levels of NAA are higher in white matter compared to gray matter.
* Post-mortem studies have demonstrated that NAA is produced in neurons, transported into white matter and broken down into aspartate and acetate in oligodendrocytes. <ref><pubmed>17275978</pubmed></ref> NAA catabolism is thus closely related to the metabolism of myelin, since it provides a crucial source of acetate which is necessary for the formation of myelin from lipid.
* Therefore due to abnormal myelin biosynthesis in schizophrenia, brain tissues can be examined by 1H-MRS studies as long as the targeted brain region involves a single tissue type (white matter) that provides the necessary information regarding the catabolic cycle of NAA.

|}

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]

Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.

* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period).

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation. <ref><pubmed>15806441</pubmed></ref>

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.<ref><pubmed>21215908</pubmed></ref>

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.<ref><pubmed>1400921</pubmed></ref>

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.<ref><pubmed>25283616</pubmed></ref>

===Fetal Alcohol Syndrome===

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status. <ref><pubmed> 24904907 </pubmed></ref>

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.<ref><pubmed> 23809349 </pubmed></ref>

{| class="wikitable"

−
|-

−
| [[File:Fetal alcohol syndrome.jpg|500px]] || [[File:Ethanol fetal neural.jpg|400px]]

−
|-

−
| The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref>|| A mechanism of the effect of ethanol on neural stem cells (NSCs). Ethanol promotes asymmetrical cell division, the formation of radial glial-like cells, leading to the premature depletion of the VZ and its NSCs, and the thickening and cell proliferation in SVZ. The increased migration during early differentiation of ethanol-treated NSCs also leads to the appearance of subpial heterotopias<ref name="PMID22623924"><pubmed>22623924</pubmed></ref>

|}

|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

* All degrees of iodine deficiency (mild: 50-99 μg/day, moderate: 20-49 μg/day and severe≤20 μg/day) affect thyroid function of both mother and the neonate as well as mental development of the child. The damage increases with the degree of deficiency; overt endemic cretinism is the most severe consequence.

* Iodine deficiency disorders refer to complications that arise when the recommended dietary allowance of iodine is not met. These complications include thyroid function abnormalities and when iodine deficiency is severe, endemic goitre and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality.

* Iodine deficiency represents the world’s greatest cause of preventable brain damage and mental retardation, resulting of a loss of 10-15 IQ points globally. Therefore it is essential that the recommended dietary requirement for iodine is met, especially during pregnancy and lactation (200–300 μg/day). <ref><pubmed>10750030</pubmed></ref>

* Clinical manifestations of hypothyroidism include: Myxedematous facies (condition characterized by thickening of the skin, blunting of the senses and intellect, and laboured speech), jaundice, a puffy face and a wide posterior fontanelle with open sutures. The nasal bridge is flat. The mouth may be slightly open revealing macroglossia. Further examination would reveal bradycardia and a protuberant abdomen with a large umbilical hernia. Neurologic examination findings include hypotonia with delayed reflexes. Skin may be cool to touch and mottled in appearance due to circulatory compromise.<ref><pubmed>2903524</pubmed></ref>

==References==

<references/>

2014 Group Project 7

2014-10-24T03:33:48Z

Z3418981: /* Fetal Alcohol Syndrome */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, recieving and integration of information from all parts of the body, serving as the processing center of the bodies nervous system. The CNS controls all bodily functions (sensory and motor), consisting of 2 main organs; The Brain and Spinal Cord.

The brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

The spinal cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into ascending bundles, which transmits sensory information from the body to the brain, and descending bundle, which transmits motor function information from the brain to the body.

Before fetal period, neurulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, including cellular processes and brain development will be discussed. Current research models and findings, and historic findings will be stated. The abnormalities associated to CNS during fetal period, and neural defects that occur during embryonic period and contribute in fetal development will be discussed.

==Development during fetal period==

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

[[File:Schematic_representation_of_the_timeline_of_human_neural_development.jpg|700px]]

A simplified timeline of human neural development (modified) <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

This simplified graph shows a timeline for major events of neural development that occur during fetal and postnatal periods. These events, which are summarized in the following table, are broadly classified by cell multiplication, cell migration, growth and differentiation and angiogenesis:

{| class="wikitable"
|-
! Major Events !! Descriptions
|-
| Cell multiplication ||
* Neurons are proliferated and generated from neural stem cells and progenitor cells (precursor cells) in a process known as neurogenesis in 2nd trimester.
* Cell death and Gliogenesis (glial cells (such as astrocytes) deriving from multipotent neural stem cells) occur in the 3rd trimester.
* Local gliogenesis continues postnatally.
|-
| Cell migration ||
* Neuronal migration is maximised during 2nd trimester while glial migration is maximised during 3rd trimester
|-
| Growth and differentiation ||
* Axonal and dendritic arborisation (fine branching structures at the end of nerve fibers) appear by the end of fetal period.
* Synaptogenesis (formation of synapses) and electrical activity is maximised in 3rd trimester (and continued postnatally).
* Cell death due to over-innervation can be observed in late fetal and postnatal period.
* Myelination occurs in late fetal and postnatal period (vast majority of postnatal growth in brain is due to myelination).
|-
| Angiogenesis ||
* Oxidative metabolism can be seen in late fetal period.
* Capillary networks develop postnatally.
|}

'''1. cell proliferation'''

[[Image:Somatosensory cortex of E20 rat.jpeg|frame|500x500px|Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) <ref name="PMID22272298"><pubmed>22272298</pubmed></ref>]]

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref name="PMID4203033"><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref name="PMID5414696"><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref name="PMID7204662"><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref name="PMID12764033"><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref name="PMID8523077"><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref name="PMID9712307"><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref name="PMID1713238"><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

'''2. cell migration'''
[[Image:CNS_passive.jpg|frame|200x150px|Passive cell displacement and outside-to-inside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]
[[Image:CNS_active.jpg|frame|350x250px|Active cell migration and inside-to-outside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways.

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus <ref name="PMID489804"><pubmed>489804</pubmed></ref>, hypothalamus <ref name="PMID5029133"><pubmed>5029133</pubmed></ref>, spinal cord <ref name="PMID4407392"><pubmed>4407392</pubmed></ref>, dentate gyrus of the hippocampal formation <ref name="PMID17533671"><pubmed>17533671</pubmed></ref> and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas <ref name="PMID17533671"><pubmed>17533671</pubmed></ref>.

{| style="width:20%; height:170px" align="center"
|-
| [[Image:Internurons migration in cerebral cortex.jpg|frame|200x400px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex <ref name="PMID17726524"><pubmed>17726524</pubmed></ref>]]
|}

'''3. cell differentiation'''<ref name="PMID10532616"><pubmed>10532616</pubmed></ref>

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

=== Brain Development ===

* The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells. By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

* The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

[[Image:Brain ventricles and ganglia development 03.jpg|frame|200x200px|Increase in size of of brain and ventricles <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]
[[Image:Brain fissure development 02.jpg|frame|200x200px|Increase in size of brain fissure <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]

* The gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding.

* The brain development begins rostral in GW8, proceeding caudally until it is complete at GW22 <ref><pubmed>560818</pubmed></ref>

* The formation of Secondary Sulci is between GW30-35, while the formation of of Tertiary Sulci begins during GW36 and into the postnatal period.

* Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

* Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

* The major fibre pathways make up the brain white matter

* AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Neuron Production'''

* The human brain contains billions of neurons which are produced by mid-gestation; during fetal development <ref><pubmed>8361683</pubmed></ref>

* Processes of Neuronal production is initiated by first increasing the size of the Neural progenitor cell population within the body, these cells are mitotic in nature and are capable of forming new cells.

* Initially (from the end of gastrulation through to embryonic day 42), the neural progenitor cell population is increased greatly when the progenitor cells divide through 'symmetrical' mode of cell division. Multiple repeats of the cell division occurs throughout this period. This 'symmetrical' division method brings about the formation of 2 new identical neural progenitor cells

* Mode of cell division changes from a symmetrical cell division type to an 'asymmetrical' cell division from the beginning of E42. This asymmetrical cell division forms 2 different cell types; one Neural progenitor & one Neuron <ref><pubmed>12764028 </pubmed></ref>

* Newly formed Neural progenitor cells remains to undergo more processes of cell division whereas the newly formed neuron moves into position in the developing neocortex

'''Neuron Migration''' <ref name="PMID21042938"><pubmed>21042938</pubmed></ref>

Outlined above was a broad summary on neuron migration. Neuron migration in the cortex will be covered below in more detail.

* The ventricular zone (VZ) is where the majority of neurons migrate radially out and into the neocortex. The type of migration utilised here is referred to as somal translocation where the neuron cell body translocates out of the VZ and into the outer brain region with the nucleus moving across the cytoplasm and into the outer brain region.

* With increasing brain size, somal translocation is no longer efficient for neuronal migration out of VZ. Since greater distances are evident, radial glial guides are adopted to allow the migration of neurons to continue. Similar to somal translocation, these cell populations establish a scaffolding system where neurons can attach to (basal process occurs) and then move into the developing cortical plate. These cell populations are comprised of neural progenitor cells and are therefore able to support mass neuron migration.

* Another mode of transport utilised by neurons situated within a second zone of the ventral telencephalon is referred to as tangential migration. The neurons here migrate tangentially to the cortical mantle whilst adopting different signalling pathways (guidance molecules) as opposed to radial migration. As a result of neuronal migration, a 6-layered structure forms within the developing neocortex.

* Once completion of the pre-plate has occurred, two regions are formed and which are the subplate (SP) and th marginal zone (MZ).In between these two regions, the cortical plate arises as well. Earliest neuron arrival forms the deepest layer of the cortex; cortical layer 6. More superficial layers of the cortex will develop with continuous cell migration. It is important to note that a specific cell class is located within the MZ in which are the Cajal-Retzius cells (CR). CR's are important for correct neuron positioning within the cortical layers as well as having an inhibitory effect on neuron migration. Rheelin, a molecular signal produced by the CR's is important here as it stops neurons from migrating and signals them to up their corresponding positions.

'''Folding: sulcation and gyration'''

[[Image:Dev anat 01.jpg|frame|200x200px|Simplified external lateral (left) view of the brain growth]]

* During the fifth and sixth month of gestation, the smooth cortex begins to fold by sulcation and gyration. <ref name=PMID21571694><pubmed>21571694</pubmed></ref>

# Sulcation: This is the development of sulci, including primary and secondary. The formation of primary sulci involve the appearance of shallow grooves on the surface of the brain, which then become more deeply infolded, while the formation of secondary sulci is due to the development of side branches of the primary ones <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.
# Gyration: This is the development of gyrus that occurs during late during fetal development until the end of the pregnancy or after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>. This process is the formation of tertiary sulci, which is the formation of other side branches of the secondary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

{| class="wikitable"
|-
! Weeks of gestation !! Visible anatomical details
|-
| 20-21 || smooth, with the impression of "lissencephalic" brain; wide Sylvian fissures; visible interhemispheric fissure and parieto-occipital fissure
|-
| 22-23 || beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || smooth cerebral cortex surface; visible shallow grooves in the central sulci, interparietal sulci and superior temporal sulci; start of opercularization of Sylvian fissures; presence of calcarine fissures and cingular sulci
|-
| 26 || presence of central and collateral sulci
|-
| 27 || presence of marginal and precentral sulci
|-
| 28 || presence of postcentral and intraparietal sulci
|-
| 29 || presence of superior and inferior frontal sulci; narrower Sylvian fissure; clear corpus callosum; bright white matter; dark cortical ribbon
|-
| 30-31 || beginning of infolding of cortex which is first apparent in the occipital lobe; narrower ventricular system and subarachnoid spaces
|-
| 32 || presence of superior and inferior temporal sulci
|-
| 33 || presence of external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration; compactly and extensively folded cortex
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table of the process of sulcation and gyration <ref name=PMID20608424><pubmed>20608424</pubmed></ref>

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations <ref><pubmed>7472570</pubmed></ref>

|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.
{|
|-bgcolor="ECCEF5"
|

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.
|}

{|
|-bgcolor="CED8F6"
|The following recent studies use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

** Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

** The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

** The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.
|}

{|
|-bgcolor="CED8F6"
|
'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.
|}

{|
|-bgcolor="ECCEF5"
|
In the following studies new models and imaging techniques have been employed to gain a better understanding of the changes in brains of patients with schizophrenia

'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

Moreover, in the following study, a neuroimaging technique known as Proton Magnetic Resonance Spectroscopy (1H-MRS) is used to examine the brain of patients with schizophrenia.

'''Multimodal neuroimaging of frontal white matter microstructure in early phase schizophrenia: the impact of early adolescent cannabis use'''
<ref><pubmed> 3852698 </pubmed></ref>

[[Image:Online_placement_of_the_1H-MRS_volume_of_interest_.jpg|400x400px|frame|Proton magnetic resonance spectroscopy (1H-MRS) is used to examine the white matter tissue in brain of patients with schizophrenia. The image shows online placement of the 1H-MRS volume of interest.The 1H-MRS volume of interest is placed parallel to the AC-PC line (AC =anterior commissure, PC = posterior commissure). <ref><pubmed> 3852698 </pubmed></ref> ]]

* The neurochemical used in this technique is N-acetylaspartate (NAA), a free amino acid that has a peak resonance at 2.02 ppm on the spectral profile in the 1H-MRS of human brain.
* In vivo concentration levels of NAA are higher in white matter compared to gray matter.
* Post-mortem studies have demonstrated that NAA is produced in neurons, transported into white matter and broken down into aspartate and acetate in oligodendrocytes. <ref><pubmed>17275978</pubmed></ref> NAA catabolism is thus closely related to the metabolism of myelin, since it provides a crucial source of acetate which is necessary for the formation of myelin from lipid.
* Therefore due to abnormal myelin biosynthesis in schizophrenia, brain tissues can be examined by 1H-MRS studies as long as the targeted brain region involves a single tissue type (white matter) that provides the necessary information regarding the catabolic cycle of NAA.

|}

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]

Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.

* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period).

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation. <ref><pubmed>15806441</pubmed></ref>

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.<ref><pubmed>21215908</pubmed></ref>

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.<ref><pubmed>1400921</pubmed></ref>

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.<ref><pubmed>25283616</pubmed></ref>

===Fetal Alcohol Syndrome===

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status. <ref><pubmed> 24904907 </pubmed></ref>

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.<ref><pubmed> 23809349 </pubmed></ref>

{| class="wikitable"

−
|-

−
| [[File:Fetal alcohol syndrome.jpg|500px]] || [[File:Ethanol fetal neural.jpg|400px]]

−
|-

−
| The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref>|| A mechanism of the effect of ethanol on neural stem cells (NSCs). Ethanol promotes asymmetrical cell division, the formation of radial glial-like cells, leading to the premature depletion of the VZ and its NSCs, and the thickening and cell proliferation in SVZ. The increased migration during early differentiation of ethanol-treated NSCs also leads to the appearance of subpial heterotopias<ref name="PMID22623924"><pubmed>22623924</pubmed></ref>

|}

|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

==References==

<references/>

2014 Group Project 7

2014-10-24T03:29:30Z

Z3418981: /* Fetal Alcohol Syndrome */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, recieving and integration of information from all parts of the body, serving as the processing center of the bodies nervous system. The CNS controls all bodily functions (sensory and motor), consisting of 2 main organs; The Brain and Spinal Cord.

The brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

The spinal cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into ascending bundles, which transmits sensory information from the body to the brain, and descending bundle, which transmits motor function information from the brain to the body.

Before fetal period, neurulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, including cellular processes and brain development will be discussed. Current research models and findings, and historic findings will be stated. The abnormalities associated to CNS during fetal period, and neural defects that occur during embryonic period and contribute in fetal development will be discussed.

==Development during fetal period==

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

[[File:Schematic_representation_of_the_timeline_of_human_neural_development.jpg|700px]]

A simplified timeline of human neural development (modified) <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

This simplified graph shows a timeline for major events of neural development that occur during fetal and postnatal periods. These events, which are summarized in the following table, are broadly classified by cell multiplication, cell migration, growth and differentiation and angiogenesis:

{| class="wikitable"
|-
! Major Events !! Descriptions
|-
| Cell multiplication ||
* Neurons are proliferated and generated from neural stem cells and progenitor cells (precursor cells) in a process known as neurogenesis in 2nd trimester.
* Cell death and Gliogenesis (glial cells (such as astrocytes) deriving from multipotent neural stem cells) occur in the 3rd trimester.
* Local gliogenesis continues postnatally.
|-
| Cell migration ||
* Neuronal migration is maximised during 2nd trimester while glial migration is maximised during 3rd trimester
|-
| Growth and differentiation ||
* Axonal and dendritic arborisation (fine branching structures at the end of nerve fibers) appear by the end of fetal period.
* Synaptogenesis (formation of synapses) and electrical activity is maximised in 3rd trimester (and continued postnatally).
* Cell death due to over-innervation can be observed in late fetal and postnatal period.
* Myelination occurs in late fetal and postnatal period (vast majority of postnatal growth in brain is due to myelination).
|-
| Angiogenesis ||
* Oxidative metabolism can be seen in late fetal period.
* Capillary networks develop postnatally.
|}

'''1. cell proliferation'''

[[Image:Somatosensory cortex of E20 rat.jpeg|frame|500x500px|Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) <ref name="PMID22272298"><pubmed>22272298</pubmed></ref>]]

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref name="PMID4203033"><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref name="PMID5414696"><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref name="PMID7204662"><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref name="PMID12764033"><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref name="PMID8523077"><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref name="PMID9712307"><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref name="PMID1713238"><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

'''2. cell migration'''
[[Image:CNS_passive.jpg|frame|200x150px|Passive cell displacement and outside-to-inside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]
[[Image:CNS_active.jpg|frame|350x250px|Active cell migration and inside-to-outside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways.

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus <ref name="PMID489804"><pubmed>489804</pubmed></ref>, hypothalamus <ref name="PMID5029133"><pubmed>5029133</pubmed></ref>, spinal cord <ref name="PMID4407392"><pubmed>4407392</pubmed></ref>, dentate gyrus of the hippocampal formation <ref name="PMID17533671"><pubmed>17533671</pubmed></ref> and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas <ref name="PMID17533671"><pubmed>17533671</pubmed></ref>.

{| style="width:20%; height:170px" align="center"
|-
| [[Image:Internurons migration in cerebral cortex.jpg|frame|200x400px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex <ref name="PMID17726524"><pubmed>17726524</pubmed></ref>]]
|}

'''3. cell differentiation'''<ref name="PMID10532616"><pubmed>10532616</pubmed></ref>

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

=== Brain Development ===

* The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells. By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

* The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

[[Image:Brain ventricles and ganglia development 03.jpg|frame|200x200px|Increase in size of of brain and ventricles <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]
[[Image:Brain fissure development 02.jpg|frame|200x200px|Increase in size of brain fissure <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]

* The gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding.

* The brain development begins rostral in GW8, proceeding caudally until it is complete at GW22 <ref><pubmed>560818</pubmed></ref>

* The formation of Secondary Sulci is between GW30-35, while the formation of of Tertiary Sulci begins during GW36 and into the postnatal period.

* Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

* Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

* The major fibre pathways make up the brain white matter

* AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Neuron Production'''

* The human brain contains billions of neurons which are produced by mid-gestation; during fetal development <ref><pubmed>8361683</pubmed></ref>

* Processes of Neuronal production is initiated by first increasing the size of the Neural progenitor cell population within the body, these cells are mitotic in nature and are capable of forming new cells.

* Initially (from the end of gastrulation through to embryonic day 42), the neural progenitor cell population is increased greatly when the progenitor cells divide through 'symmetrical' mode of cell division. Multiple repeats of the cell division occurs throughout this period. This 'symmetrical' division method brings about the formation of 2 new identical neural progenitor cells

* Mode of cell division changes from a symmetrical cell division type to an 'asymmetrical' cell division from the beginning of E42. This asymmetrical cell division forms 2 different cell types; one Neural progenitor & one Neuron <ref><pubmed>12764028 </pubmed></ref>

* Newly formed Neural progenitor cells remains to undergo more processes of cell division whereas the newly formed neuron moves into position in the developing neocortex

'''Neuron Migration''' <ref name="PMID21042938"><pubmed>21042938</pubmed></ref>

Outlined above was a broad summary on neuron migration. Neuron migration in the cortex will be covered below in more detail.

* The ventricular zone (VZ) is where the majority of neurons migrate radially out and into the neocortex. The type of migration utilised here is referred to as somal translocation where the neuron cell body translocates out of the VZ and into the outer brain region with the nucleus moving across the cytoplasm and into the outer brain region.

* With increasing brain size, somal translocation is no longer efficient for neuronal migration out of VZ. Since greater distances are evident, radial glial guides are adopted to allow the migration of neurons to continue. Similar to somal translocation, these cell populations establish a scaffolding system where neurons can attach to (basal process occurs) and then move into the developing cortical plate. These cell populations are comprised of neural progenitor cells and are therefore able to support mass neuron migration.

* Another mode of transport utilised by neurons situated within a second zone of the ventral telencephalon is referred to as tangential migration. The neurons here migrate tangentially to the cortical mantle whilst adopting different signalling pathways (guidance molecules) as opposed to radial migration. As a result of neuronal migration, a 6-layered structure forms within the developing neocortex.

* Once completion of the pre-plate has occurred, two regions are formed and which are the subplate (SP) and th marginal zone (MZ).In between these two regions, the cortical plate arises as well. Earliest neuron arrival forms the deepest layer of the cortex; cortical layer 6. More superficial layers of the cortex will develop with continuous cell migration. It is important to note that a specific cell class is located within the MZ in which are the Cajal-Retzius cells (CR). CR's are important for correct neuron positioning within the cortical layers as well as having an inhibitory effect on neuron migration. Rheelin, a molecular signal produced by the CR's is important here as it stops neurons from migrating and signals them to up their corresponding positions.

'''Folding: sulcation and gyration'''

[[Image:Dev anat 01.jpg|frame|200x200px|Simplified external lateral (left) view of the brain growth]]

* During the fifth and sixth month of gestation, the smooth cortex begins to fold by sulcation and gyration. <ref name=PMID21571694><pubmed>21571694</pubmed></ref>

# Sulcation: This is the development of sulci, including primary and secondary. The formation of primary sulci involve the appearance of shallow grooves on the surface of the brain, which then become more deeply infolded, while the formation of secondary sulci is due to the development of side branches of the primary ones <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.
# Gyration: This is the development of gyrus that occurs during late during fetal development until the end of the pregnancy or after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>. This process is the formation of tertiary sulci, which is the formation of other side branches of the secondary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

{| class="wikitable"
|-
! Weeks of gestation !! Visible anatomical details
|-
| 20-21 || smooth, with the impression of "lissencephalic" brain; wide Sylvian fissures; visible interhemispheric fissure and parieto-occipital fissure
|-
| 22-23 || beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || smooth cerebral cortex surface; visible shallow grooves in the central sulci, interparietal sulci and superior temporal sulci; start of opercularization of Sylvian fissures; presence of calcarine fissures and cingular sulci
|-
| 26 || presence of central and collateral sulci
|-
| 27 || presence of marginal and precentral sulci
|-
| 28 || presence of postcentral and intraparietal sulci
|-
| 29 || presence of superior and inferior frontal sulci; narrower Sylvian fissure; clear corpus callosum; bright white matter; dark cortical ribbon
|-
| 30-31 || beginning of infolding of cortex which is first apparent in the occipital lobe; narrower ventricular system and subarachnoid spaces
|-
| 32 || presence of superior and inferior temporal sulci
|-
| 33 || presence of external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration; compactly and extensively folded cortex
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table of the process of sulcation and gyration <ref name=PMID20608424><pubmed>20608424</pubmed></ref>

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations <ref><pubmed>7472570</pubmed></ref>

|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.
{|
|-bgcolor="ECCEF5"
|

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.
|}

{|
|-bgcolor="CED8F6"
|The following recent studies use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

** Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

** The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

** The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.
|}

{|
|-bgcolor="CED8F6"
|
'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.
|}

{|
|-bgcolor="ECCEF5"
|
In the following studies new models and imaging techniques have been employed to gain a better understanding of the changes in brains of patients with schizophrenia

'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

Moreover, in the following study, a neuroimaging technique known as Proton Magnetic Resonance Spectroscopy (1H-MRS) is used to examine the brain of patients with schizophrenia.

'''Multimodal neuroimaging of frontal white matter microstructure in early phase schizophrenia: the impact of early adolescent cannabis use'''
<ref><pubmed> 3852698 </pubmed></ref>

[[Image:Online_placement_of_the_1H-MRS_volume_of_interest_.jpg|400x400px|frame|Proton magnetic resonance spectroscopy (1H-MRS) is used to examine the white matter tissue in brain of patients with schizophrenia. The image shows online placement of the 1H-MRS volume of interest.The 1H-MRS volume of interest is placed parallel to the AC-PC line (AC =anterior commissure, PC = posterior commissure). <ref><pubmed> 3852698 </pubmed></ref> ]]

* The neurochemical used in this technique is N-acetylaspartate (NAA), a free amino acid that has a peak resonance at 2.02 ppm on the spectral profile in the 1H-MRS of human brain.
* In vivo concentration levels of NAA are higher in white matter compared to gray matter.
* Post-mortem studies have demonstrated that NAA is produced in neurons, transported into white matter and broken down into aspartate and acetate in oligodendrocytes. <ref><pubmed>17275978</pubmed></ref> NAA catabolism is thus closely related to the metabolism of myelin, since it provides a crucial source of acetate which is necessary for the formation of myelin from lipid.
* Therefore due to abnormal myelin biosynthesis in schizophrenia, brain tissues can be examined by 1H-MRS studies as long as the targeted brain region involves a single tissue type (white matter) that provides the necessary information regarding the catabolic cycle of NAA.

|}

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]

Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.

* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period).

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation. <ref><pubmed>15806441</pubmed></ref>

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.<ref><pubmed>21215908</pubmed></ref>

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.<ref><pubmed>1400921</pubmed></ref>

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.<ref><pubmed>25283616</pubmed></ref>

===Fetal Alcohol Syndrome===

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status. <ref><pubmed> 24904907 </pubmed></ref>

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.<ref><pubmed> 23809349 </pubmed></ref>

{| class="wikitable"

−
|-

−
| [[File:Fetal alcohol syndrome.jpg|500px]] || [[File:Ethanol fetal neural.jpg|400px]]

−
|-

−
| The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref>|| A mechanism of the effect of ethanol on neural stem cells (NSCs). Ethanol promotes asymmetrical cell division, the formation of radial glial-like cells, leading to the premature depletion of the VZ and its NSCs, and the thickening and cell proliferation in SVZ. The increased migration during early differentiation of ethanol-treated NSCs also leads to the appearance of subpial heterotopias<ref name="PMID22623924"><pubmed>22623924</pubmed></ref>

|}

|}

==References==

<references/>

2014 Group Project 7

2014-10-24T03:27:12Z

Z3418981: /* Fetal Alcohol Syndrome */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, recieving and integration of information from all parts of the body, serving as the processing center of the bodies nervous system. The CNS controls all bodily functions (sensory and motor), consisting of 2 main organs; The Brain and Spinal Cord.

The brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

The spinal cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into ascending bundles, which transmits sensory information from the body to the brain, and descending bundle, which transmits motor function information from the brain to the body.

Before fetal period, neurulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, including cellular processes and brain development will be discussed. Current research models and findings, and historic findings will be stated. The abnormalities associated to CNS during fetal period, and neural defects that occur during embryonic period and contribute in fetal development will be discussed.

==Development during fetal period==

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

[[File:Schematic_representation_of_the_timeline_of_human_neural_development.jpg|700px]]

A simplified timeline of human neural development (modified) <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

This simplified graph shows a timeline for major events of neural development that occur during fetal and postnatal periods. These events, which are summarized in the following table, are broadly classified by cell multiplication, cell migration, growth and differentiation and angiogenesis:

{| class="wikitable"
|-
! Major Events !! Descriptions
|-
| Cell multiplication ||
* Neurons are proliferated and generated from neural stem cells and progenitor cells (precursor cells) in a process known as neurogenesis in 2nd trimester.
* Cell death and Gliogenesis (glial cells (such as astrocytes) deriving from multipotent neural stem cells) occur in the 3rd trimester.
* Local gliogenesis continues postnatally.
|-
| Cell migration ||
* Neuronal migration is maximised during 2nd trimester while glial migration is maximised during 3rd trimester
|-
| Growth and differentiation ||
* Axonal and dendritic arborisation (fine branching structures at the end of nerve fibers) appear by the end of fetal period.
* Synaptogenesis (formation of synapses) and electrical activity is maximised in 3rd trimester (and continued postnatally).
* Cell death due to over-innervation can be observed in late fetal and postnatal period.
* Myelination occurs in late fetal and postnatal period (vast majority of postnatal growth in brain is due to myelination).
|-
| Angiogenesis ||
* Oxidative metabolism can be seen in late fetal period.
* Capillary networks develop postnatally.
|}

'''1. cell proliferation'''

[[Image:Somatosensory cortex of E20 rat.jpeg|frame|500x500px|Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) <ref name="PMID22272298"><pubmed>22272298</pubmed></ref>]]

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref name="PMID4203033"><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref name="PMID5414696"><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref name="PMID7204662"><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref name="PMID12764033"><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref name="PMID8523077"><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref name="PMID9712307"><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref name="PMID1713238"><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

'''2. cell migration'''
[[Image:CNS_passive.jpg|frame|200x150px|Passive cell displacement and outside-to-inside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]
[[Image:CNS_active.jpg|frame|350x250px|Active cell migration and inside-to-outside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways.

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus <ref name="PMID489804"><pubmed>489804</pubmed></ref>, hypothalamus <ref name="PMID5029133"><pubmed>5029133</pubmed></ref>, spinal cord <ref name="PMID4407392"><pubmed>4407392</pubmed></ref>, dentate gyrus of the hippocampal formation <ref name="PMID17533671"><pubmed>17533671</pubmed></ref> and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas <ref name="PMID17533671"><pubmed>17533671</pubmed></ref>.

{| style="width:20%; height:170px" align="center"
|-
| [[Image:Internurons migration in cerebral cortex.jpg|frame|200x400px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex <ref name="PMID17726524"><pubmed>17726524</pubmed></ref>]]
|}

'''3. cell differentiation'''<ref name="PMID10532616"><pubmed>10532616</pubmed></ref>

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

=== Brain Development ===

* The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells. By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

* The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

[[Image:Brain ventricles and ganglia development 03.jpg|frame|200x200px|Increase in size of of brain and ventricles <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]
[[Image:Brain fissure development 02.jpg|frame|200x200px|Increase in size of brain fissure <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]

* The gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding.

* The brain development begins rostral in GW8, proceeding caudally until it is complete at GW22 <ref><pubmed>560818</pubmed></ref>

* The formation of Secondary Sulci is between GW30-35, while the formation of of Tertiary Sulci begins during GW36 and into the postnatal period.

* Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

* Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

* The major fibre pathways make up the brain white matter

* AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Neuron Production'''

* The human brain contains billions of neurons which are produced by mid-gestation; during fetal development <ref><pubmed>8361683</pubmed></ref>

* Processes of Neuronal production is initiated by first increasing the size of the Neural progenitor cell population within the body, these cells are mitotic in nature and are capable of forming new cells.

* Initially (from the end of gastrulation through to embryonic day 42), the neural progenitor cell population is increased greatly when the progenitor cells divide through 'symmetrical' mode of cell division. Multiple repeats of the cell division occurs throughout this period. This 'symmetrical' division method brings about the formation of 2 new identical neural progenitor cells

* Mode of cell division changes from a symmetrical cell division type to an 'asymmetrical' cell division from the beginning of E42. This asymmetrical cell division forms 2 different cell types; one Neural progenitor & one Neuron <ref><pubmed>12764028 </pubmed></ref>

* Newly formed Neural progenitor cells remains to undergo more processes of cell division whereas the newly formed neuron moves into position in the developing neocortex

'''Neuron Migration''' <ref name="PMID21042938"><pubmed>21042938</pubmed></ref>

Outlined above was a broad summary on neuron migration. Neuron migration in the cortex will be covered below in more detail.

* The ventricular zone (VZ) is where the majority of neurons migrate radially out and into the neocortex. The type of migration utilised here is referred to as somal translocation where the neuron cell body translocates out of the VZ and into the outer brain region with the nucleus moving across the cytoplasm and into the outer brain region.

* With increasing brain size, somal translocation is no longer efficient for neuronal migration out of VZ. Since greater distances are evident, radial glial guides are adopted to allow the migration of neurons to continue. Similar to somal translocation, these cell populations establish a scaffolding system where neurons can attach to (basal process occurs) and then move into the developing cortical plate. These cell populations are comprised of neural progenitor cells and are therefore able to support mass neuron migration.

* Another mode of transport utilised by neurons situated within a second zone of the ventral telencephalon is referred to as tangential migration. The neurons here migrate tangentially to the cortical mantle whilst adopting different signalling pathways (guidance molecules) as opposed to radial migration. As a result of neuronal migration, a 6-layered structure forms within the developing neocortex.

* Once completion of the pre-plate has occurred, two regions are formed and which are the subplate (SP) and th marginal zone (MZ).In between these two regions, the cortical plate arises as well. Earliest neuron arrival forms the deepest layer of the cortex; cortical layer 6. More superficial layers of the cortex will develop with continuous cell migration. It is important to note that a specific cell class is located within the MZ in which are the Cajal-Retzius cells (CR). CR's are important for correct neuron positioning within the cortical layers as well as having an inhibitory effect on neuron migration. Rheelin, a molecular signal produced by the CR's is important here as it stops neurons from migrating and signals them to up their corresponding positions.

'''Folding: sulcation and gyration'''

[[Image:Dev anat 01.jpg|frame|200x200px|Simplified external lateral (left) view of the brain growth]]

* During the fifth and sixth month of gestation, the smooth cortex begins to fold by sulcation and gyration. <ref name=PMID21571694><pubmed>21571694</pubmed></ref>

# Sulcation: This is the development of sulci, including primary and secondary. The formation of primary sulci involve the appearance of shallow grooves on the surface of the brain, which then become more deeply infolded, while the formation of secondary sulci is due to the development of side branches of the primary ones <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.
# Gyration: This is the development of gyrus that occurs during late during fetal development until the end of the pregnancy or after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>. This process is the formation of tertiary sulci, which is the formation of other side branches of the secondary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

{| class="wikitable"
|-
! Weeks of gestation !! Visible anatomical details
|-
| 20-21 || smooth, with the impression of "lissencephalic" brain; wide Sylvian fissures; visible interhemispheric fissure and parieto-occipital fissure
|-
| 22-23 || beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || smooth cerebral cortex surface; visible shallow grooves in the central sulci, interparietal sulci and superior temporal sulci; start of opercularization of Sylvian fissures; presence of calcarine fissures and cingular sulci
|-
| 26 || presence of central and collateral sulci
|-
| 27 || presence of marginal and precentral sulci
|-
| 28 || presence of postcentral and intraparietal sulci
|-
| 29 || presence of superior and inferior frontal sulci; narrower Sylvian fissure; clear corpus callosum; bright white matter; dark cortical ribbon
|-
| 30-31 || beginning of infolding of cortex which is first apparent in the occipital lobe; narrower ventricular system and subarachnoid spaces
|-
| 32 || presence of superior and inferior temporal sulci
|-
| 33 || presence of external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration; compactly and extensively folded cortex
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table of the process of sulcation and gyration <ref name=PMID20608424><pubmed>20608424</pubmed></ref>

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations <ref><pubmed>7472570</pubmed></ref>

|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.
{|
|-bgcolor="ECCEF5"
|

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.
|}

{|
|-bgcolor="CED8F6"
|The following recent studies use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

** Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

** The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

** The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.
|}

{|
|-bgcolor="CED8F6"
|
'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.
|}

{|
|-bgcolor="ECCEF5"
|
In the following studies new models and imaging techniques have been employed to gain a better understanding of the changes in brains of patients with schizophrenia

'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

Moreover, in the following study, a neuroimaging technique known as Proton Magnetic Resonance Spectroscopy (1H-MRS) is used to examine the brain of patients with schizophrenia.

'''Multimodal neuroimaging of frontal white matter microstructure in early phase schizophrenia: the impact of early adolescent cannabis use'''
<ref><pubmed> 3852698 </pubmed></ref>

[[Image:Online_placement_of_the_1H-MRS_volume_of_interest_.jpg|400x400px|frame|Proton magnetic resonance spectroscopy (1H-MRS) is used to examine the white matter tissue in brain of patients with schizophrenia. The image shows online placement of the 1H-MRS volume of interest.The 1H-MRS volume of interest is placed parallel to the AC-PC line (AC =anterior commissure, PC = posterior commissure). <ref><pubmed> 3852698 </pubmed></ref> ]]

* The neurochemical used in this technique is N-acetylaspartate (NAA), a free amino acid that has a peak resonance at 2.02 ppm on the spectral profile in the 1H-MRS of human brain.
* In vivo concentration levels of NAA are higher in white matter compared to gray matter.
* Post-mortem studies have demonstrated that NAA is produced in neurons, transported into white matter and broken down into aspartate and acetate in oligodendrocytes. <ref><pubmed>17275978</pubmed></ref> NAA catabolism is thus closely related to the metabolism of myelin, since it provides a crucial source of acetate which is necessary for the formation of myelin from lipid.
* Therefore due to abnormal myelin biosynthesis in schizophrenia, brain tissues can be examined by 1H-MRS studies as long as the targeted brain region involves a single tissue type (white matter) that provides the necessary information regarding the catabolic cycle of NAA.

|}

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]

Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.

* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period).

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation. <ref><pubmed>15806441</pubmed></ref>

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.<ref><pubmed>21215908</pubmed></ref>

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.<ref><pubmed>1400921</pubmed></ref>

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.<ref><pubmed>25283616</pubmed></ref>

===Fetal Alcohol Syndrome===

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status. <ref><pubmed> 24904907 </pubmed></ref>

==References==

<references/>

2014 Group Project 7

2014-10-24T03:21:03Z

Z3418981: /* Microcephaly, Macrocephaly and Hydrocephalus */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, recieving and integration of information from all parts of the body, serving as the processing center of the bodies nervous system. The CNS controls all bodily functions (sensory and motor), consisting of 2 main organs; The Brain and Spinal Cord.

The brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

The spinal cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into ascending bundles, which transmits sensory information from the body to the brain, and descending bundle, which transmits motor function information from the brain to the body.

Before fetal period, neurulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, including cellular processes and brain development will be discussed. Current research models and findings, and historic findings will be stated. The abnormalities associated to CNS during fetal period, and neural defects that occur during embryonic period and contribute in fetal development will be discussed.

==Development during fetal period==

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

[[File:Schematic_representation_of_the_timeline_of_human_neural_development.jpg|700px]]

A simplified timeline of human neural development (modified) <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

This simplified graph shows a timeline for major events of neural development that occur during fetal and postnatal periods. These events, which are summarized in the following table, are broadly classified by cell multiplication, cell migration, growth and differentiation and angiogenesis:

{| class="wikitable"
|-
! Major Events !! Descriptions
|-
| Cell multiplication ||
* Neurons are proliferated and generated from neural stem cells and progenitor cells (precursor cells) in a process known as neurogenesis in 2nd trimester.
* Cell death and Gliogenesis (glial cells (such as astrocytes) deriving from multipotent neural stem cells) occur in the 3rd trimester.
* Local gliogenesis continues postnatally.
|-
| Cell migration ||
* Neuronal migration is maximised during 2nd trimester while glial migration is maximised during 3rd trimester
|-
| Growth and differentiation ||
* Axonal and dendritic arborisation (fine branching structures at the end of nerve fibers) appear by the end of fetal period.
* Synaptogenesis (formation of synapses) and electrical activity is maximised in 3rd trimester (and continued postnatally).
* Cell death due to over-innervation can be observed in late fetal and postnatal period.
* Myelination occurs in late fetal and postnatal period (vast majority of postnatal growth in brain is due to myelination).
|-
| Angiogenesis ||
* Oxidative metabolism can be seen in late fetal period.
* Capillary networks develop postnatally.
|}

'''1. cell proliferation'''

[[Image:Somatosensory cortex of E20 rat.jpeg|frame|500x500px|Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) <ref name="PMID22272298"><pubmed>22272298</pubmed></ref>]]

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref name="PMID4203033"><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref name="PMID5414696"><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref name="PMID7204662"><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref name="PMID12764033"><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref name="PMID8523077"><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref name="PMID9712307"><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref name="PMID1713238"><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

'''2. cell migration'''
[[Image:CNS_passive.jpg|frame|200x150px|Passive cell displacement and outside-to-inside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]
[[Image:CNS_active.jpg|frame|350x250px|Active cell migration and inside-to-outside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways.

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus <ref name="PMID489804"><pubmed>489804</pubmed></ref>, hypothalamus <ref name="PMID5029133"><pubmed>5029133</pubmed></ref>, spinal cord <ref name="PMID4407392"><pubmed>4407392</pubmed></ref>, dentate gyrus of the hippocampal formation <ref name="PMID17533671"><pubmed>17533671</pubmed></ref> and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas <ref name="PMID17533671"><pubmed>17533671</pubmed></ref>.

{| style="width:20%; height:170px" align="center"
|-
| [[Image:Internurons migration in cerebral cortex.jpg|frame|200x400px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex <ref name="PMID17726524"><pubmed>17726524</pubmed></ref>]]
|}

'''3. cell differentiation'''<ref name="PMID10532616"><pubmed>10532616</pubmed></ref>

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

=== Brain Development ===

* The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells. By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

* The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

[[Image:Brain ventricles and ganglia development 03.jpg|frame|200x200px|Increase in size of of brain and ventricles <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]
[[Image:Brain fissure development 02.jpg|frame|200x200px|Increase in size of brain fissure <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]

* The gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding.

* The brain development begins rostral in GW8, proceeding caudally until it is complete at GW22 <ref><pubmed>560818</pubmed></ref>

* The formation of Secondary Sulci is between GW30-35, while the formation of of Tertiary Sulci begins during GW36 and into the postnatal period.

* Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

* Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

* The major fibre pathways make up the brain white matter

* AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Neuron Production'''

* The human brain contains billions of neurons which are produced by mid-gestation; during fetal development <ref><pubmed>8361683</pubmed></ref>

* Processes of Neuronal production is initiated by first increasing the size of the Neural progenitor cell population within the body, these cells are mitotic in nature and are capable of forming new cells.

* Initially (from the end of gastrulation through to embryonic day 42), the neural progenitor cell population is increased greatly when the progenitor cells divide through 'symmetrical' mode of cell division. Multiple repeats of the cell division occurs throughout this period. This 'symmetrical' division method brings about the formation of 2 new identical neural progenitor cells

* Mode of cell division changes from a symmetrical cell division type to an 'asymmetrical' cell division from the beginning of E42. This asymmetrical cell division forms 2 different cell types; one Neural progenitor & one Neuron <ref><pubmed>12764028 </pubmed></ref>

* Newly formed Neural progenitor cells remains to undergo more processes of cell division whereas the newly formed neuron moves into position in the developing neocortex

'''Neuron Migration''' <ref name="PMID21042938"><pubmed>21042938</pubmed></ref>

Outlined above was a broad summary on neuron migration. Neuron migration in the cortex will be covered below in more detail.

* The ventricular zone (VZ) is where the majority of neurons migrate radially out and into the neocortex. The type of migration utilised here is referred to as somal translocation where the neuron cell body translocates out of the VZ and into the outer brain region with the nucleus moving across the cytoplasm and into the outer brain region.

* With increasing brain size, somal translocation is no longer efficient for neuronal migration out of VZ. Since greater distances are evident, radial glial guides are adopted to allow the migration of neurons to continue. Similar to somal translocation, these cell populations establish a scaffolding system where neurons can attach to (basal process occurs) and then move into the developing cortical plate. These cell populations are comprised of neural progenitor cells and are therefore able to support mass neuron migration.

* Another mode of transport utilised by neurons situated within a second zone of the ventral telencephalon is referred to as tangential migration. The neurons here migrate tangentially to the cortical mantle whilst adopting different signalling pathways (guidance molecules) as opposed to radial migration. As a result of neuronal migration, a 6-layered structure forms within the developing neocortex.

* Once completion of the pre-plate has occurred, two regions are formed and which are the subplate (SP) and th marginal zone (MZ).In between these two regions, the cortical plate arises as well. Earliest neuron arrival forms the deepest layer of the cortex; cortical layer 6. More superficial layers of the cortex will develop with continuous cell migration. It is important to note that a specific cell class is located within the MZ in which are the Cajal-Retzius cells (CR). CR's are important for correct neuron positioning within the cortical layers as well as having an inhibitory effect on neuron migration. Rheelin, a molecular signal produced by the CR's is important here as it stops neurons from migrating and signals them to up their corresponding positions.

'''Folding: sulcation and gyration'''

[[Image:Dev anat 01.jpg|frame|200x200px|Simplified external lateral (left) view of the brain growth]]

* During the fifth and sixth month of gestation, the smooth cortex begins to fold by sulcation and gyration. <ref name=PMID21571694><pubmed>21571694</pubmed></ref>

# Sulcation: This is the development of sulci, including primary and secondary. The formation of primary sulci involve the appearance of shallow grooves on the surface of the brain, which then become more deeply infolded, while the formation of secondary sulci is due to the development of side branches of the primary ones <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.
# Gyration: This is the development of gyrus that occurs during late during fetal development until the end of the pregnancy or after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>. This process is the formation of tertiary sulci, which is the formation of other side branches of the secondary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

{| class="wikitable"
|-
! Weeks of gestation !! Visible anatomical details
|-
| 20-21 || smooth, with the impression of "lissencephalic" brain; wide Sylvian fissures; visible interhemispheric fissure and parieto-occipital fissure
|-
| 22-23 || beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || smooth cerebral cortex surface; visible shallow grooves in the central sulci, interparietal sulci and superior temporal sulci; start of opercularization of Sylvian fissures; presence of calcarine fissures and cingular sulci
|-
| 26 || presence of central and collateral sulci
|-
| 27 || presence of marginal and precentral sulci
|-
| 28 || presence of postcentral and intraparietal sulci
|-
| 29 || presence of superior and inferior frontal sulci; narrower Sylvian fissure; clear corpus callosum; bright white matter; dark cortical ribbon
|-
| 30-31 || beginning of infolding of cortex which is first apparent in the occipital lobe; narrower ventricular system and subarachnoid spaces
|-
| 32 || presence of superior and inferior temporal sulci
|-
| 33 || presence of external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration; compactly and extensively folded cortex
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table of the process of sulcation and gyration <ref name=PMID20608424><pubmed>20608424</pubmed></ref>

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations <ref><pubmed>7472570</pubmed></ref>

|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.
{|
|-bgcolor="ECCEF5"
|

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.
|}

{|
|-bgcolor="CED8F6"
|The following recent studies use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

** Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

** The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

** The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.
|}

{|
|-bgcolor="CED8F6"
|
'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.
|}

{|
|-bgcolor="ECCEF5"
|
In the following studies new models and imaging techniques have been employed to gain a better understanding of the changes in brains of patients with schizophrenia

'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

Moreover, in the following study, a neuroimaging technique known as Proton Magnetic Resonance Spectroscopy (1H-MRS) is used to examine the brain of patients with schizophrenia.

'''Multimodal neuroimaging of frontal white matter microstructure in early phase schizophrenia: the impact of early adolescent cannabis use'''
<ref><pubmed> 3852698 </pubmed></ref>

[[Image:Online_placement_of_the_1H-MRS_volume_of_interest_.jpg|400x400px|frame|Proton magnetic resonance spectroscopy (1H-MRS) is used to examine the white matter tissue in brain of patients with schizophrenia. The image shows online placement of the 1H-MRS volume of interest.The 1H-MRS volume of interest is placed parallel to the AC-PC line (AC =anterior commissure, PC = posterior commissure). <ref><pubmed> 3852698 </pubmed></ref> ]]

* The neurochemical used in this technique is N-acetylaspartate (NAA), a free amino acid that has a peak resonance at 2.02 ppm on the spectral profile in the 1H-MRS of human brain.
* In vivo concentration levels of NAA are higher in white matter compared to gray matter.
* Post-mortem studies have demonstrated that NAA is produced in neurons, transported into white matter and broken down into aspartate and acetate in oligodendrocytes. <ref><pubmed>17275978</pubmed></ref> NAA catabolism is thus closely related to the metabolism of myelin, since it provides a crucial source of acetate which is necessary for the formation of myelin from lipid.
* Therefore due to abnormal myelin biosynthesis in schizophrenia, brain tissues can be examined by 1H-MRS studies as long as the targeted brain region involves a single tissue type (white matter) that provides the necessary information regarding the catabolic cycle of NAA.

|}

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]

Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.

* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period).

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation. <ref><pubmed>15806441</pubmed></ref>

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.<ref><pubmed>21215908</pubmed></ref>

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.<ref><pubmed>1400921</pubmed></ref>

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.<ref><pubmed>25283616</pubmed></ref>

===Fetal Alcohol Syndrome===

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

==References==

<references/>

2014 Group Project 7

2014-10-24T03:18:30Z

Z3418981: /* Microcephaly, Macrocephaly and Hydrocephalus */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, recieving and integration of information from all parts of the body, serving as the processing center of the bodies nervous system. The CNS controls all bodily functions (sensory and motor), consisting of 2 main organs; The Brain and Spinal Cord.

The brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

The spinal cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into ascending bundles, which transmits sensory information from the body to the brain, and descending bundle, which transmits motor function information from the brain to the body.

Before fetal period, neurulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, including cellular processes and brain development will be discussed. Current research models and findings, and historic findings will be stated. The abnormalities associated to CNS during fetal period, and neural defects that occur during embryonic period and contribute in fetal development will be discussed.

==Development during fetal period==

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

[[File:Schematic_representation_of_the_timeline_of_human_neural_development.jpg|700px]]

A simplified timeline of human neural development (modified) <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

This simplified graph shows a timeline for major events of neural development that occur during fetal and postnatal periods. These events, which are summarized in the following table, are broadly classified by cell multiplication, cell migration, growth and differentiation and angiogenesis:

{| class="wikitable"
|-
! Major Events !! Descriptions
|-
| Cell multiplication ||
* Neurons are proliferated and generated from neural stem cells and progenitor cells (precursor cells) in a process known as neurogenesis in 2nd trimester.
* Cell death and Gliogenesis (glial cells (such as astrocytes) deriving from multipotent neural stem cells) occur in the 3rd trimester.
* Local gliogenesis continues postnatally.
|-
| Cell migration ||
* Neuronal migration is maximised during 2nd trimester while glial migration is maximised during 3rd trimester
|-
| Growth and differentiation ||
* Axonal and dendritic arborisation (fine branching structures at the end of nerve fibers) appear by the end of fetal period.
* Synaptogenesis (formation of synapses) and electrical activity is maximised in 3rd trimester (and continued postnatally).
* Cell death due to over-innervation can be observed in late fetal and postnatal period.
* Myelination occurs in late fetal and postnatal period (vast majority of postnatal growth in brain is due to myelination).
|-
| Angiogenesis ||
* Oxidative metabolism can be seen in late fetal period.
* Capillary networks develop postnatally.
|}

'''1. cell proliferation'''

[[Image:Somatosensory cortex of E20 rat.jpeg|frame|500x500px|Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) <ref name="PMID22272298"><pubmed>22272298</pubmed></ref>]]

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref name="PMID4203033"><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref name="PMID5414696"><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref name="PMID7204662"><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref name="PMID12764033"><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref name="PMID8523077"><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref name="PMID9712307"><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref name="PMID1713238"><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

'''2. cell migration'''
[[Image:CNS_passive.jpg|frame|200x150px|Passive cell displacement and outside-to-inside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]
[[Image:CNS_active.jpg|frame|350x250px|Active cell migration and inside-to-outside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways.

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus <ref name="PMID489804"><pubmed>489804</pubmed></ref>, hypothalamus <ref name="PMID5029133"><pubmed>5029133</pubmed></ref>, spinal cord <ref name="PMID4407392"><pubmed>4407392</pubmed></ref>, dentate gyrus of the hippocampal formation <ref name="PMID17533671"><pubmed>17533671</pubmed></ref> and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas <ref name="PMID17533671"><pubmed>17533671</pubmed></ref>.

{| style="width:20%; height:170px" align="center"
|-
| [[Image:Internurons migration in cerebral cortex.jpg|frame|200x400px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex <ref name="PMID17726524"><pubmed>17726524</pubmed></ref>]]
|}

'''3. cell differentiation'''<ref name="PMID10532616"><pubmed>10532616</pubmed></ref>

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

=== Brain Development ===

* The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells. By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

* The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

[[Image:Brain ventricles and ganglia development 03.jpg|frame|200x200px|Increase in size of of brain and ventricles <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]
[[Image:Brain fissure development 02.jpg|frame|200x200px|Increase in size of brain fissure <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]

* The gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding.

* The brain development begins rostral in GW8, proceeding caudally until it is complete at GW22 <ref><pubmed>560818</pubmed></ref>

* The formation of Secondary Sulci is between GW30-35, while the formation of of Tertiary Sulci begins during GW36 and into the postnatal period.

* Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

* Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

* The major fibre pathways make up the brain white matter

* AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Neuron Production'''

* The human brain contains billions of neurons which are produced by mid-gestation; during fetal development <ref><pubmed>8361683</pubmed></ref>

* Processes of Neuronal production is initiated by first increasing the size of the Neural progenitor cell population within the body, these cells are mitotic in nature and are capable of forming new cells.

* Initially (from the end of gastrulation through to embryonic day 42), the neural progenitor cell population is increased greatly when the progenitor cells divide through 'symmetrical' mode of cell division. Multiple repeats of the cell division occurs throughout this period. This 'symmetrical' division method brings about the formation of 2 new identical neural progenitor cells

* Mode of cell division changes from a symmetrical cell division type to an 'asymmetrical' cell division from the beginning of E42. This asymmetrical cell division forms 2 different cell types; one Neural progenitor & one Neuron <ref><pubmed>12764028 </pubmed></ref>

* Newly formed Neural progenitor cells remains to undergo more processes of cell division whereas the newly formed neuron moves into position in the developing neocortex

'''Neuron Migration''' <ref name="PMID21042938"><pubmed>21042938</pubmed></ref>

Outlined above was a broad summary on neuron migration. Neuron migration in the cortex will be covered below in more detail.

* The ventricular zone (VZ) is where the majority of neurons migrate radially out and into the neocortex. The type of migration utilised here is referred to as somal translocation where the neuron cell body translocates out of the VZ and into the outer brain region with the nucleus moving across the cytoplasm and into the outer brain region.

* With increasing brain size, somal translocation is no longer efficient for neuronal migration out of VZ. Since greater distances are evident, radial glial guides are adopted to allow the migration of neurons to continue. Similar to somal translocation, these cell populations establish a scaffolding system where neurons can attach to (basal process occurs) and then move into the developing cortical plate. These cell populations are comprised of neural progenitor cells and are therefore able to support mass neuron migration.

* Another mode of transport utilised by neurons situated within a second zone of the ventral telencephalon is referred to as tangential migration. The neurons here migrate tangentially to the cortical mantle whilst adopting different signalling pathways (guidance molecules) as opposed to radial migration. As a result of neuronal migration, a 6-layered structure forms within the developing neocortex.

* Once completion of the pre-plate has occurred, two regions are formed and which are the subplate (SP) and th marginal zone (MZ).In between these two regions, the cortical plate arises as well. Earliest neuron arrival forms the deepest layer of the cortex; cortical layer 6. More superficial layers of the cortex will develop with continuous cell migration. It is important to note that a specific cell class is located within the MZ in which are the Cajal-Retzius cells (CR). CR's are important for correct neuron positioning within the cortical layers as well as having an inhibitory effect on neuron migration. Rheelin, a molecular signal produced by the CR's is important here as it stops neurons from migrating and signals them to up their corresponding positions.

'''Folding: sulcation and gyration'''

[[Image:Dev anat 01.jpg|frame|200x200px|Simplified external lateral (left) view of the brain growth]]

* During the fifth and sixth month of gestation, the smooth cortex begins to fold by sulcation and gyration. <ref name=PMID21571694><pubmed>21571694</pubmed></ref>

# Sulcation: This is the development of sulci, including primary and secondary. The formation of primary sulci involve the appearance of shallow grooves on the surface of the brain, which then become more deeply infolded, while the formation of secondary sulci is due to the development of side branches of the primary ones <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.
# Gyration: This is the development of gyrus that occurs during late during fetal development until the end of the pregnancy or after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>. This process is the formation of tertiary sulci, which is the formation of other side branches of the secondary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

{| class="wikitable"
|-
! Weeks of gestation !! Visible anatomical details
|-
| 20-21 || smooth, with the impression of "lissencephalic" brain; wide Sylvian fissures; visible interhemispheric fissure and parieto-occipital fissure
|-
| 22-23 || beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || smooth cerebral cortex surface; visible shallow grooves in the central sulci, interparietal sulci and superior temporal sulci; start of opercularization of Sylvian fissures; presence of calcarine fissures and cingular sulci
|-
| 26 || presence of central and collateral sulci
|-
| 27 || presence of marginal and precentral sulci
|-
| 28 || presence of postcentral and intraparietal sulci
|-
| 29 || presence of superior and inferior frontal sulci; narrower Sylvian fissure; clear corpus callosum; bright white matter; dark cortical ribbon
|-
| 30-31 || beginning of infolding of cortex which is first apparent in the occipital lobe; narrower ventricular system and subarachnoid spaces
|-
| 32 || presence of superior and inferior temporal sulci
|-
| 33 || presence of external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration; compactly and extensively folded cortex
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table of the process of sulcation and gyration <ref name=PMID20608424><pubmed>20608424</pubmed></ref>

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations <ref><pubmed>7472570</pubmed></ref>

|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.
{|
|-bgcolor="ECCEF5"
|

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.
|}

{|
|-bgcolor="CED8F6"
|The following recent studies use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

** Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

** The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

** The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.
|}

{|
|-bgcolor="CED8F6"
|
'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.
|}

{|
|-bgcolor="ECCEF5"
|
In the following studies new models and imaging techniques have been employed to gain a better understanding of the changes in brains of patients with schizophrenia

'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

Moreover, in the following study, a neuroimaging technique known as Proton Magnetic Resonance Spectroscopy (1H-MRS) is used to examine the brain of patients with schizophrenia.

'''Multimodal neuroimaging of frontal white matter microstructure in early phase schizophrenia: the impact of early adolescent cannabis use'''
<ref><pubmed> 3852698 </pubmed></ref>

[[Image:Online_placement_of_the_1H-MRS_volume_of_interest_.jpg|400x400px|frame|Proton magnetic resonance spectroscopy (1H-MRS) is used to examine the white matter tissue in brain of patients with schizophrenia. The image shows online placement of the 1H-MRS volume of interest.The 1H-MRS volume of interest is placed parallel to the AC-PC line (AC =anterior commissure, PC = posterior commissure). <ref><pubmed> 3852698 </pubmed></ref> ]]

* The neurochemical used in this technique is N-acetylaspartate (NAA), a free amino acid that has a peak resonance at 2.02 ppm on the spectral profile in the 1H-MRS of human brain.
* In vivo concentration levels of NAA are higher in white matter compared to gray matter.
* Post-mortem studies have demonstrated that NAA is produced in neurons, transported into white matter and broken down into aspartate and acetate in oligodendrocytes. <ref><pubmed>17275978</pubmed></ref> NAA catabolism is thus closely related to the metabolism of myelin, since it provides a crucial source of acetate which is necessary for the formation of myelin from lipid.
* Therefore due to abnormal myelin biosynthesis in schizophrenia, brain tissues can be examined by 1H-MRS studies as long as the targeted brain region involves a single tissue type (white matter) that provides the necessary information regarding the catabolic cycle of NAA.

|}

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]

Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.

* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period).

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation. <ref><pubmed>15806441</pubmed></ref>

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.<ref><pubmed>21215908</pubmed></ref>

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.<ref><pubmed>1400921</pubmed></ref>

==References==

<references/>

2014 Group Project 7

2014-10-24T03:16:02Z

Z3418981: /* Microcephaly, Macrocephaly and Hydrocephalus */

2014 Group Project 7

2014-10-24T03:12:44Z

Z3418981: /* Microcephaly, Macrocephaly and Hydrocephalus */

2014 Group Project 7

2014-10-24T03:09:03Z

Z3418981: /* Microcephaly, Macrocephaly and Hydrocephalus */

2014 Group Project 7

2014-10-24T03:06:54Z

Z3418981: /* Microcephaly, Macrocephaly and Hydrocephalus */

2014 Group Project 7

2014-10-24T03:04:32Z

Z3418981: /* Current research models and findings */

2014 Group Project 7

2014-10-23T15:36:42Z

Z3418981: /* Current Research */

2014 Group Project 7

2014-10-23T15:27:00Z

Z3418981: /* Current research models and findings */

2014 Group Project 7

2014-10-23T15:22:11Z

Z3418981: /* Abnormalities */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, recieving and integration of information from all parts of the body, serving as the processing center of the bodies nervous system. The CNS controls all bodily functions (sensory and motor), consisting of 2 main organs; The Brain and Spinal Cord.

The brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

The spinal cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into ascending bundles, which transmits sensory information from the body to the brain, and descending bundle, which transmits motor function information from the brain to the body.

Before fetal period, neurulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, including cellular processes and brain development will be discussed. Current research models and findings, and historic findings will be stated. The abnormalities associated to CNS during fetal period, and neural defects that occur during embryonic period and contribute in fetal development will be discussed.

==Development during fetal period==

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

[[File:Schematic_representation_of_the_timeline_of_human_neural_development.jpg|700px]]

A simplified timeline of human neural development (modified) <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

This simplified graph shows a timeline for major events of neural development that occur during fetal and postnatal periods. These events, which are summarized in the following table, are broadly classified by cell multiplication, cell migration, growth and differentiation and angiogenesis:

{| class="wikitable"
|-
! Major Events !! Descriptions
|-
| Cell multiplication ||
* Neurons are proliferated and generated from neural stem cells and progenitor cells (precursor cells) in a process known as neurogenesis in 2nd trimester.
* Cell death and Gliogenesis (glial cells (such as astrocytes) deriving from multipotent neural stem cells) occur in the 3rd trimester.
* Local gliogenesis continues postnatally.
|-
| Cell migration ||
* Neuronal migration is maximised during 2nd trimester while glial migration is maximised during 3rd trimester
|-
| Growth and differentiation ||
* Axonal and dendritic arborisation (fine branching structures at the end of nerve fibers) appear by the end of fetal period.
* Synaptogenesis (formation of synapses) and electrical activity is maximised in 3rd trimester (and continued postnatally).
* Cell death due to over-innervation can be observed in late fetal and postnatal period.
* Myelination occurs in late fetal and postnatal period (vast majority of postnatal growth in brain is due to myelination).
|-
| Angiogenesis ||
* Oxidative metabolism can be seen in late fetal period.
* Capillary networks develop postnatally.
|}

'''1. cell proliferation'''

[[Image:Somatosensory cortex of E20 rat.jpeg|frame|500x500px|Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) <ref name="PMID22272298"><pubmed>22272298</pubmed></ref>]]

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref name="PMID4203033"><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref name="PMID5414696"><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref name="PMID7204662"><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref name="PMID12764033"><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref name="PMID8523077"><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref name="PMID9712307"><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref name="PMID1713238"><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

'''2. cell migration'''
[[Image:CNS_passive.jpg|frame|200x150px|Passive cell displacement and outside-to-inside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]
[[Image:CNS_active.jpg|frame|350x250px|Active cell migration and inside-to-outside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways.

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus <ref name="PMID489804"><pubmed>489804</pubmed></ref>, hypothalamus <ref name="PMID5029133"><pubmed>5029133</pubmed></ref>, spinal cord <ref name="PMID4407392"><pubmed>4407392</pubmed></ref>, dentate gyrus of the hippocampal formation <ref name="PMID17533671"><pubmed>17533671</pubmed></ref> and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas <ref name="PMID17533671"><pubmed>17533671</pubmed></ref>.

{| style="width:20%; height:170px" align="center"
|-
| [[Image:Internurons migration in cerebral cortex.jpg|frame|200x400px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex <ref name="PMID17726524"><pubmed>17726524</pubmed></ref>]]
|}

'''3. cell differentiation'''<ref name="PMID10532616"><pubmed>10532616</pubmed></ref>

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

=== Brain Development ===

* The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells. By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

* The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

[[Image:Brain ventricles and ganglia development 03.jpg|frame|200x200px|Increase in size of of brain and ventricles <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]
[[Image:Brain fissure development 02.jpg|frame|200x200px|Increase in size of brain fissure <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]

* The gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding.

* The brain development begins rostral in GW8, proceeding caudally until it is complete at GW22 <ref><pubmed>560818</pubmed></ref>

* The formation of Secondary Sulci is between GW30-35, while the formation of of Tertiary Sulci begins during GW36 and into the postnatal period.

* Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

* Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

* The major fibre pathways make up the brain white matter

* AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Neuron Production'''

* The human brain contains billions of neurons which are produced by mid-gestation; during fetal development <ref><pubmed>8361683</pubmed></ref>

* Processes of Neuronal production is initiated by first increasing the size of the Neural progenitor cell population within the body, these cells are mitotic in nature and are capable of forming new cells.

* Initially (from the end of gastrulation through to embryonic day 42), the neural progenitor cell population is increased greatly when the progenitor cells divide through 'symmetrical' mode of cell division. Multiple repeats of the cell division occurs throughout this period. This 'symmetrical' division method brings about the formation of 2 new identical neural progenitor cells

* Mode of cell division changes from a symmetrical cell division type to an 'asymmetrical' cell division from the beginning of E42. This asymmetrical cell division forms 2 different cell types; one Neural progenitor & one Neuron <ref><pubmed>12764028 </pubmed></ref>

* Newly formed Neural progenitor cells remains to undergo more processes of cell division whereas the newly formed neuron moves into position in the developing neocortex

'''Neuron Migration''' <ref name="PMID21042938"><pubmed>21042938</pubmed></ref>

Outlined above was a broad summary on neuron migration. Neuron migration in the cortex will be covered below in more detail.

* The ventricular zone (VZ) is where the majority of neurons migrate radially out and into the neocortex. The type of migration utilised here is referred to as somal translocation where the neuron cell body translocates out of the VZ and into the outer brain region with the nucleus moving across the cytoplasm and into the outer brain region.

* With increasing brain size, somal translocation is no longer efficient for neuronal migration out of VZ. Since greater distances are evident, radial glial guides are adopted to allow the migration of neurons to continue. Similar to somal translocation, these cell populations establish a scaffolding system where neurons can attach to (basal process occurs) and then move into the developing cortical plate. These cell populations are comprised of neural progenitor cells and are therefore able to support mass neuron migration.

* Another mode of transport utilised by neurons situated within a second zone of the ventral telencephalon is referred to as tangential migration. The neurons here migrate tangentially to the cortical mantle whilst adopting different signalling pathways (guidance molecules) as opposed to radial migration. As a result of neuronal migration, a 6-layered structure forms within the developing neocortex.

* Once completion of the pre-plate has occurred, two regions are formed and which are the subplate (SP) and th marginal zone (MZ).In between these two regions, the cortical plate arises as well. Earliest neuron arrival forms the deepest layer of the cortex; cortical layer 6. More superficial layers of the cortex will develop with continuous cell migration. It is important to note that a specific cell class is located within the MZ in which are the Cajal-Retzius cells (CR). CR's are important for correct neuron positioning within the cortical layers as well as having an inhibitory effect on neuron migration. Rheelin, a molecular signal produced by the CR's is important here as it stops neurons from migrating and signals them to up their corresponding positions.

'''Folding: sulcation and gyration'''

[[Image:Dev anat 01.jpg|frame|200x200px|Simplified external lateral (left) view of the brain growth]]

* During the fifth and sixth month of gestation, the smooth cortex begins to fold by sulcation and gyration. <ref name=PMID21571694><pubmed>21571694</pubmed></ref>

# Sulcation: This is the development of sulci, including primary and secondary. The formation of primary sulci involve the appearance of shallow grooves on the surface of the brain, which then become more deeply infolded, while the formation of secondary sulci is due to the development of side branches of the primary ones <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.
# Gyration: This is the development of gyrus that occurs during late during fetal development until the end of the pregnancy or after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>. This process is the formation of tertiary sulci, which is the formation of other side branches of the secondary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

{| class="wikitable"
|-
! Weeks of gestation !! Visible anatomical details
|-
| 20-21 || smooth, with the impression of "lissencephalic" brain; wide Sylvian fissures; visible interhemispheric fissure and parieto-occipital fissure
|-
| 22-23 || beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || smooth cerebral cortex surface; visible shallow grooves in the central sulci, interparietal sulci and superior temporal sulci; start of opercularization of Sylvian fissures; presence of calcarine fissures and cingular sulci
|-
| 26 || presence of central and collateral sulci
|-
| 27 || presence of marginal and precentral sulci
|-
| 28 || presence of postcentral and intraparietal sulci
|-
| 29 || presence of superior and inferior frontal sulci; narrower Sylvian fissure; clear corpus callosum; bright white matter; dark cortical ribbon
|-
| 30-31 || beginning of infolding of cortex which is first apparent in the occipital lobe; narrower ventricular system and subarachnoid spaces
|-
| 32 || presence of superior and inferior temporal sulci
|-
| 33 || presence of external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration; compactly and extensively folded cortex
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table of the process of sulcation and gyration <ref name=PMID20608424><pubmed>20608424</pubmed></ref>

=== Spinal Cord Development ===
The spinal cord is formed from parts of the neural tube during embryonic and fetal development

=== Meninges Development ===

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations <ref><pubmed>7472570</pubmed></ref>

|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.
{|
|-bgcolor="ECCEF5"
|

[[Image:Cerebral_Brain_Image.jpg|400x400px|frame|Local growth pattern of cerebral brain tissue]]

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.
|}

{|
|-bgcolor="CED8F6"
|The following are recent studies that use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

-Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

-The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

-The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.
|}
{|
|-bgcolor="ECCEF5"
|
'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

|}
{|
|-bgcolor="CED8F6"
|
'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.
|}
{|
|-bgcolor="ECCEF5"
|
'''Cortical Overgrowth in Fetuses With Isolated Ventriculomegaly'''
<ref><pubmed> 23508710 </pubmed></ref>

* The condition fetal ventriculomegaly is characterised by dilation of lateral ventricles whilst sharing associations with other malformations. It was hypothesised that using relative brain overgrowth as marked measure of altered brain development is due to the occurrence of ventriculomegaly and to evaluate this brain overgrowth through the use of magnetic resonance imaging (MRI) of fetuses isolated with enlarged ventricles (3rd and 4th ventricles as well as cerebrospinal fluid). Furthermore, significant changes to thalamic volumes, basal ganglia and white matter did not occur between cohorts.

* The study found that there was a sufficient increase in brain volume (overgrowth) of fetuses that had ventriculomegaly in comparison to controls. Also, larger lateral ventricle volumes were yielded with fetuses with ventriculomegaly assessed via 2-dimensional movement of the atrial diameter (ultrasound and MRi) as well as a larger total brain tissue volume. This provides support for the hypothesis in that brain overgrowth can be used as a marked measure for ventriculomegaly with results showing that overgrowth was not localised in one region but across both hemispheres and thus lead to a neural deficit in children (altered neural connectivity).

* Hence, this study has assisted in the improved understanding of the effects of ventriculomegaly on cognition, language and behaviour in children.
|}

===Future Research===

===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.
{|
|-bgcolor="ECCEF5"
|

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.
|}

{|
|-bgcolor="CED8F6"
|The following recent studies use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

-Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

-The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

-The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.
|}

{|
|-bgcolor="CED8F6"
|
'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.
|}

{|
|-bgcolor="ECCEF5"
|
In the following studies new models and imaging techniques have been employed to gain a better understanding of the changes in brains of patients with schizophrenia

'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

Moreover, in the following study, a neuroimaging technique known as Proton Magnetic Resonance Spectroscopy (1H-MRS) is used to examine the brain of patients with schizophrenia.

'''Multimodal neuroimaging of frontal white matter microstructure in early phase schizophrenia: the impact of early adolescent cannabis use'''
<ref><pubmed> 3852698 </pubmed></ref>

[[Image:Online_placement_of_the_1H-MRS_volume_of_interest_.jpg|400x400px|frame|The 1H-MRS volume of interest is placed parallel to the AC-PC line (AC =anterior commissure, PC = posterior commissure). <ref><pubmed> 3852698 </pubmed></ref> ]]

* The neurochemical used in this technique is N-acetylaspartate (NAA), a free amino acid that has a peak resonance at 2.02 ppm on the spectral profile in the 1H-MRS of human brain.
* In vivo concentration levels of NAA are higher in white matter compared to gray matter.
* Post-mortem studies have demonstrated that NAA is produced in neurons, transported into white matter and broken down into aspartate and acetate in oligodendrocytes. <ref><pubmed>17275978</pubmed></ref> NAA catabolism is thus closely related to the metabolism of myelin, since it provides a crucial source of acetate which is necessary for the formation of myelin from lipid.
* Therefore due to abnormal myelin biosynthesis in schizophrenia, brain tissues can be examined by 1H-MRS studies as long as the targeted brain region involves a single tissue type (white matter) that provides the necessary information regarding the catabolic cycle of NAA.

|}

==References==

<references/>

File:Online placement of the 1H-MRS volume of interest .jpg

2014-10-23T14:45:23Z

Z3418981: ==Online placement of the 1H-MRS volume of interest== The 1H-MRS volume of interest is placed parallel to the AC-PC line (AC =Anterior Commissure, PC = Posterior Commissure). '''Reference''' <ref name=PMID3852698><pubmed>3852698</pubmed></ref> <refe...

==Online placement of the 1H-MRS volume of interest==

The 1H-MRS volume of interest is placed parallel to the AC-PC line (AC =Anterior Commissure, PC = Posterior Commissure).

'''Reference'''
<ref name=PMID3852698><pubmed>3852698</pubmed></ref>
<references/>

'''Copyright:'''
© 2013 Bernier et al.; licensee BioMed Central Ltd.This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

{{Template:Student Image}}

File:Online placement of the 1H-MRS volume of interest.tif

2014-10-23T14:41:07Z

Z3418981: == Online placement of the 1H-MRS volume of interest == The 1H-MRS volume of interest is placed parallel to the AC-PC line (AC =anterior commissure, PC = posterior commissure). '''Reference''' <ref name=PMID3852698><pubmed>3852698</pubmed></ref> <re...

== Online placement of the 1H-MRS volume of interest ==

The 1H-MRS volume of interest is placed parallel to the AC-PC line (AC =anterior commissure, PC = posterior commissure).

'''Reference'''
<ref name=PMID3852698><pubmed>3852698</pubmed></ref>
<references/>

'''Copyright:'''
© 2013 Bernier et al.; licensee BioMed Central Ltd.This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

{{Template:Student Image}}

2014 Group Project 7

2014-10-23T13:07:35Z

Z3418981: /* Abnormalities */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, recieving and integration of information from all parts of the body, serving as the processing center of the bodies nervous system. The CNS controls all bodily functions (sensory and motor), consisting of 2 main organs; The Brain and Spinal Cord

==='''Brain'''===

The Brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

==='''Spinal Cord'''===

The Spinal Cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into

1) Ascending bundles - Transmits Sensory information from the body to the brain

2) Descending bundle - Transmits Motor function information from the brain to the body

Before fetal period, nerulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, the current research models and finding, historic findings and abnormalities that can occur in the fetal period is identified.

==Development during fetal period==

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

[[File:Schematic_representation_of_the_timeline_of_human_neural_development.jpg|700px]]

A simplified timeline of human neural development (modified) <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

This simplified graph shows a timeline for major events of neural development that occur during fetal and postnatal periods. These events, which are summarized in the following table, are broadly classified by cell multiplication, cell migration, growth and differentiation and angiogenesis:

{| class="wikitable"
|-
! Major Events !! Descriptions
|-
| Cell multiplication ||
* Neurons are proliferated and generated from neural stem cells and progenitor cells (precursor cells) in a process known as neurogenesis in 2nd trimester.
* Cell death and Gliogenesis (glial cells (such as astrocytes) deriving from multipotent neural stem cells) occur in the 3rd trimester.
* Local gliogenesis continues postnatally.
|-
| Cell migration || * Neuronal migration is maximised during 2nd trimester while glial migration is maximised during 3rd trimester
|-
| Growth and differentiation ||
* Axonal and dendritic arborisation (fine branching structures at the end of nerve fibers) appear by the end of fetal period.
* Synaptogenesis (formation of synapses) and electrical activity is maximised in 3rd trimester (and continued postnatally).
* Cell death due to over-innervation can be observed in late fetal and postnatal period.
* Myelination occurs in late fetal and postnatal period (vast majority of postnatal growth in brain is due to myelination).
|-
| Angiogenesis ||
* Oxidative metabolism can be seen in late fetal period.
* Capillary networks develop postnatally.
|}

'''1. cell proliferation'''

[[Image:Somatosensory cortex of E20 rat.jpeg|frame|500x500px|Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) <ref name="PMID22272298"><pubmed>22272298</pubmed></ref>]]

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref name="PMID4203033"><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref name="PMID5414696"><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref name="PMID7204662"><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref name="PMID12764033"><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref name="PMID8523077"><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref name="PMID9712307"><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref name="PMID1713238"><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

'''2. cell migration'''
[[Image:CNS_passive.jpg|frame|200x150px|Passive cell displacement and outside-to-inside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]
[[Image:CNS_active.jpg|frame|350x250px|Active cell migration and inside-to-outside spatiotemporal gradient <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>]]

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways.

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus <ref name="PMID489804"><pubmed>489804</pubmed></ref>, hypothalamus <ref name="PMID5029133"><pubmed>5029133</pubmed></ref>, spinal cord <ref name="PMID4407392"><pubmed>4407392</pubmed></ref>, dentate gyrus of the hippocampal formation <ref name="PMID17533671"><pubmed>17533671</pubmed></ref> and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas <ref name="PMID17533671"><pubmed>17533671</pubmed></ref>.

{| style="width:20%; height:170px" align="center"
|-
| [[Image:Internurons migration in cerebral cortex.jpg|frame|200x400px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex <ref name="PMID17726524"><pubmed>17726524</pubmed></ref>]]
|}

'''3. cell differentiation'''<ref name="PMID10532616"><pubmed>10532616</pubmed></ref>

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref name="PMID10532616"><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

=== Brain Development ===

* The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells. By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

* The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

[[Image:Brain ventricles and ganglia development 03.jpg|frame|200x200px|Increase in size of of brain and ventricles <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]
[[Image:Brain fissure development 02.jpg|frame|200x200px|Increase in size of brain fissure <ref name=PMID19339620><pubmed>19339620</pubmed></ref>]]

* The gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding.

* The brain development begins rostral in GW8, proceeding caudally until it is complete at GW22 <ref><pubmed>560818</pubmed></ref>

* The formation of Secondary Sulci is between GW30-35, while the formation of of Tertiary Sulci begins during GW36 and into the postnatal period.

* Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

* Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

* The major fibre pathways make up the brain white matter

* AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Neuron Production'''

* The human brain contains billions of neurons which are produced by mid-gestation; during fetal development <ref><pubmed>8361683</pubmed></ref>

* Processes of Neuronal production is initiated by first increasing the size of the Neural progenitor cell population within the body, these cells are mitotic in nature and are capable of forming new cells.

* Initially (from the end of gastrulation through to embryonic day 42), the neural progenitor cell population is increased greatly when the progenitor cells divide through 'symmetrical' mode of cell division. Multiple repeats of the cell division occurs throughout this period. This 'symmetrical' division method brings about the formation of 2 new identical neural progenitor cells

* Mode of cell division changes from a symmetrical cell division type to an 'asymmetrical' cell division from the beginning of E42. This asymmetrical cell division forms 2 different cell types; one Neural progenitor & one Neuron <ref><pubmed>12764028 </pubmed></ref>

* Newly formed Neural progenitor cells remains to undergo more processes of cell division whereas the newly formed neuron moves into position in the developing neocortex

'''folding: sulcation and gyration'''

[[Image:Dev anat 01.jpg|frame|200x200px|Simplified external lateral (left) view of the brain growth]]

* During the fifth and sixth month of gestation, the smooth cortex begins to fold by sulcation and gyration. <ref name=PMID21571694><pubmed>21571694</pubmed></ref>

# Sulcation: This is the development of sulci, including primary and secondary. The formation of primary sulci involve the appearance of shallow grooves on the surface of the brain, which then become more deeply infolded, while the formation of secondary sulci is due to the development of side branches of the primary ones <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.
# Gyration: This is the development of gyrus that occurs during late during fetal development until the end of the pregnancy or after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>. This process is the formation of tertiary sulci, which is the formation of other side branches of the secondary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

{| class="wikitable"
|-
! Weeks of gestation !! Visible anatomical details
|-
| 20-21 || smooth, with the impression of "lissencephalic" brain; wide Sylvian fissures; visible interhemispheric fissure and parieto-occipital fissure
|-
| 22-23 || beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || smooth cerebral cortex surface; visible shallow grooves in the central sulci, interparietal sulci and superior temporal sulci; start of opercularization of Sylvian fissures; presence of calcarine fissures and cingular sulci
|-
| 26 || presence of central and collateral sulci
|-
| 27 || presence of marginal and precentral sulci
|-
| 28 || presence of postcentral and intraparietal sulci
|-
| 29 || presence of superior and inferior frontal sulci; narrower Sylvian fissure; clear corpus callosum; bright white matter; dark cortical ribbon
|-
| 30-31 || beginning of infolding of cortex which is first apparent in the occipital lobe; narrower ventricular system and subarachnoid spaces
|-
| 32 || presence of superior and inferior temporal sulci
|-
| 33 || presence of external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration; compactly and extensively folded cortex
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table of the process of sulcation and gyration <ref name=PMID20608424><pubmed>20608424</pubmed></ref>

=== Spinal Cord Development ===
The spinal cord is formed from parts of the neural tube during embryonic and fetal development

=== Meninges Development ===

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations <ref><pubmed>7472570</pubmed></ref>

|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.
{|
|-bgcolor="ECCEF5"
|

[[Image:Cerebral_Brain_Image.jpg|400x400px|frame|Local growth pattern of cerebral brain tissue]]

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.
|}

{|
|-bgcolor="CED8F6"
|The following are recent studies that use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

-Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

-The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

-The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.
|}
{|
|-bgcolor="ECCEF5"
|
'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

|}
{|
|-bgcolor="CED8F6"
|
'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.
|}
{|
|-bgcolor="ECCEF5"
|
'''Cortical Overgrowth in Fetuses With Isolated Ventriculomegaly'''
<ref><pubmed> 23508710 </pubmed></ref>

* The condition fetal ventriculomegaly is characterised by dilation of lateral ventricles whilst sharing associations with other malformations. It was hypothesised that using relative brain overgrowth as marked measure of altered brain development is due to the occurrence of ventriculomegaly and to evaluate this brain overgrowth through the use of magnetic resonance imaging (MRI) of fetuses isolated with enlarged ventricles (3rd and 4th ventricles as well as cerebrospinal fluid). Furthermore, significant changes to thalamic volumes, basal ganglia and white matter did not occur between cohorts.

* The study found that there was a sufficient increase in brain volume (overgrowth) of fetuses that had ventriculomegaly in comparison to controls. Also, larger lateral ventricle volumes were yielded with fetuses with ventriculomegaly assessed via 2-dimensional movement of the atrial diameter (ultrasound and MRi) as well as a larger total brain tissue volume. This provides support for the hypothesis in that brain overgrowth can be used as a marked measure for ventriculomegaly with results showing that overgrowth was not localised in one region but across both hemispheres and thus lead to a neural deficit in children (altered neural connectivity).

* Hence, this study has assisted in the improved understanding of the effects of ventriculomegaly on cognition, language and behaviour in children.
|}

===Future Research===

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]
Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.
* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period).

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation. <ref><pubmed>15806441</pubmed></ref>

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.<ref><pubmed>21215908</pubmed></ref>

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.<ref><pubmed>1400921</pubmed></ref>

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.<ref><pubmed>25283616</pubmed></ref>

===Fetal Alcohol Syndrome===

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status. <ref><pubmed> 24904907 </pubmed></ref>

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.<ref><pubmed> 23809349 </pubmed></ref>

{| class="wikitable"
|-
| [[File:Fetal alcohol syndrome.jpg|500px]] || [[File:Ethanol fetal neural.jpg|400px]]
|-
| The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref>|| A mechanism of the effect of ethanol on neural stem cells (NSCs). Ethanol promotes asymmetrical cell division, the formation of radial glial-like cells, leading to the premature depletion of the VZ and its NSCs, and the thickening and cell proliferation in SVZ. The increased migration during early differentiation of ethanol-treated NSCs also leads to the appearance of subpial heterotopias<ref name="PMID22623924"><pubmed>22623924</pubmed></ref>
|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

* All degrees of iodine deficiency (mild: 50-99 μg/day, moderate: 20-49 μg/day and severe≤20 μg/day) affect thyroid function of both mother and the neonate as well as mental development of the child. The damage increases with the degree of deficiency; overt endemic cretinism is the most severe consequence.

* Iodine deficiency disorders refer to complications that arise when the recommended dietary allowance of iodine is not met. These complications include thyroid function abnormalities and when iodine deficiency is severe, endemic goitre and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality.

* Iodine deficiency represents the world’s greatest cause of preventable brain damage and mental retardation, resulting of a loss of 10-15 IQ points globally. Therefore it is essential that the recommended dietary requirement for iodine is met, especially during pregnancy and lactation (200–300 μg/day). <ref><pubmed>10750030</pubmed></ref>

* Clinical manifestations of hypothyroidism include: Myxedematous facies (condition characterized by thickening of the skin, blunting of the senses and intellect, and laboured speech), jaundice, a puffy face and a wide posterior fontanelle with open sutures. The nasal bridge is flat. The mouth may be slightly open revealing macroglossia. Further examination would reveal bradycardia and a protuberant abdomen with a large umbilical hernia. Neurologic examination findings include hypotonia with delayed reflexes. Skin may be cool to touch and mottled in appearance due to circulatory compromise.<ref><pubmed>2903524</pubmed></ref>

===Abnormalities associated with apoptosis and migration of cells in the fetal CNS===

* The migration of cells and cell death are critically important to fetal brain and CNS development. Abnormalities in each of these processes, programmed cell death (apoptosis) in particular, have been shown to result in severe developmental abnormalities in experimental animals. Apoptosis is critically important for appropriate brain development; certain areas in brain may experience up to 50% cell death. <ref><pubmed> 11589424 </pubmed></ref>

In an experiment conducted by kuida et. al 1996, it was observed that mice that were deficient for CPP32 (a protease responsible for apoptosis), were born at a lower frequency than expected, were smaller in size compared to the normal mice and died at an early age. Brain development is significantly affected in CPP32-deficient mice resulting in a variety of hyperplasia and disorganised cell development. <ref><pubmed>8934524</pubmed></ref>

On the other hand, disrupted neuronal migration can lead to an abnormality in cell position. When this happens, the neurons are said to be heterotopic. Abnormalities in neuronal migration have been studied extensively in human cerebral cortex where these defects are associated with a variety of syndromes and diseases, ranging from behavioural disorders (including some forms of schizophrenia, dyslexia and autism) to extremely severe mental retardation and failure to thrive. <ref><pubmed>10532616</pubmed></ref>

===Neural Tube Defects===

Defects which affect the either the brain or the spinal cord in which openings remain. Grastulation occurs in week 3 of embryonic development where specialized cells (dorsal side) structurally change shape leading to the formation of the neural tube. If the neural tube does not close or fuse together properly, then openings remain which lead to various neural tube defects such as Spina bifida cystica and Spina bifida occulta.

'''Anencephaly'''

* A neural tube defect involving abnormal development of the brain and incomplete skull formation leading to high infant mortality rates with infants being stillborn or dying within a few hours after birth.

* The failure of the neural tube to close around the 23rd and 26th day into embryonic development is characteristic of this condition. As a result, the forebrain is severely affected where the cerebrum does not grow and hence partial growth occurs only. The cerebrum has a key importance in maintaining thought, consciousness and coordination whilst having no intact cerebrum rules out the probability of the affected fetus gaining consciousness .

* Increasing one's dietary intake of folic acid notably reduces the incidence of neural tube defects. Consuming 0.4mg of folic acid is sufficient to induce these results.

* Since incomplete skull formation occurs, brain tissue becomes exposed due to the absence of bone covering and therefore leading to further complications.

'''Encephaloceles'''

* Another neural tube defect in which a sac-like projections (including membrane covering) that occurs around the 3-4 week of embryonic development in which neural tube closure has not successfully occurred. The location of these protrusions varies but can be naso-frontal (nose and head), naso-ethmoidal (nose and ethmoid bone), naso-orbital (nose and eyes), meningocele (cerebrospinal fluid and membrane covering) and encephalomeningocele (meningocele with brain tissue as well).

* These sac-like protrusions lead to a variety of abnormal effects which include cerebro-spinal fluid build-up in brain, microcephaly, hydrocephaly, mental retardation, developmental problems, uncoordinated muscle movement and seizures. Consumption of folic acid again has been shown to significantly reduce the occurrence of encephaloceles in infants.

'''Hydranencephaly'''

* A very rare neural tube defect in which the cerebral hemispheres are destroyed (necrotic tissue) with the occupied space being replaced by cerebro-spinal fluid, cortex and white matter remnants within a membranous sac. Interestingly, this condition can also develop in the postnatal peroid due to viral infections or traumatic brain injury. The brain stem may remain intact and functioning in hydranencephalic infants.

* Accompanied with this condition are many effects in which include seizures, hydrocephalus, increases in head circumference,impairment in vision/ body temperature regulation and cerebral palsy. Infants affected by hydranencephaly live typically short lives being no longer than 1 year of age. Lastly, there are no viable treatment options for this condition and only supportive care is available.

'''Iniencephaly'''

* Another neural tube defect involving severe backward bending of the head (retroflexion) with subsequent spinal distortions as well. Affected infants have no neck and hence the scalp of the head is directly joined to the skin of the back (also skin of the face connected to skin of the chest). Other conditions that develop along with iniencephaly are cyclopia, cephalocele and anencephaly. The development of this condition is not solely due to one factor but from various causes (both genetic and environmental factors).

* There are specific factors that have been shown to increase the occurrence of this condition. Malnutrition, reduced folic acid intake and elevated levels of homocysteine in blood are environmental factors that increase the risk of iniencephaly <ref><pubmed> 22408660 </pubmed></ref>. Intake of certain drugs such as anti-histamines and sulphonamide/tetracycline (antibiotics) have also increases this risk <ref><pubmed> 22439066 </pubmed></ref>. Furthermore obesity has been shown to have a significant effect on the incidence of iniencephaly with 1.7-3 fold increase <ref><pubmed> 18538144 </pubmed></ref>.

* In terms of treatment, folic acid supplementation as well as avoiding certain drugs such as those outlined above significantly reduces the occurrence of this condition.

'''Spina Bifida Cystica'''

* A neural tube defect in which involves either the formation of a meningocele or myelomeningocele. Of the two, the meningocele, is the least debilitating in that a cyst-like structure forms when the neural tube does not close properly. The membrane (meninges) is pushed into openings of the vertebrae where spinal fluid builds up within the cyst. The myelomeningocele leads to severe problems as the portion of the nueral tube that is unfused allows the spinal cord to protrude through. As a result, neuronal tissue is highly exposed due to myeloschisis as well as infections and hence may lead to severe complications.

'''Spina Bifida Occulta'''

* A neural tube defect that has minimal complications in comparison to other defects. Furthermore, this defect is hidden in that a tethered spinal cord may arise as well as a thicker filum terminale and diastematomyelia (spinal cord split into two). It is also important to note that no cysts form as opposed to the other more severe spina bifida defects.

==References==

<references/>

2014 Group Project 7

2014-10-23T05:19:43Z

Z3418981: /* Fetal Alcohol Syndrome */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, recieving and integration of information from all parts of the body, serving as the processing center of the bodies nervous system. The CNS controls all bodily functions (sensory and motor), consisting of 2 main organs; The Brain and Spinal Cord

==='''Brain'''===

The Brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

==='''Spinal Cord'''===

The Spinal Cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into

1) Ascending bundles - Transmits Sensory information from the body to the brain

2) Descending bundle - Transmits Motor function information from the brain to the body

Before fetal period, nerulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, the current research models and finding, historic findings and abnormalities that can occur in the fetal period is identified.

==Development during fetal period==

[[File:Schematic_representation_of_the_timeline_of_human_neural_development.jpg|800px]]

A simplified timeline of human neural development (modified) <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

This simplified graph shows a timeline for major events of neural development that occur during fetal and postnatal periods. These events are broadly classified by cell multiplication, cell migration, growth and differentiation and angiogenesis:

* Cell multiplication
** Neurons are proliferated and generated from neural stem cells and progenitor cells (precursor cells) in a process known as neurogenesis in 2nd trimester.
** Cell death and Gliogenesis (glial cells (such as astrocytes) deriving from multipotent neural stem cells) occur in the 3rd trimester.
** Local gliogenesis continues postnatally.

* Cell migration
** Neuronal migration is maximised during 2nd trimester while glial migration is maximised during 3rd trimester

* Growth and differentiation
** Axonal and dendritic arborisation (fine branching structures at the end of nerve fibers) appear by the end of fetal period.
** Synaptogenesis (formation of synapses) and electrical activity is maximised in 3rd trimester (and continued postnatally).
** Cell death due to over-innervation can be observed in late fetal and postnatal period.
** Myelination occurs in late fetal and postnatal period (vast majority of postnatal growth in brain is due to myelination).

* Angiogenesis
** Oxidative metabolism can be seen in late fetal period.
** Capillary networks develop postnatally.

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

'''1. cell proliferation'''

[[Image:Somatosensory cortex of E20 rat.jpeg|frame|400x400px|Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) <ref name="PMID22272298"><pubmed>22272298</pubmed></ref>]]

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

'''2. cell migration'''
[[Image:CNS_passive.jpg|frame|200x150px|Passive cell displacement and outside-to-inside spatiotemporal gradient]][[Image:CNS_active.jpg|frame|350x250px|Active cell migration and inside-to-outside spatiotemporal gradient]]

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways.

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus, hypothalamus, spinal cord, retina, dentate gyrus of the hippocampal formation and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas.

{| style="width:20%; height:170px" align="center"
|-
| [[Image:Internurons migration in cerebral cortex.jpg|frame|500x500px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex <ref name="PMID17726524"><pubmed>17726524</pubmed></ref>]]
|}

'''3. cell differentiation'''

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

=== Brain Development ===

* The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells

* By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

* The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

* Extends from the ninth gestational weeks through to the end of gestation

* Gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding

* Brain development begins rostral in GW8, proceeding caudally until it is complete at GW22 <ref><pubmed>560818</pubmed></ref>

* Formation of Secondary Sulci between GW30-35

* Formation of Tertiary Sulci begins during GW36 and into the postnatal period

* Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

* Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

* The major fibre pathways make up the brain white matter

* AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Neuron Production'''
* The human brain contains billions of neurons which are produced by mid-gestation; during fetal development <ref><pubmed>8361683</pubmed></ref>

* Processes of Neuronal production is initiated by first increasing the size of the Neural progenitor cell population within the body, these cells are mitotic in nature and are capable of forming new cells.

* Initially (from the end of gastrulation through to embryonic day 42), the neural progenitor cell population is increased greatly when the progenitor cells divide through 'symmetrical' mode of cell division. Multiple repeats of the cell division occurs throughout this period. This 'symmetrical' division method brings about the formation of 2 new identical neural progenitor cells

* Mode of cell division changes from a symmetrical cell division type to an 'asymmetrical' cell division from the beginning of E42. This asymmetrical cell division forms 2 different cell types; one Neural progenitor & one Neuron <ref><pubmed>12764028 </pubmed></ref>

* Newly formed Neural progenitor cells remains to undergo more processes of cell division whereas the newly formed neuron moves into position in the developing neocortex

'''Increase in size and weight'''

[[File:Brain ventricles and ganglia development 03.jpg|300px]]

Image of brain and ventricular development <ref name=PMID19339620><pubmed>19339620</pubmed></ref>

[[File:Brain fissure development 02.jpg|300px]]

Image of brain fissure development <ref name=PMID19339620><pubmed>19339620</pubmed></ref>

'''folding: sulcation and gyration'''

[[Image:Dev anat 01.jpg|frame|200x150px|Simplified external lateral (left) view of the brain growth]]

During the fifth and sixth month of gestation, the smooth cortex begins to fold by sulcation and gyration. <ref name=PMID21571694><pubmed>21571694</pubmed></ref>

Sulcation: This is the development of sulci, including primary and secondary. The formation of primary sulci involve the appearance of shallow grooves on the surface of the brain, which then become more deeply infolded, while the formation of secondary sulci is due to the development of side branches of the primary ones <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

Gyration: This is the development of gyrus that occurs during late during fetal development until the end of the pregnancy or after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>. This process is the formation of tertiary sulci, which is the formation of other side branches of the secondary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

{| class="wikitable"
|-
! Weeks of gestation !! Visible anatomical details
|-
| 20-21 || smooth, with the impression of "lissencephalic" brain; wide Sylvian fissures; visible interhemispheric fissure and parieto-occipital fissure
|-
| 22-23 || beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || smooth cerebral cortex surface; visible shallow grooves in the central sulci, interparietal sulci and superior temporal sulci; start of opercularization of Sylvian fissures; presence of calcarine fissures and cingular sulci
|-
| 26 || presence of central and collateral sulci
|-
| 27 || presence of marginal and precentral sulci
|-
| 28 || presence of postcentral and intraparietal sulci
|-
| 29 || presence of superior and inferior frontal sulci; narrower Sylvian fissure; clear corpus callosum; bright white matter; dark cortical ribbon
|-
| 30-31 || beginning of infolding of cortex which is first apparent in the occipital lobe; narrower ventricular system and subarachnoid spaces
|-
| 32 || presence of superior and inferior temporal sulci
|-
| 33 || presence of external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration; compactly and extensively folded cortex
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table of the process of sulcation and gyration <ref name=PMID20608424><pubmed>20608424</pubmed></ref>

=== Spinal Cord Development ===
The spinal cord is formed from parts of the neural tube during embryonic and fetal development

=== Meninges Development ===

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations
|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

{|
|-bgcolor="ECCEF5"
|
===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.

|}
{|
|-bgcolor="CED8F6"
|The following are recent studies that use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

-Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

-The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

-The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.
|}
{|
|-bgcolor="ECCEF5"
|
'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

|}
{|
|-bgcolor="CED8F6"
|
'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.
|}
{|
|-bgcolor="ECCEF5"
|
'''Cortical Overgrowth in Fetuses With Isolated Ventriculomegaly'''
<ref><pubmed> 23508710 </pubmed></ref>

* The condition fetal ventriculomegaly is characterised by dilation of lateral ventricles whilst sharing associations with other malformations. It was hypothesised that using relative brain overgrowth as marked measure of altered brain development is due to the occurrence of ventriculomegaly and to evaluate this brain overgrowth through the use of magnetic resonance imaging (MRI) of fetuses isolated with enlarged ventricles (3rd and 4th ventricles as well as cerebrospinal fluid). Furthermore, significant changes to thalamic volumes, basal ganglia and white matter did not occur between cohorts.

* The study found that there was a sufficient increase in brain volume (overgrowth) of fetuses that had ventriculomegaly in comparison to controls. Also, larger lateral ventricle volumes were yielded with fetuses with ventriculomegaly assessed via 2-dimensional movement of the atrial diameter (ultrasound and MRi) as well as a larger total brain tissue volume. This provides support for the hypothesis in that brain overgrowth can be used as a marked measure for ventriculomegaly with results showing that overgrowth was not localised in one region but across both hemispheres and thus lead to a neural deficit in children (altered neural connectivity).

* Hence, this study has assisted in the improved understanding of the effects of ventriculomegaly on cognition, language and behaviour in children.

===Future Research===

|}

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]
Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age. The most frequent cause of macrocephaly is hydrocephalus.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.
* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period) in the secondary type.

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation.

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.

===Fetal Alcohol Syndrome===
<ref><pubmed> 23809349 </pubmed></ref>

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status.

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.

{| style="width:5%; height:170px" align="center"
|-
| [[Image: Fetal alcohol syndrome.jpg|frame|250x250px|The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref> ]]
|-
| [[Image: Ethanol fetal neural.jpg|frame|350x350px|A mechanism of the effect of ethanol on neural stem cells (NSCs). Ethanol promotes asymmetrical cell division, the formation of radial glial-like cells, leading to the premature depletion of the VZ and its NSCs, and the thickening and cell proliferation in SVZ. The increased migration during early differentiation of ethanol-treated NSCs also leads to the appearance of subpial heterotopias<ref name="PMID22623924"><pubmed>22623924</pubmed></ref>.]]
|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

* All degrees of iodine deficiency (mild: 50-99 μg/day, moderate: 20-49 μg/day and severe≤20 μg/day) affect thyroid function of both mother and the neonate as well as mental development of the child. The damage increases with the degree of deficiency; overt endemic cretinism is the most severe consequence.

* Iodine deficiency disorders refer to complications that arise when the recommended dietary allowance of iodine is not met. These complications include thyroid function abnormalities and when iodine deficiency is severe, endemic goitre and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality.

* Iodine deficiency represents the world’s greatest cause of preventable brain damage and mental retardation, resulting of a loss of 10-15 IQ points globally. Therefore it is essential that the recommended dietary requirement for iodine is met, especially during pregnancy and lactation (200–300 μg/day). <ref><pubmed>10750030</pubmed></ref>

* Clinical manifestations of hypothyroidism include: Myxedematous facies (condition characterized by thickening of the skin, blunting of the senses and intellect, and laboured speech), jaundice, a puffy face and a wide posterior fontanelle with open sutures. The nasal bridge is flat. The mouth may be slightly open revealing macroglossia. Further examination would reveal bradycardia and a protuberant abdomen with a large umbilical hernia. Neurologic examination findings include hypotonia with delayed reflexes. Skin may be cool to touch and mottled in appearance due to circulatory compromise.<ref><pubmed>2903524</pubmed></ref>

===Abnormalities associated with apoptosis and migration of cells in the fetal CNS===

* The migration of cells and cell death are critically important to fetal brain and CNS development. Abnormalities in each of these processes, programmed cell death (apoptosis) in particular, have been shown to result in severe developmental abnormalities in experimental animals. Apoptosis is critically important for appropriate brain development; certain areas in brain may experience up to 50% cell death. <ref><pubmed> 11589424 </pubmed></ref>

In an experiment conducted by kuida et. al 1996, it was observed that mice that were deficient for CPP32 (a protease responsible for apoptosis), were born at a lower frequency than expected, were smaller in size compared to the normal mice and died at an early age. Brain development is significantly affected in CPP32-deficient mice resulting in a variety of hyperplasia and disorganised cell development. <ref><pubmed>8934524</pubmed></ref>

On the other hand, disrupted neuronal migration can lead to an abnormality in cell position. When this happens, the neurons are said to be heterotopic. Abnormalities in neuronal migration have been studied extensively in human cerebral cortex where these defects are associated with a variety of syndromes and diseases, ranging from behavioural disorders (including some forms of schizophrenia, dyslexia and autism) to extremely severe mental retardation and failure to thrive. <ref><pubmed>10532616</pubmed></ref>

===Neural Tube Defects===

Defects which affect the either the brain or the spinal cord in which openings remain. Grastulation occurs in week 3 of embryonic development where specialized cells (dorsal side) structurally change shape leading to the formation of the neural tube. If the neural tube does not close or fuse together properly, then openings remain which lead to various neural tube defects such as Spina bifida cystica and Spina bifida occulta.

'''Anencephaly'''

* A neural tube defect involving abnormal development of the brain and incomplete skull formation leading to high infant mortality rates with infants being stillborn or dying within a few hours after birth.

* The failure of the neural tube to close around the 23rd and 26th day into embryonic development is characteristic of this condition. As a result, the forebrain is severely affected where the cerebrum does not grow and hence partial growth occurs only. The cerebrum has a key importance in maintaining thought, consciousness and coordination whilst having no intact cerebrum rules out the probability of the affected fetus gaining consciousness .

* Increasing one's dietary intake of folic acid notably reduces the incidence of neural tube defects. Consuming 0.4mg of folic acid is sufficient to induce these results.

* Since incomplete skull formation occurs, brain tissue becomes exposed due to the absence of bone covering and therefore leading to further complications.

'''Encephaloceles'''

* Another neural tube defect in which a sac-like projections (including membrane covering) that occurs around the 3-4 week of embryonic development in which neural tube closure has not successfully occurred. The location of these protrusions varies but can be naso-frontal (nose and head), naso-ethmoidal (nose and ethmoid bone), naso-orbital (nose and eyes), meningocele (cerebrospinal fluid and membrane covering) and encephalomeningocele (meningocele with brain tissue as well).

* These sac-like protrusions lead to a variety of abnormal effects which include cerebro-spinal fluid build-up in brain, microcephaly, hydrocephaly, mental retardation, developmental problems, uncoordinated muscle movement and seizures. Consumption of folic acid again has been shown to significantly reduce the occurrence of encephaloceles in infants.

'''Hydranencephaly'''

* A very rare neural tube defect in which the cerebral hemispheres are destroyed (necrotic tissue) with the occupied space being replaced by cerebro-spinal fluid, cortex and white matter remnants within a membranous sac. Interestingly, this condition can also develop in the postnatal peroid due to viral infections or traumatic brain injury. The brain stem may remain intact and functioning in hydranencephalic infants.

* Accompanied with this condition are many effects in which include seizures, hydrocephalus, increases in head circumference,impairment in vision/ body temperature regulation and cerebral palsy. Infants affected by hydranencephaly live typically short lives being no longer than 1 year of age. Lastly, there are no viable treatment options for this condition and only supportive care is available.

'''Iniencephaly'''

* Another neural tube defect involving severe backward bending of the head (retroflexion) with subsequent spinal distortions as well. Affected infants have no neck and hence the scalp of the head is directly joined to the skin of the back (also skin of the face connected to skin of the chest). Other conditions that develop along with iniencephaly are cyclopia, cephalocele and anencephaly. The development of this condition is not solely due to one factor but from various causes (both genetic and environmental factors).

* There are specific factors that have been shown to increase the occurrence of this condition. Malnutrition, reduced folic acid intake and elevated levels of homocysteine in blood are environmental factors that increase the risk of iniencephaly <ref><pubmed> 22408660 </pubmed></ref>. Intake of certain drugs such as anti-histamines and sulphonamide/tetracycline (antibiotics) have also increases this risk <ref><pubmed> 22439066 </pubmed></ref>. Furthermore obesity has been shown to have a significant effect on the incidence of iniencephaly with 1.7-3 fold increase <ref><pubmed> 18538144 </pubmed></ref>.

* In terms of treatment, folic acid supplementation as well as avoiding certain drugs such as those outlined above significantly reduces the occurrence of this condition.

'''Spina Bifida Cystica'''

* A neural tube defect in which involves either the formation of a meningocele or myelomeningocele. Of the two, the meningocele, is the least debilitating in that a cyst-like structure forms when the neural tube does not close properly. The membrane (meninges) is pushed into openings of the vertebrae where spinal fluid builds up within the cyst. The myelomeningocele leads to severe problems as the portion of the nueral tube that is unfused allows the spinal cord to protrude through. As a result, neuronal tissue is highly exposed due to myeloschisis as well as infections and hence may lead to severe complications.

'''Spina Bifida Occulta'''

* A neural tube defect that has minimal complications in comparison to other defects. Furthermore, this defect is hidden in that a tethered spinal cord may arise as well as a thicker filum terminale and diastematomyelia (spinal cord split into two). It is also important to note that no cysts form as opposed to the other more severe spina bifida defects.

==References==

<references/>

2014 Group Project 7

2014-10-23T04:59:06Z

Z3418981: /* Development during fetal period */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, recieving and integration of information from all parts of the body, serving as the processing center of the bodies nervous system. The CNS controls all bodily functions (sensory and motor), consisting of 2 main organs; The Brain and Spinal Cord

==='''Brain'''===

The Brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

==='''Spinal Cord'''===

The Spinal Cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into

1) Ascending bundles - Transmits Sensory information from the body to the brain

2) Descending bundle - Transmits Motor function information from the brain to the body

Before fetal period, nerulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, the current research models and finding, historic findings and abnormalities that can occur in the fetal period is identified.

==Development during fetal period==

[[File:Schematic_representation_of_the_timeline_of_human_neural_development.jpg|800px]]

A simplified timeline of human neural development (modified) <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

This simplified graph shows a timeline for major events of neural development that occur during fetal and postnatal periods. These events are broadly classified by cell multiplication, cell migration, growth and differentiation and angiogenesis:

* Cell multiplication
** Neurons are proliferated and generated from neural stem cells and progenitor cells (precursor cells) in a process known as neurogenesis in 2nd trimester.
** Cell death and Gliogenesis (glial cells (such as astrocytes) deriving from multipotent neural stem cells) occur in the 3rd trimester.
** Local gliogenesis continues postnatally.

* Cell migration
** Neuronal migration is maximised during 2nd trimester while glial migration is maximised during 3rd trimester

* Growth and differentiation
** Axonal and dendritic arborisation (fine branching structures at the end of nerve fibers) appear by the end of fetal period.
** Synaptogenesis (formation of synapses) and electrical activity is maximised in 3rd trimester (and continued postnatally).
** Cell death due to over-innervation can be observed in late fetal and postnatal period.
** Myelination occurs in late fetal and postnatal period (vast majority of postnatal growth in brain is due to myelination).

* Angiogenesis
** Oxidative metabolism can be seen in late fetal period.
** Capillary networks develop postnatally.

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

'''1. cell proliferation'''

[[Image:Somatosensory cortex of E20 rat.jpeg|frame|400x400px|Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) <ref name="PMID22272298"><pubmed>22272298</pubmed></ref>]]

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

'''2. cell migration'''
[[Image:CNS_passive.jpg|frame|200x150px|Passive cell displacement and outside-to-inside spatiotemporal gradient]][[Image:CNS_active.jpg|frame|350x250px|Active cell migration and inside-to-outside spatiotemporal gradient]]

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways.

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus, hypothalamus, spinal cord, retina, dentate gyrus of the hippocampal formation and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas.

{| style="width:20%; height:170px" align="center"
|-
| [[Image:Internurons migration in cerebral cortex.jpg|frame|500x500px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex <ref name="PMID17726524"><pubmed>17726524</pubmed></ref>]]
|}

'''3. cell differentiation'''

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

=== Brain Development ===

* The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells

* By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

* The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

* Extends from the ninth gestational weeks through to the end of gestation

* Gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding

* Brain development begins rostral in GW8, proceeding caudally until it is complete at GW22 <ref><pubmed>560818</pubmed></ref>

* Formation of Secondary Sulci between GW30-35

* Formation of Tertiary Sulci begins during GW36 and into the postnatal period

* Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

* Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

* The major fibre pathways make up the brain white matter

* AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Neuron Production'''
* The human brain contains billions of neurons which are produced by mid-gestation; during fetal development <ref><pubmed>8361683</pubmed></ref>

* Processes of Neuronal production is initiated by first increasing the size of the Neural progenitor cell population within the body, these cells are mitotic in nature and are capable of forming new cells.

* Initially (from the end of gastrulation through to embryonic day 42), the neural progenitor cell population is increased greatly when the progenitor cells divide through 'symmetrical' mode of cell division. Multiple repeats of the cell division occurs throughout this period. This 'symmetrical' division method brings about the formation of 2 new identical neural progenitor cells

* Mode of cell division changes from a symmetrical cell division type to an 'asymmetrical' cell division from the beginning of E42. This asymmetrical cell division forms 2 different cell types; one Neural progenitor & one Neuron <ref><pubmed>12764028 </pubmed></ref>

* Newly formed Neural progenitor cells remains to undergo more processes of cell division whereas the newly formed neuron moves into position in the developing neocortex

'''Increase in size and weight'''

[[File:Brain ventricles and ganglia development 03.jpg|300px]]

Image of brain and ventricular development <ref name=PMID19339620><pubmed>19339620</pubmed></ref>

[[File:Brain fissure development 02.jpg|300px]]

Image of brain fissure development <ref name=PMID19339620><pubmed>19339620</pubmed></ref>

'''folding: sulcation and gyration'''

[[Image:Dev anat 01.jpg|frame|200x150px|Simplified external lateral (left) view of the brain growth]]

During the fifth and sixth month of gestation, the smooth cortex begins to fold by sulcation and gyration. <ref name=PMID21571694><pubmed>21571694</pubmed></ref>

Sulcation: This is the development of sulci, including primary and secondary. The formation of primary sulci involve the appearance of shallow grooves on the surface of the brain, which then become more deeply infolded, while the formation of secondary sulci is due to the development of side branches of the primary ones <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

Gyration: This is the development of gyrus that occurs during late during fetal development until the end of the pregnancy or after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>. This process is the formation of tertiary sulci, which is the formation of other side branches of the secondary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

{| class="wikitable"
|-
! Weeks of gestation !! Visible anatomical details
|-
| 20-21 || smooth, with the impression of "lissencephalic" brain; wide Sylvian fissures; visible interhemispheric fissure and parieto-occipital fissure
|-
| 22-23 || beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || smooth cerebral cortex surface; visible shallow grooves in the central sulci, interparietal sulci and superior temporal sulci; start of opercularization of Sylvian fissures; presence of calcarine fissures and cingular sulci
|-
| 26 || presence of central and collateral sulci
|-
| 27 || presence of marginal and precentral sulci
|-
| 28 || presence of postcentral and intraparietal sulci
|-
| 29 || presence of superior and inferior frontal sulci; narrower Sylvian fissure; clear corpus callosum; bright white matter; dark cortical ribbon
|-
| 30-31 || beginning of infolding of cortex which is first apparent in the occipital lobe; narrower ventricular system and subarachnoid spaces
|-
| 32 || presence of superior and inferior temporal sulci
|-
| 33 || presence of external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration; compactly and extensively folded cortex
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table of the process of sulcation and gyration <ref name=PMID20608424><pubmed>20608424</pubmed></ref>

=== Spinal Cord Development ===
The spinal cord is formed from parts of the neural tube during embryonic and fetal development

=== Meninges Development ===

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations
|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

{|
|-bgcolor="ECCEF5"
|
===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.

|}
{|
|-bgcolor="CED8F6"
|The following are recent studies that use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

-Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

-The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

-The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.
|}
{|
|-bgcolor="ECCEF5"
|
'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

|}
{|
|-bgcolor="CED8F6"
|
'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.
|}
{|
|-bgcolor="ECCEF5"
|
'''Cortical Overgrowth in Fetuses With Isolated Ventriculomegaly'''
<ref><pubmed> 23508710 </pubmed></ref>

* The condition fetal ventriculomegaly is characterised by dilation of lateral ventricles whilst sharing associations with other malformations. It was hypothesised that using relative brain overgrowth as marked measure of altered brain development is due to the occurrence of ventriculomegaly and to evaluate this brain overgrowth through the use of magnetic resonance imaging (MRI) of fetuses isolated with enlarged ventricles (3rd and 4th ventricles as well as cerebrospinal fluid). Furthermore, significant changes to thalamic volumes, basal ganglia and white matter did not occur between cohorts.

* The study found that there was a sufficient increase in brain volume (overgrowth) of fetuses that had ventriculomegaly in comparison to controls. Also, larger lateral ventricle volumes were yielded with fetuses with ventriculomegaly assessed via 2-dimensional movement of the atrial diameter (ultrasound and MRi) as well as a larger total brain tissue volume. This provides support for the hypothesis in that brain overgrowth can be used as a marked measure for ventriculomegaly with results showing that overgrowth was not localised in one region but across both hemispheres and thus lead to a neural deficit in children (altered neural connectivity).

* Hence, this study has assisted in the improved understanding of the effects of ventriculomegaly on cognition, language and behaviour in children.

===Future Research===

|}

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]
Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age. The most frequent cause of macrocephaly is hydrocephalus.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.
* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period) in the secondary type.

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation.

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.

===Fetal Alcohol Syndrome===
<ref><pubmed> 23809349 </pubmed></ref>

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status.

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.

{| style="width:40%; height:170px" align="center"
|-
| [[Image: Fetal alcohol syndrome.jpg|frame|250x250px|The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref> ]]
|-
| [[Image: Ethanol fetal neural.jpg|frame|350x350px|A mechanism of the effect of ethanol on neural stem cells (NSCs). Ethanol promotes asymmetrical cell division, the formation of radial glial-like cells, leading to the premature depletion of the VZ and its NSCs, and the thickening and cell proliferation in SVZ. The increased migration during early differentiation of ethanol-treated NSCs also leads to the appearance of subpial heterotopias<ref name="PMID22623924"><pubmed>22623924</pubmed></ref>.]]
|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

* All degrees of iodine deficiency (mild: 50-99 μg/day, moderate: 20-49 μg/day and severe≤20 μg/day) affect thyroid function of both mother and the neonate as well as mental development of the child. The damage increases with the degree of deficiency; overt endemic cretinism is the most severe consequence.

* Iodine deficiency disorders refer to complications that arise when the recommended dietary allowance of iodine is not met. These complications include thyroid function abnormalities and when iodine deficiency is severe, endemic goitre and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality.

* Iodine deficiency represents the world’s greatest cause of preventable brain damage and mental retardation, resulting of a loss of 10-15 IQ points globally. Therefore it is essential that the recommended dietary requirement for iodine is met, especially during pregnancy and lactation (200–300 μg/day). <ref><pubmed>10750030</pubmed></ref>

* Clinical manifestations of hypothyroidism include: Myxedematous facies (condition characterized by thickening of the skin, blunting of the senses and intellect, and laboured speech), jaundice, a puffy face and a wide posterior fontanelle with open sutures. The nasal bridge is flat. The mouth may be slightly open revealing macroglossia. Further examination would reveal bradycardia and a protuberant abdomen with a large umbilical hernia. Neurologic examination findings include hypotonia with delayed reflexes. Skin may be cool to touch and mottled in appearance due to circulatory compromise.<ref><pubmed>2903524</pubmed></ref>

===Abnormalities associated with apoptosis and migration of cells in the fetal CNS===

* The migration of cells and cell death are critically important to fetal brain and CNS development. Abnormalities in each of these processes, programmed cell death (apoptosis) in particular, have been shown to result in severe developmental abnormalities in experimental animals. Apoptosis is critically important for appropriate brain development; certain areas in brain may experience up to 50% cell death. <ref><pubmed> 11589424 </pubmed></ref>

In an experiment conducted by kuida et. al 1996, it was observed that mice that were deficient for CPP32 (a protease responsible for apoptosis), were born at a lower frequency than expected, were smaller in size compared to the normal mice and died at an early age. Brain development is significantly affected in CPP32-deficient mice resulting in a variety of hyperplasia and disorganised cell development. <ref><pubmed>8934524</pubmed></ref>

On the other hand, disrupted neuronal migration can lead to an abnormality in cell position. When this happens, the neurons are said to be heterotopic. Abnormalities in neuronal migration have been studied extensively in human cerebral cortex where these defects are associated with a variety of syndromes and diseases, ranging from behavioural disorders (including some forms of schizophrenia, dyslexia and autism) to extremely severe mental retardation and failure to thrive. <ref><pubmed>10532616</pubmed></ref>

===Neural Tube Defects===

Defects which affect the either the brain or the spinal cord in which openings remain. Grastulation occurs in week 3 of embryonic development where specialized cells (dorsal side) structurally change shape leading to the formation of the neural tube. If the neural tube does not close or fuse together properly, then openings remain which lead to various neural tube defects such as Spina bifida cystica and Spina bifida occulta.

'''Anencephaly'''

* A neural tube defect involving abnormal development of the brain and incomplete skull formation leading to high infant mortality rates with infants being stillborn or dying within a few hours after birth.

* The failure of the neural tube to close around the 23rd and 26th day into embryonic development is characteristic of this condition. As a result, the forebrain is severely affected where the cerebrum does not grow and hence partial growth occurs only. The cerebrum has a key importance in maintaining thought, consciousness and coordination whilst having no intact cerebrum rules out the probability of the affected fetus gaining consciousness .

* Increasing one's dietary intake of folic acid notably reduces the incidence of neural tube defects. Consuming 0.4mg of folic acid is sufficient to induce these results.

* Since incomplete skull formation occurs, brain tissue becomes exposed due to the absence of bone covering and therefore leading to further complications.

'''Encephaloceles'''

* Another neural tube defect in which a sac-like projections (including membrane covering) that occurs around the 3-4 week of embryonic development in which neural tube closure has not successfully occurred. The location of these protrusions varies but can be naso-frontal (nose and head), naso-ethmoidal (nose and ethmoid bone), naso-orbital (nose and eyes), meningocele (cerebrospinal fluid and membrane covering) and encephalomeningocele (meningocele with brain tissue as well).

* These sac-like protrusions lead to a variety of abnormal effects which include cerebro-spinal fluid build-up in brain, microcephaly, hydrocephaly, mental retardation, developmental problems, uncoordinated muscle movement and seizures. Consumption of folic acid again has been shown to significantly reduce the occurrence of encephaloceles in infants.

'''Hydranencephaly'''

* A very rare neural tube defect in which the cerebral hemispheres are destroyed (necrotic tissue) with the occupied space being replaced by cerebro-spinal fluid, cortex and white matter remnants within a membranous sac. Interestingly, this condition can also develop in the postnatal peroid due to viral infections or traumatic brain injury. The brain stem may remain intact and functioning in hydranencephalic infants.

* Accompanied with this condition are many effects in which include seizures, hydrocephalus, increases in head circumference,impairment in vision/ body temperature regulation and cerebral palsy. Infants affected by hydranencephaly live typically short lives being no longer than 1 year of age. Lastly, there are no viable treatment options for this condition and only supportive care is available.

'''Iniencephaly'''

* Another neural tube defect involving severe backward bending of the head (retroflexion) with subsequent spinal distortions as well. Affected infants have no neck and hence the scalp of the head is directly joined to the skin of the back (also skin of the face connected to skin of the chest). Other conditions that develop along with iniencephaly are cyclopia, cephalocele and anencephaly. The development of this condition is not solely due to one factor but from various causes (both genetic and environmental factors).

* There are specific factors that have been shown to increase the occurrence of this condition. Malnutrition, reduced folic acid intake and elevated levels of homocysteine in blood are environmental factors that increase the risk of iniencephaly <ref><pubmed> 22408660 </pubmed></ref>. Intake of certain drugs such as anti-histamines and sulphonamide/tetracycline (antibiotics) have also increases this risk <ref><pubmed> 22439066 </pubmed></ref>. Furthermore obesity has been shown to have a significant effect on the incidence of iniencephaly with 1.7-3 fold increase <ref><pubmed> 18538144 </pubmed></ref>.

* In terms of treatment, folic acid supplementation as well as avoiding certain drugs such as those outlined above significantly reduces the occurrence of this condition.

'''Spina Bifida Cystica'''

* A neural tube defect in which involves either the formation of a meningocele or myelomeningocele. Of the two, the meningocele, is the least debilitating in that a cyst-like structure forms when the neural tube does not close properly. The membrane (meninges) is pushed into openings of the vertebrae where spinal fluid builds up within the cyst. The myelomeningocele leads to severe problems as the portion of the nueral tube that is unfused allows the spinal cord to protrude through. As a result, neuronal tissue is highly exposed due to myeloschisis as well as infections and hence may lead to severe complications.

'''Spina Bifida Occulta'''

* A neural tube defect that has minimal complications in comparison to other defects. Furthermore, this defect is hidden in that a tethered spinal cord may arise as well as a thicker filum terminale and diastematomyelia (spinal cord split into two). It is also important to note that no cysts form as opposed to the other more severe spina bifida defects.

==References==

<references/>

2014 Group Project 7

2014-10-23T04:52:45Z

Z3418981: /* Cellular process */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, recieving and integration of information from all parts of the body, serving as the processing center of the bodies nervous system. The CNS controls all bodily functions (sensory and motor), consisting of 2 main organs; The Brain and Spinal Cord

==='''Brain'''===

The Brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

==='''Spinal Cord'''===

The Spinal Cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into

1) Ascending bundles - Transmits Sensory information from the body to the brain

2) Descending bundle - Transmits Motor function information from the brain to the body

Before fetal period, nerulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, the current research models and finding, historic findings and abnormalities that can occur in the fetal period is identified.

==Development during fetal period==

[[File:Schematic_representation_of_the_timeline_of_human_neural_development.jpg|800px]]

A simplified timeline of human neural development <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

This simplified graph shows a timeline for major events of neural development that occur during fetal and postnatal periods. These events are broadly classified by cell multiplication, cell migration, growth and differentiation and angiogenesis:

'''Cell multiplication'''
* Neurons are proliferated and generated from neural stem cells and progenitor cells (precursor cells) in a process known as neurogenesis in 2nd trimester.
* Cell death and Gliogenesis (glial cells (such as astrocytes) deriving from multipotent neural stem cells) occur in the 3rd trimester.
* Local gliogenesis continues postnatally.

'''Cell migration'''
* Neuronal migration is maximised during 2nd trimester while glial migration is maximised during 3rd trimester

'''Growth and differentiation'''
* Axonal and dendritic arborisation (fine branching structures at the end of nerve fibers) appear by the end of fetal period.
* Synaptogenesis (formation of synapses) and electrical activity is maximised in 3rd trimester (and continued postnatally).
* Cell death due to over-innervation can be observed in late fetal and postnatal period.
* Myelination occurs in late fetal and postnatal period (vast majority of postnatal growth in brain is due to myelination).

'''Angiogenesis'''
* Oxidative metabolism can be seen in late fetal period.
* Capillary networks develop postnatally.

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

'''1. cell proliferation'''

[[Image:Somatosensory cortex of E20 rat.jpeg|frame|400x400px|Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) <ref name="PMID22272298"><pubmed>22272298</pubmed></ref>]]

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

'''2. cell migration'''
[[Image:CNS_passive.jpg|frame|200x150px|Passive cell displacement and outside-to-inside spatiotemporal gradient]][[Image:CNS_active.jpg|frame|350x250px|Active cell migration and inside-to-outside spatiotemporal gradient]]

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways.

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus, hypothalamus, spinal cord, retina, dentate gyrus of the hippocampal formation and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas.

{| style="width:20%; height:170px" align="center"
|-
| [[Image:Internurons migration in cerebral cortex.jpg|frame|500x500px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex <ref name="PMID17726524"><pubmed>17726524</pubmed></ref>]]
|}

'''3. cell differentiation'''

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

=== Brain Development ===

* The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells

* By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

* The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

* Extends from the ninth gestational weeks through to the end of gestation

* Gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding

* Brain development begins rostral in GW8, proceeding caudally until it is complete at GW22 <ref><pubmed>560818</pubmed></ref>

* Formation of Secondary Sulci between GW30-35

* Formation of Tertiary Sulci begins during GW36 and into the postnatal period

* Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

* Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

* The major fibre pathways make up the brain white matter

* AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Neuron Production'''
* The human brain contains billions of neurons which are produced by mid-gestation; during fetal development <ref><pubmed>8361683</pubmed></ref>

* Processes of Neuronal production is initiated by first increasing the size of the Neural progenitor cell population within the body, these cells are mitotic in nature and are capable of forming new cells.

* Initially (from the end of gastrulation through to embryonic day 42), the neural progenitor cell population is increased greatly when the progenitor cells divide through 'symmetrical' mode of cell division. Multiple repeats of the cell division occurs throughout this period. This 'symmetrical' division method brings about the formation of 2 new identical neural progenitor cells

* Mode of cell division changes from a symmetrical cell division type to an 'asymmetrical' cell division from the beginning of E42. This asymmetrical cell division forms 2 different cell types; one Neural progenitor & one Neuron <ref><pubmed>12764028 </pubmed></ref>

* Newly formed Neural progenitor cells remains to undergo more processes of cell division whereas the newly formed neuron moves into position in the developing neocortex

'''Increase in size and weight'''

[[File:Brain ventricles and ganglia development 03.jpg|300px]]

Image of brain and ventricular development <ref name=PMID19339620><pubmed>19339620</pubmed></ref>

[[File:Brain fissure development 02.jpg|300px]]

Image of brain fissure development <ref name=PMID19339620><pubmed>19339620</pubmed></ref>

'''folding: sulcation and gyration'''

[[Image:Dev anat 01.jpg|frame|200x150px|Simplified external lateral (left) view of the brain growth]]

During the fifth and sixth month of gestation, the smooth cortex begins to fold by sulcation and gyration. <ref name=PMID21571694><pubmed>21571694</pubmed></ref>

Sulcation: This is the development of sulci, including primary and secondary. The formation of primary sulci involve the appearance of shallow grooves on the surface of the brain, which then become more deeply infolded, while the formation of secondary sulci is due to the development of side branches of the primary ones <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

Gyration: This is the development of gyrus that occurs during late during fetal development until the end of the pregnancy or after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>. This process is the formation of tertiary sulci, which is the formation of other side branches of the secondary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

{| class="wikitable"
|-
! Weeks of gestation !! Visible anatomical details
|-
| 20-21 || smooth, with the impression of "lissencephalic" brain; wide Sylvian fissures; visible interhemispheric fissure and parieto-occipital fissure
|-
| 22-23 || beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || smooth cerebral cortex surface; visible shallow grooves in the central sulci, interparietal sulci and superior temporal sulci; start of opercularization of Sylvian fissures; presence of calcarine fissures and cingular sulci
|-
| 26 || presence of central and collateral sulci
|-
| 27 || presence of marginal and precentral sulci
|-
| 28 || presence of postcentral and intraparietal sulci
|-
| 29 || presence of superior and inferior frontal sulci; narrower Sylvian fissure; clear corpus callosum; bright white matter; dark cortical ribbon
|-
| 30-31 || beginning of infolding of cortex which is first apparent in the occipital lobe; narrower ventricular system and subarachnoid spaces
|-
| 32 || presence of superior and inferior temporal sulci
|-
| 33 || presence of external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration; compactly and extensively folded cortex
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table of the process of sulcation and gyration <ref name=PMID20608424><pubmed>20608424</pubmed></ref>

=== Spinal Cord Development ===
The spinal cord is formed from parts of the neural tube during embryonic and fetal development

=== Meninges Development ===

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations
|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

{|
|-bgcolor="ECCEF5"
|
===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.

|}
{|
|-bgcolor="CED8F6"
|The following are recent studies that use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

-Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

-The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

-The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.
|}
{|
|-bgcolor="ECCEF5"
|
'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

|}
{|
|-bgcolor="CED8F6"
|
'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.
|}
{|
|-bgcolor="ECCEF5"
|
'''Cortical Overgrowth in Fetuses With Isolated Ventriculomegaly'''
<ref><pubmed> 23508710 </pubmed></ref>

* The condition fetal ventriculomegaly is characterised by dilation of lateral ventricles whilst sharing associations with other malformations. It was hypothesised that using relative brain overgrowth as marked measure of altered brain development is due to the occurrence of ventriculomegaly and to evaluate this brain overgrowth through the use of magnetic resonance imaging (MRI) of fetuses isolated with enlarged ventricles (3rd and 4th ventricles as well as cerebrospinal fluid). Furthermore, significant changes to thalamic volumes, basal ganglia and white matter did not occur between cohorts.

* The study found that there was a sufficient increase in brain volume (overgrowth) of fetuses that had ventriculomegaly in comparison to controls. Also, larger lateral ventricle volumes were yielded with fetuses with ventriculomegaly assessed via 2-dimensional movement of the atrial diameter (ultrasound and MRi) as well as a larger total brain tissue volume. This provides support for the hypothesis in that brain overgrowth can be used as a marked measure for ventriculomegaly with results showing that overgrowth was not localised in one region but across both hemispheres and thus lead to a neural deficit in children (altered neural connectivity).

* Hence, this study has assisted in the improved understanding of the effects of ventriculomegaly on cognition, language and behaviour in children.

===Future Research===

|}

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]
Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age. The most frequent cause of macrocephaly is hydrocephalus.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.
* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period) in the secondary type.

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation.

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.

===Fetal Alcohol Syndrome===
<ref><pubmed> 23809349 </pubmed></ref>

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status.

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.

{| style="width:40%; height:170px" align="center"
|-
| [[Image: Fetal alcohol syndrome.jpg|frame|250x250px|The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref> ]]
|-
| [[Image: Ethanol fetal neural.jpg|frame|350x350px|A mechanism of the effect of ethanol on neural stem cells (NSCs). Ethanol promotes asymmetrical cell division, the formation of radial glial-like cells, leading to the premature depletion of the VZ and its NSCs, and the thickening and cell proliferation in SVZ. The increased migration during early differentiation of ethanol-treated NSCs also leads to the appearance of subpial heterotopias<ref name="PMID22623924"><pubmed>22623924</pubmed></ref>.]]
|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

* All degrees of iodine deficiency (mild: 50-99 μg/day, moderate: 20-49 μg/day and severe≤20 μg/day) affect thyroid function of both mother and the neonate as well as mental development of the child. The damage increases with the degree of deficiency; overt endemic cretinism is the most severe consequence.

* Iodine deficiency disorders refer to complications that arise when the recommended dietary allowance of iodine is not met. These complications include thyroid function abnormalities and when iodine deficiency is severe, endemic goitre and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality.

* Iodine deficiency represents the world’s greatest cause of preventable brain damage and mental retardation, resulting of a loss of 10-15 IQ points globally. Therefore it is essential that the recommended dietary requirement for iodine is met, especially during pregnancy and lactation (200–300 μg/day). <ref><pubmed>10750030</pubmed></ref>

* Clinical manifestations of hypothyroidism include: Myxedematous facies (condition characterized by thickening of the skin, blunting of the senses and intellect, and laboured speech), jaundice, a puffy face and a wide posterior fontanelle with open sutures. The nasal bridge is flat. The mouth may be slightly open revealing macroglossia. Further examination would reveal bradycardia and a protuberant abdomen with a large umbilical hernia. Neurologic examination findings include hypotonia with delayed reflexes. Skin may be cool to touch and mottled in appearance due to circulatory compromise.<ref><pubmed>2903524</pubmed></ref>

===Abnormalities associated with apoptosis and migration of cells in the fetal CNS===

* The migration of cells and cell death are critically important to fetal brain and CNS development. Abnormalities in each of these processes, programmed cell death (apoptosis) in particular, have been shown to result in severe developmental abnormalities in experimental animals. Apoptosis is critically important for appropriate brain development; certain areas in brain may experience up to 50% cell death. <ref><pubmed> 11589424 </pubmed></ref>

In an experiment conducted by kuida et. al 1996, it was observed that mice that were deficient for CPP32 (a protease responsible for apoptosis), were born at a lower frequency than expected, were smaller in size compared to the normal mice and died at an early age. Brain development is significantly affected in CPP32-deficient mice resulting in a variety of hyperplasia and disorganised cell development. <ref><pubmed>8934524</pubmed></ref>

On the other hand, disrupted neuronal migration can lead to an abnormality in cell position. When this happens, the neurons are said to be heterotopic. Abnormalities in neuronal migration have been studied extensively in human cerebral cortex where these defects are associated with a variety of syndromes and diseases, ranging from behavioural disorders (including some forms of schizophrenia, dyslexia and autism) to extremely severe mental retardation and failure to thrive. <ref><pubmed>10532616</pubmed></ref>

===Neural Tube Defects===

Defects which affect the either the brain or the spinal cord in which openings remain. Grastulation occurs in week 3 of embryonic development where specialized cells (dorsal side) structurally change shape leading to the formation of the neural tube. If the neural tube does not close or fuse together properly, then openings remain which lead to various neural tube defects such as Spina bifida cystica and Spina bifida occulta.

'''Anencephaly'''

* A neural tube defect involving abnormal development of the brain and incomplete skull formation leading to high infant mortality rates with infants being stillborn or dying within a few hours after birth.

* The failure of the neural tube to close around the 23rd and 26th day into embryonic development is characteristic of this condition. As a result, the forebrain is severely affected where the cerebrum does not grow and hence partial growth occurs only. The cerebrum has a key importance in maintaining thought, consciousness and coordination whilst having no intact cerebrum rules out the probability of the affected fetus gaining consciousness .

* Increasing one's dietary intake of folic acid notably reduces the incidence of neural tube defects. Consuming 0.4mg of folic acid is sufficient to induce these results.

* Since incomplete skull formation occurs, brain tissue becomes exposed due to the absence of bone covering and therefore leading to further complications.

'''Encephaloceles'''

* Another neural tube defect in which a sac-like projections (including membrane covering) that occurs around the 3-4 week of embryonic development in which neural tube closure has not successfully occurred. The location of these protrusions varies but can be naso-frontal (nose and head), naso-ethmoidal (nose and ethmoid bone), naso-orbital (nose and eyes), meningocele (cerebrospinal fluid and membrane covering) and encephalomeningocele (meningocele with brain tissue as well).

* These sac-like protrusions lead to a variety of abnormal effects which include cerebro-spinal fluid build-up in brain, microcephaly, hydrocephaly, mental retardation, developmental problems, uncoordinated muscle movement and seizures. Consumption of folic acid again has been shown to significantly reduce the occurrence of encephaloceles in infants.

'''Hydranencephaly'''

* A very rare neural tube defect in which the cerebral hemispheres are destroyed (necrotic tissue) with the occupied space being replaced by cerebro-spinal fluid, cortex and white matter remnants within a membranous sac. Interestingly, this condition can also develop in the postnatal peroid due to viral infections or traumatic brain injury. The brain stem may remain intact and functioning in hydranencephalic infants.

* Accompanied with this condition are many effects in which include seizures, hydrocephalus, increases in head circumference,impairment in vision/ body temperature regulation and cerebral palsy. Infants affected by hydranencephaly live typically short lives being no longer than 1 year of age. Lastly, there are no viable treatment options for this condition and only supportive care is available.

'''Iniencephaly'''

* Another neural tube defect involving severe backward bending of the head (retroflexion) with subsequent spinal distortions as well. Affected infants have no neck and hence the scalp of the head is directly joined to the skin of the back (also skin of the face connected to skin of the chest). Other conditions that develop along with iniencephaly are cyclopia, cephalocele and anencephaly. The development of this condition is not solely due to one factor but from various causes (both genetic and environmental factors).

* There are specific factors that have been shown to increase the occurrence of this condition. Malnutrition, reduced folic acid intake and elevated levels of homocysteine in blood are environmental factors that increase the risk of iniencephaly <ref><pubmed> 22408660 </pubmed></ref>. Intake of certain drugs such as anti-histamines and sulphonamide/tetracycline (antibiotics) have also increases this risk <ref><pubmed> 22439066 </pubmed></ref>. Furthermore obesity has been shown to have a significant effect on the incidence of iniencephaly with 1.7-3 fold increase <ref><pubmed> 18538144 </pubmed></ref>.

* In terms of treatment, folic acid supplementation as well as avoiding certain drugs such as those outlined above significantly reduces the occurrence of this condition.

'''Spina Bifida Cystica'''

* A neural tube defect in which involves either the formation of a meningocele or myelomeningocele. Of the two, the meningocele, is the least debilitating in that a cyst-like structure forms when the neural tube does not close properly. The membrane (meninges) is pushed into openings of the vertebrae where spinal fluid builds up within the cyst. The myelomeningocele leads to severe problems as the portion of the nueral tube that is unfused allows the spinal cord to protrude through. As a result, neuronal tissue is highly exposed due to myeloschisis as well as infections and hence may lead to severe complications.

'''Spina Bifida Occulta'''

* A neural tube defect that has minimal complications in comparison to other defects. Furthermore, this defect is hidden in that a tethered spinal cord may arise as well as a thicker filum terminale and diastematomyelia (spinal cord split into two). It is also important to note that no cysts form as opposed to the other more severe spina bifida defects.

==References==

<references/>

2014 Group Project 7

2014-10-23T04:50:33Z

Z3418981: /* Cellular process */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, recieving and integration of information from all parts of the body, serving as the processing center of the bodies nervous system. The CNS controls all bodily functions (sensory and motor), consisting of 2 main organs; The Brain and Spinal Cord

==='''Brain'''===

The Brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

==='''Spinal Cord'''===

The Spinal Cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into

1) Ascending bundles - Transmits Sensory information from the body to the brain

2) Descending bundle - Transmits Motor function information from the brain to the body

Before fetal period, nerulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, the current research models and finding, historic findings and abnormalities that can occur in the fetal period is identified.

==Development during fetal period==

[[File:Schematic_representation_of_the_timeline_of_human_neural_development.jpg|800px]]

A simplified timeline of human neural development <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

This simplified graph shows a timeline for major events of neural development that occur during fetal and postnatal periods. These events are broadly classified by cell multiplication, cell migration, growth and differentiation and angiogenesis:

'''Cell multiplication'''
* Neurons are proliferated and generated from neural stem cells and progenitor cells (precursor cells) in a process known as neurogenesis in 2nd trimester.
* Cell death and Gliogenesis (glial cells (such as astrocytes) deriving from multipotent neural stem cells) occur in the 3rd trimester.
* Local gliogenesis continues postnatally.

'''Cell migration'''
* Neuronal migration is maximised during 2nd trimester while glial migration is maximised during 3rd trimester

'''Growth and differentiation'''
* Axonal and dendritic arborisation (fine branching structures at the end of nerve fibers) appear by the end of fetal period.
* Synaptogenesis (formation of synapses) and electrical activity is maximised in 3rd trimester (and continued postnatally).
* Cell death due to over-innervation can be observed in late fetal and postnatal period.
* Myelination occurs in late fetal and postnatal period (vast majority of postnatal growth in brain is due to myelination).

'''Angiogenesis'''
* Oxidative metabolism can be seen in late fetal period.
* Capillary networks develop postnatally.

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

'''1. cell proliferation'''

[[Image:Somatosensory cortex of E20 rat.jpeg|frame|400x400px|Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) <ref name="PMID22272298"><pubmed>22272298</pubmed></ref>]]

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

'''2. cell migration'''
[[Image:CNS_passive.jpg|frame|200x150px|Passive cell displacement and outside-to-inside spatiotemporal gradient]][[Image:CNS_active.jpg|frame|350x250px|Active cell migration and inside-to-outside spatiotemporal gradient]]

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways.

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus, hypothalamus, spinal cord, retina, dentate gyrus of the hippocampal formation and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas.

{| style="width:80%; height:170px" align="center"
|-
| [[Image:Internurons migration in cerebral cortex.jpg|frame|500x500px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex <ref name="PMID17726524"><pubmed>17726524</pubmed></ref>]]
|}

'''3. cell differentiation'''

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

=== Brain Development ===

* The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells

* By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

* The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

* Extends from the ninth gestational weeks through to the end of gestation

* Gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding

* Brain development begins rostral in GW8, proceeding caudally until it is complete at GW22 <ref><pubmed>560818</pubmed></ref>

* Formation of Secondary Sulci between GW30-35

* Formation of Tertiary Sulci begins during GW36 and into the postnatal period

* Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

* Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

* The major fibre pathways make up the brain white matter

* AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Neuron Production'''
* The human brain contains billions of neurons which are produced by mid-gestation; during fetal development <ref><pubmed>8361683</pubmed></ref>

* Processes of Neuronal production is initiated by first increasing the size of the Neural progenitor cell population within the body, these cells are mitotic in nature and are capable of forming new cells.

* Initially (from the end of gastrulation through to embryonic day 42), the neural progenitor cell population is increased greatly when the progenitor cells divide through 'symmetrical' mode of cell division. Multiple repeats of the cell division occurs throughout this period. This 'symmetrical' division method brings about the formation of 2 new identical neural progenitor cells

* Mode of cell division changes from a symmetrical cell division type to an 'asymmetrical' cell division from the beginning of E42. This asymmetrical cell division forms 2 different cell types; one Neural progenitor & one Neuron <ref><pubmed>12764028 </pubmed></ref>

* Newly formed Neural progenitor cells remains to undergo more processes of cell division whereas the newly formed neuron moves into position in the developing neocortex

'''Increase in size and weight'''

[[File:Brain ventricles and ganglia development 03.jpg|300px]]

Image of brain and ventricular development <ref name=PMID19339620><pubmed>19339620</pubmed></ref>

[[File:Brain fissure development 02.jpg|300px]]

Image of brain fissure development <ref name=PMID19339620><pubmed>19339620</pubmed></ref>

'''folding: sulcation and gyration'''

[[Image:Dev anat 01.jpg|frame|200x150px|Simplified external lateral (left) view of the brain growth]]

During the fifth and sixth month of gestation, the smooth cortex begins to fold by sulcation and gyration. <ref name=PMID21571694><pubmed>21571694</pubmed></ref>

Sulcation: This is the development of sulci, including primary and secondary. The formation of primary sulci involve the appearance of shallow grooves on the surface of the brain, which then become more deeply infolded, while the formation of secondary sulci is due to the development of side branches of the primary ones <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

Gyration: This is the development of gyrus that occurs during late during fetal development until the end of the pregnancy or after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>. This process is the formation of tertiary sulci, which is the formation of other side branches of the secondary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

{| class="wikitable"
|-
! Weeks of gestation !! Visible anatomical details
|-
| 20-21 || smooth, with the impression of "lissencephalic" brain; wide Sylvian fissures; visible interhemispheric fissure and parieto-occipital fissure
|-
| 22-23 || beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || smooth cerebral cortex surface; visible shallow grooves in the central sulci, interparietal sulci and superior temporal sulci; start of opercularization of Sylvian fissures; presence of calcarine fissures and cingular sulci
|-
| 26 || presence of central and collateral sulci
|-
| 27 || presence of marginal and precentral sulci
|-
| 28 || presence of postcentral and intraparietal sulci
|-
| 29 || presence of superior and inferior frontal sulci; narrower Sylvian fissure; clear corpus callosum; bright white matter; dark cortical ribbon
|-
| 30-31 || beginning of infolding of cortex which is first apparent in the occipital lobe; narrower ventricular system and subarachnoid spaces
|-
| 32 || presence of superior and inferior temporal sulci
|-
| 33 || presence of external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration; compactly and extensively folded cortex
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table of the process of sulcation and gyration <ref name=PMID20608424><pubmed>20608424</pubmed></ref>

=== Spinal Cord Development ===
The spinal cord is formed from parts of the neural tube during embryonic and fetal development

=== Meninges Development ===

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations
|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

{|
|-bgcolor="ECCEF5"
|
===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.

|}
{|
|-bgcolor="CED8F6"
|The following are recent studies that use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

-Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

-The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

-The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.
|}
{|
|-bgcolor="ECCEF5"
|
'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

|}
{|
|-bgcolor="CED8F6"
|
'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.
|}
{|
|-bgcolor="ECCEF5"
|
'''Cortical Overgrowth in Fetuses With Isolated Ventriculomegaly'''
<ref><pubmed> 23508710 </pubmed></ref>

* The condition fetal ventriculomegaly is characterised by dilation of lateral ventricles whilst sharing associations with other malformations. It was hypothesised that using relative brain overgrowth as marked measure of altered brain development is due to the occurrence of ventriculomegaly and to evaluate this brain overgrowth through the use of magnetic resonance imaging (MRI) of fetuses isolated with enlarged ventricles (3rd and 4th ventricles as well as cerebrospinal fluid). Furthermore, significant changes to thalamic volumes, basal ganglia and white matter did not occur between cohorts.

* The study found that there was a sufficient increase in brain volume (overgrowth) of fetuses that had ventriculomegaly in comparison to controls. Also, larger lateral ventricle volumes were yielded with fetuses with ventriculomegaly assessed via 2-dimensional movement of the atrial diameter (ultrasound and MRi) as well as a larger total brain tissue volume. This provides support for the hypothesis in that brain overgrowth can be used as a marked measure for ventriculomegaly with results showing that overgrowth was not localised in one region but across both hemispheres and thus lead to a neural deficit in children (altered neural connectivity).

* Hence, this study has assisted in the improved understanding of the effects of ventriculomegaly on cognition, language and behaviour in children.

===Future Research===

|}

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]
Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age. The most frequent cause of macrocephaly is hydrocephalus.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.
* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period) in the secondary type.

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation.

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.

===Fetal Alcohol Syndrome===
<ref><pubmed> 23809349 </pubmed></ref>

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status.

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.

{| style="width:40%; height:170px" align="center"
|-
| [[Image: Fetal alcohol syndrome.jpg|frame|250x250px|The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref> ]]
|-
| [[Image: Ethanol fetal neural.jpg|frame|350x350px|A mechanism of the effect of ethanol on neural stem cells (NSCs). Ethanol promotes asymmetrical cell division, the formation of radial glial-like cells, leading to the premature depletion of the VZ and its NSCs, and the thickening and cell proliferation in SVZ. The increased migration during early differentiation of ethanol-treated NSCs also leads to the appearance of subpial heterotopias<ref name="PMID22623924"><pubmed>22623924</pubmed></ref>.]]
|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

* All degrees of iodine deficiency (mild: 50-99 μg/day, moderate: 20-49 μg/day and severe≤20 μg/day) affect thyroid function of both mother and the neonate as well as mental development of the child. The damage increases with the degree of deficiency; overt endemic cretinism is the most severe consequence.

* Iodine deficiency disorders refer to complications that arise when the recommended dietary allowance of iodine is not met. These complications include thyroid function abnormalities and when iodine deficiency is severe, endemic goitre and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality.

* Iodine deficiency represents the world’s greatest cause of preventable brain damage and mental retardation, resulting of a loss of 10-15 IQ points globally. Therefore it is essential that the recommended dietary requirement for iodine is met, especially during pregnancy and lactation (200–300 μg/day). <ref><pubmed>10750030</pubmed></ref>

* Clinical manifestations of hypothyroidism include: Myxedematous facies (condition characterized by thickening of the skin, blunting of the senses and intellect, and laboured speech), jaundice, a puffy face and a wide posterior fontanelle with open sutures. The nasal bridge is flat. The mouth may be slightly open revealing macroglossia. Further examination would reveal bradycardia and a protuberant abdomen with a large umbilical hernia. Neurologic examination findings include hypotonia with delayed reflexes. Skin may be cool to touch and mottled in appearance due to circulatory compromise.<ref><pubmed>2903524</pubmed></ref>

===Abnormalities associated with apoptosis and migration of cells in the fetal CNS===

* The migration of cells and cell death are critically important to fetal brain and CNS development. Abnormalities in each of these processes, programmed cell death (apoptosis) in particular, have been shown to result in severe developmental abnormalities in experimental animals. Apoptosis is critically important for appropriate brain development; certain areas in brain may experience up to 50% cell death. <ref><pubmed> 11589424 </pubmed></ref>

In an experiment conducted by kuida et. al 1996, it was observed that mice that were deficient for CPP32 (a protease responsible for apoptosis), were born at a lower frequency than expected, were smaller in size compared to the normal mice and died at an early age. Brain development is significantly affected in CPP32-deficient mice resulting in a variety of hyperplasia and disorganised cell development. <ref><pubmed>8934524</pubmed></ref>

On the other hand, disrupted neuronal migration can lead to an abnormality in cell position. When this happens, the neurons are said to be heterotopic. Abnormalities in neuronal migration have been studied extensively in human cerebral cortex where these defects are associated with a variety of syndromes and diseases, ranging from behavioural disorders (including some forms of schizophrenia, dyslexia and autism) to extremely severe mental retardation and failure to thrive. <ref><pubmed>10532616</pubmed></ref>

===Neural Tube Defects===

Defects which affect the either the brain or the spinal cord in which openings remain. Grastulation occurs in week 3 of embryonic development where specialized cells (dorsal side) structurally change shape leading to the formation of the neural tube. If the neural tube does not close or fuse together properly, then openings remain which lead to various neural tube defects such as Spina bifida cystica and Spina bifida occulta.

'''Anencephaly'''

* A neural tube defect involving abnormal development of the brain and incomplete skull formation leading to high infant mortality rates with infants being stillborn or dying within a few hours after birth.

* The failure of the neural tube to close around the 23rd and 26th day into embryonic development is characteristic of this condition. As a result, the forebrain is severely affected where the cerebrum does not grow and hence partial growth occurs only. The cerebrum has a key importance in maintaining thought, consciousness and coordination whilst having no intact cerebrum rules out the probability of the affected fetus gaining consciousness .

* Increasing one's dietary intake of folic acid notably reduces the incidence of neural tube defects. Consuming 0.4mg of folic acid is sufficient to induce these results.

* Since incomplete skull formation occurs, brain tissue becomes exposed due to the absence of bone covering and therefore leading to further complications.

'''Encephaloceles'''

* Another neural tube defect in which a sac-like projections (including membrane covering) that occurs around the 3-4 week of embryonic development in which neural tube closure has not successfully occurred. The location of these protrusions varies but can be naso-frontal (nose and head), naso-ethmoidal (nose and ethmoid bone), naso-orbital (nose and eyes), meningocele (cerebrospinal fluid and membrane covering) and encephalomeningocele (meningocele with brain tissue as well).

* These sac-like protrusions lead to a variety of abnormal effects which include cerebro-spinal fluid build-up in brain, microcephaly, hydrocephaly, mental retardation, developmental problems, uncoordinated muscle movement and seizures. Consumption of folic acid again has been shown to significantly reduce the occurrence of encephaloceles in infants.

'''Hydranencephaly'''

* A very rare neural tube defect in which the cerebral hemispheres are destroyed (necrotic tissue) with the occupied space being replaced by cerebro-spinal fluid, cortex and white matter remnants within a membranous sac. Interestingly, this condition can also develop in the postnatal peroid due to viral infections or traumatic brain injury. The brain stem may remain intact and functioning in hydranencephalic infants.

* Accompanied with this condition are many effects in which include seizures, hydrocephalus, increases in head circumference,impairment in vision/ body temperature regulation and cerebral palsy. Infants affected by hydranencephaly live typically short lives being no longer than 1 year of age. Lastly, there are no viable treatment options for this condition and only supportive care is available.

'''Iniencephaly'''

* Another neural tube defect involving severe backward bending of the head (retroflexion) with subsequent spinal distortions as well. Affected infants have no neck and hence the scalp of the head is directly joined to the skin of the back (also skin of the face connected to skin of the chest). Other conditions that develop along with iniencephaly are cyclopia, cephalocele and anencephaly. The development of this condition is not solely due to one factor but from various causes (both genetic and environmental factors).

* There are specific factors that have been shown to increase the occurrence of this condition. Malnutrition, reduced folic acid intake and elevated levels of homocysteine in blood are environmental factors that increase the risk of iniencephaly <ref><pubmed> 22408660 </pubmed></ref>. Intake of certain drugs such as anti-histamines and sulphonamide/tetracycline (antibiotics) have also increases this risk <ref><pubmed> 22439066 </pubmed></ref>. Furthermore obesity has been shown to have a significant effect on the incidence of iniencephaly with 1.7-3 fold increase <ref><pubmed> 18538144 </pubmed></ref>.

* In terms of treatment, folic acid supplementation as well as avoiding certain drugs such as those outlined above significantly reduces the occurrence of this condition.

'''Spina Bifida Cystica'''

* A neural tube defect in which involves either the formation of a meningocele or myelomeningocele. Of the two, the meningocele, is the least debilitating in that a cyst-like structure forms when the neural tube does not close properly. The membrane (meninges) is pushed into openings of the vertebrae where spinal fluid builds up within the cyst. The myelomeningocele leads to severe problems as the portion of the nueral tube that is unfused allows the spinal cord to protrude through. As a result, neuronal tissue is highly exposed due to myeloschisis as well as infections and hence may lead to severe complications.

'''Spina Bifida Occulta'''

* A neural tube defect that has minimal complications in comparison to other defects. Furthermore, this defect is hidden in that a tethered spinal cord may arise as well as a thicker filum terminale and diastematomyelia (spinal cord split into two). It is also important to note that no cysts form as opposed to the other more severe spina bifida defects.

==References==

<references/>

2014 Group Project 7

2014-10-23T04:47:42Z

Z3418981: /* Cellular process */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, recieving and integration of information from all parts of the body, serving as the processing center of the bodies nervous system. The CNS controls all bodily functions (sensory and motor), consisting of 2 main organs; The Brain and Spinal Cord

==='''Brain'''===

The Brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

==='''Spinal Cord'''===

The Spinal Cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into

1) Ascending bundles - Transmits Sensory information from the body to the brain

2) Descending bundle - Transmits Motor function information from the brain to the body

Before fetal period, nerulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, the current research models and finding, historic findings and abnormalities that can occur in the fetal period is identified.

==Development during fetal period==

[[File:Schematic_representation_of_the_timeline_of_human_neural_development.jpg|800px]]

A simplified timeline of human neural development <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

This simplified graph shows a timeline for major events of neural development that occur during fetal and postnatal periods. These events are broadly classified by cell multiplication, cell migration, growth and differentiation and angiogenesis:

'''Cell multiplication'''
* Neurons are proliferated and generated from neural stem cells and progenitor cells (precursor cells) in a process known as neurogenesis in 2nd trimester.
* Cell death and Gliogenesis (glial cells (such as astrocytes) deriving from multipotent neural stem cells) occur in the 3rd trimester.
* Local gliogenesis continues postnatally.

'''Cell migration'''
* Neuronal migration is maximised during 2nd trimester while glial migration is maximised during 3rd trimester

'''Growth and differentiation'''
* Axonal and dendritic arborisation (fine branching structures at the end of nerve fibers) appear by the end of fetal period.
* Synaptogenesis (formation of synapses) and electrical activity is maximised in 3rd trimester (and continued postnatally).
* Cell death due to over-innervation can be observed in late fetal and postnatal period.
* Myelination occurs in late fetal and postnatal period (vast majority of postnatal growth in brain is due to myelination).

'''Angiogenesis'''
* Oxidative metabolism can be seen in late fetal period.
* Capillary networks develop postnatally.

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

'''1. cell proliferation'''

[[Image:Somatosensory cortex of E20 rat.jpeg|frame|400x400px|Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) <ref name="PMID22272298"><pubmed>22272298</pubmed></ref>]]

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

'''2. cell migration'''
[[Image:CNS_passive.jpg|frame|200x150px|Passive cell displacement and outside-to-inside spatiotemporal gradient]][[Image:CNS_active.jpg|frame|350x250px|Active cell migration and inside-to-outside spatiotemporal gradient]]

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways.

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus, hypothalamus, spinal cord, retina, dentate gyrus of the hippocampal formation and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas.

{| style="width:50%; height:170px" align="center"
|-
| [[Image:Internurons migration in cerebral cortex.jpg|frame|500x500px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex <ref name="PMID17726524"><pubmed>17726524</pubmed></ref>]]
|}

'''3. cell differentiation'''

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

=== Brain Development ===

* The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells

* By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

* The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

* Extends from the ninth gestational weeks through to the end of gestation

* Gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding

* Brain development begins rostral in GW8, proceeding caudally until it is complete at GW22 <ref><pubmed>560818</pubmed></ref>

* Formation of Secondary Sulci between GW30-35

* Formation of Tertiary Sulci begins during GW36 and into the postnatal period

* Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

* Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

* The major fibre pathways make up the brain white matter

* AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Neuron Production'''
* The human brain contains billions of neurons which are produced by mid-gestation; during fetal development <ref><pubmed>8361683</pubmed></ref>

* Processes of Neuronal production is initiated by first increasing the size of the Neural progenitor cell population within the body, these cells are mitotic in nature and are capable of forming new cells.

* Initially (from the end of gastrulation through to embryonic day 42), the neural progenitor cell population is increased greatly when the progenitor cells divide through 'symmetrical' mode of cell division. Multiple repeats of the cell division occurs throughout this period. This 'symmetrical' division method brings about the formation of 2 new identical neural progenitor cells

* Mode of cell division changes from a symmetrical cell division type to an 'asymmetrical' cell division from the beginning of E42. This asymmetrical cell division forms 2 different cell types; one Neural progenitor & one Neuron <ref><pubmed>12764028 </pubmed></ref>

* Newly formed Neural progenitor cells remains to undergo more processes of cell division whereas the newly formed neuron moves into position in the developing neocortex

'''Increase in size and weight'''

[[File:Brain ventricles and ganglia development 03.jpg|300px]]

Image of brain and ventricular development <ref name=PMID19339620><pubmed>19339620</pubmed></ref>

[[File:Brain fissure development 02.jpg|300px]]

Image of brain fissure development <ref name=PMID19339620><pubmed>19339620</pubmed></ref>

'''folding: sulcation and gyration'''

[[Image:Dev anat 01.jpg|frame|200x150px|Simplified external lateral (left) view of the brain growth]]

During the fifth and sixth month of gestation, the smooth cortex begins to fold by sulcation and gyration. <ref name=PMID21571694><pubmed>21571694</pubmed></ref>

Sulcation: This is the development of sulci, including primary and secondary. The formation of primary sulci involve the appearance of shallow grooves on the surface of the brain, which then become more deeply infolded, while the formation of secondary sulci is due to the development of side branches of the primary ones <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

Gyration: This is the development of gyrus that occurs during late during fetal development until the end of the pregnancy or after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>. This process is the formation of tertiary sulci, which is the formation of other side branches of the secondary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

{| class="wikitable"
|-
! Weeks of gestation !! Visible anatomical details
|-
| 20-21 || smooth, with the impression of "lissencephalic" brain; wide Sylvian fissures; visible interhemispheric fissure and parieto-occipital fissure
|-
| 22-23 || beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || smooth cerebral cortex surface; visible shallow grooves in the central sulci, interparietal sulci and superior temporal sulci; start of opercularization of Sylvian fissures; presence of calcarine fissures and cingular sulci
|-
| 26 || presence of central and collateral sulci
|-
| 27 || presence of marginal and precentral sulci
|-
| 28 || presence of postcentral and intraparietal sulci
|-
| 29 || presence of superior and inferior frontal sulci; narrower Sylvian fissure; clear corpus callosum; bright white matter; dark cortical ribbon
|-
| 30-31 || beginning of infolding of cortex which is first apparent in the occipital lobe; narrower ventricular system and subarachnoid spaces
|-
| 32 || presence of superior and inferior temporal sulci
|-
| 33 || presence of external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration; compactly and extensively folded cortex
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table of the process of sulcation and gyration <ref name=PMID20608424><pubmed>20608424</pubmed></ref>

=== Spinal Cord Development ===
The spinal cord is formed from parts of the neural tube during embryonic and fetal development

=== Meninges Development ===

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations
|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

{|
|-bgcolor="ECCEF5"
|
===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.

|}
{|
|-bgcolor="CED8F6"
|The following are recent studies that use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

-Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

-The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

-The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.
|}
{|
|-bgcolor="ECCEF5"
|
'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

|}
{|
|-bgcolor="CED8F6"
|
'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.
|}
{|
|-bgcolor="ECCEF5"
|
'''Cortical Overgrowth in Fetuses With Isolated Ventriculomegaly'''
<ref><pubmed> 23508710 </pubmed></ref>

* The condition fetal ventriculomegaly is characterised by dilation of lateral ventricles whilst sharing associations with other malformations. It was hypothesised that using relative brain overgrowth as marked measure of altered brain development is due to the occurrence of ventriculomegaly and to evaluate this brain overgrowth through the use of magnetic resonance imaging (MRI) of fetuses isolated with enlarged ventricles (3rd and 4th ventricles as well as cerebrospinal fluid). Furthermore, significant changes to thalamic volumes, basal ganglia and white matter did not occur between cohorts.

* The study found that there was a sufficient increase in brain volume (overgrowth) of fetuses that had ventriculomegaly in comparison to controls. Also, larger lateral ventricle volumes were yielded with fetuses with ventriculomegaly assessed via 2-dimensional movement of the atrial diameter (ultrasound and MRi) as well as a larger total brain tissue volume. This provides support for the hypothesis in that brain overgrowth can be used as a marked measure for ventriculomegaly with results showing that overgrowth was not localised in one region but across both hemispheres and thus lead to a neural deficit in children (altered neural connectivity).

* Hence, this study has assisted in the improved understanding of the effects of ventriculomegaly on cognition, language and behaviour in children.

===Future Research===

|}

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]
Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age. The most frequent cause of macrocephaly is hydrocephalus.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.
* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period) in the secondary type.

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation.

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.

===Fetal Alcohol Syndrome===
<ref><pubmed> 23809349 </pubmed></ref>

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status.

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.

{| style="width:40%; height:170px" align="center"
|-
| [[Image: Fetal alcohol syndrome.jpg|frame|250x250px|The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref> ]]
|-
| [[Image: Ethanol fetal neural.jpg|frame|350x350px|A mechanism of the effect of ethanol on neural stem cells (NSCs). Ethanol promotes asymmetrical cell division, the formation of radial glial-like cells, leading to the premature depletion of the VZ and its NSCs, and the thickening and cell proliferation in SVZ. The increased migration during early differentiation of ethanol-treated NSCs also leads to the appearance of subpial heterotopias<ref name="PMID22623924"><pubmed>22623924</pubmed></ref>.]]
|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

* All degrees of iodine deficiency (mild: 50-99 μg/day, moderate: 20-49 μg/day and severe≤20 μg/day) affect thyroid function of both mother and the neonate as well as mental development of the child. The damage increases with the degree of deficiency; overt endemic cretinism is the most severe consequence.

* Iodine deficiency disorders refer to complications that arise when the recommended dietary allowance of iodine is not met. These complications include thyroid function abnormalities and when iodine deficiency is severe, endemic goitre and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality.

* Iodine deficiency represents the world’s greatest cause of preventable brain damage and mental retardation, resulting of a loss of 10-15 IQ points globally. Therefore it is essential that the recommended dietary requirement for iodine is met, especially during pregnancy and lactation (200–300 μg/day). <ref><pubmed>10750030</pubmed></ref>

* Clinical manifestations of hypothyroidism include: Myxedematous facies (condition characterized by thickening of the skin, blunting of the senses and intellect, and laboured speech), jaundice, a puffy face and a wide posterior fontanelle with open sutures. The nasal bridge is flat. The mouth may be slightly open revealing macroglossia. Further examination would reveal bradycardia and a protuberant abdomen with a large umbilical hernia. Neurologic examination findings include hypotonia with delayed reflexes. Skin may be cool to touch and mottled in appearance due to circulatory compromise.<ref><pubmed>2903524</pubmed></ref>

===Abnormalities associated with apoptosis and migration of cells in the fetal CNS===

* The migration of cells and cell death are critically important to fetal brain and CNS development. Abnormalities in each of these processes, programmed cell death (apoptosis) in particular, have been shown to result in severe developmental abnormalities in experimental animals. Apoptosis is critically important for appropriate brain development; certain areas in brain may experience up to 50% cell death. <ref><pubmed> 11589424 </pubmed></ref>

In an experiment conducted by kuida et. al 1996, it was observed that mice that were deficient for CPP32 (a protease responsible for apoptosis), were born at a lower frequency than expected, were smaller in size compared to the normal mice and died at an early age. Brain development is significantly affected in CPP32-deficient mice resulting in a variety of hyperplasia and disorganised cell development. <ref><pubmed>8934524</pubmed></ref>

On the other hand, disrupted neuronal migration can lead to an abnormality in cell position. When this happens, the neurons are said to be heterotopic. Abnormalities in neuronal migration have been studied extensively in human cerebral cortex where these defects are associated with a variety of syndromes and diseases, ranging from behavioural disorders (including some forms of schizophrenia, dyslexia and autism) to extremely severe mental retardation and failure to thrive. <ref><pubmed>10532616</pubmed></ref>

===Neural Tube Defects===

Defects which affect the either the brain or the spinal cord in which openings remain. Grastulation occurs in week 3 of embryonic development where specialized cells (dorsal side) structurally change shape leading to the formation of the neural tube. If the neural tube does not close or fuse together properly, then openings remain which lead to various neural tube defects such as Spina bifida cystica and Spina bifida occulta.

'''Anencephaly'''

* A neural tube defect involving abnormal development of the brain and incomplete skull formation leading to high infant mortality rates with infants being stillborn or dying within a few hours after birth.

* The failure of the neural tube to close around the 23rd and 26th day into embryonic development is characteristic of this condition. As a result, the forebrain is severely affected where the cerebrum does not grow and hence partial growth occurs only. The cerebrum has a key importance in maintaining thought, consciousness and coordination whilst having no intact cerebrum rules out the probability of the affected fetus gaining consciousness .

* Increasing one's dietary intake of folic acid notably reduces the incidence of neural tube defects. Consuming 0.4mg of folic acid is sufficient to induce these results.

* Since incomplete skull formation occurs, brain tissue becomes exposed due to the absence of bone covering and therefore leading to further complications.

'''Encephaloceles'''

* Another neural tube defect in which a sac-like projections (including membrane covering) that occurs around the 3-4 week of embryonic development in which neural tube closure has not successfully occurred. The location of these protrusions varies but can be naso-frontal (nose and head), naso-ethmoidal (nose and ethmoid bone), naso-orbital (nose and eyes), meningocele (cerebrospinal fluid and membrane covering) and encephalomeningocele (meningocele with brain tissue as well).

* These sac-like protrusions lead to a variety of abnormal effects which include cerebro-spinal fluid build-up in brain, microcephaly, hydrocephaly, mental retardation, developmental problems, uncoordinated muscle movement and seizures. Consumption of folic acid again has been shown to significantly reduce the occurrence of encephaloceles in infants.

'''Hydranencephaly'''

* A very rare neural tube defect in which the cerebral hemispheres are destroyed (necrotic tissue) with the occupied space being replaced by cerebro-spinal fluid, cortex and white matter remnants within a membranous sac. Interestingly, this condition can also develop in the postnatal peroid due to viral infections or traumatic brain injury. The brain stem may remain intact and functioning in hydranencephalic infants.

* Accompanied with this condition are many effects in which include seizures, hydrocephalus, increases in head circumference,impairment in vision/ body temperature regulation and cerebral palsy. Infants affected by hydranencephaly live typically short lives being no longer than 1 year of age. Lastly, there are no viable treatment options for this condition and only supportive care is available.

'''Iniencephaly'''

* Another neural tube defect involving severe backward bending of the head (retroflexion) with subsequent spinal distortions as well. Affected infants have no neck and hence the scalp of the head is directly joined to the skin of the back (also skin of the face connected to skin of the chest). Other conditions that develop along with iniencephaly are cyclopia, cephalocele and anencephaly. The development of this condition is not solely due to one factor but from various causes (both genetic and environmental factors).

* There are specific factors that have been shown to increase the occurrence of this condition. Malnutrition, reduced folic acid intake and elevated levels of homocysteine in blood are environmental factors that increase the risk of iniencephaly <ref><pubmed> 22408660 </pubmed></ref>. Intake of certain drugs such as anti-histamines and sulphonamide/tetracycline (antibiotics) have also increases this risk <ref><pubmed> 22439066 </pubmed></ref>. Furthermore obesity has been shown to have a significant effect on the incidence of iniencephaly with 1.7-3 fold increase <ref><pubmed> 18538144 </pubmed></ref>.

* In terms of treatment, folic acid supplementation as well as avoiding certain drugs such as those outlined above significantly reduces the occurrence of this condition.

'''Spina Bifida Cystica'''

* A neural tube defect in which involves either the formation of a meningocele or myelomeningocele. Of the two, the meningocele, is the least debilitating in that a cyst-like structure forms when the neural tube does not close properly. The membrane (meninges) is pushed into openings of the vertebrae where spinal fluid builds up within the cyst. The myelomeningocele leads to severe problems as the portion of the nueral tube that is unfused allows the spinal cord to protrude through. As a result, neuronal tissue is highly exposed due to myeloschisis as well as infections and hence may lead to severe complications.

'''Spina Bifida Occulta'''

* A neural tube defect that has minimal complications in comparison to other defects. Furthermore, this defect is hidden in that a tethered spinal cord may arise as well as a thicker filum terminale and diastematomyelia (spinal cord split into two). It is also important to note that no cysts form as opposed to the other more severe spina bifida defects.

==References==

<references/>

2014 Group Project 7

2014-10-23T04:42:54Z

Z3418981: /* Cellular process */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, recieving and integration of information from all parts of the body, serving as the processing center of the bodies nervous system. The CNS controls all bodily functions (sensory and motor), consisting of 2 main organs; The Brain and Spinal Cord

==='''Brain'''===

The Brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

==='''Spinal Cord'''===

The Spinal Cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into

1) Ascending bundles - Transmits Sensory information from the body to the brain

2) Descending bundle - Transmits Motor function information from the brain to the body

Before fetal period, nerulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, the current research models and finding, historic findings and abnormalities that can occur in the fetal period is identified.

==Development during fetal period==

[[File:Schematic_representation_of_the_timeline_of_human_neural_development.jpg|800px]]

A simplified timeline of human neural development <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

This simplified graph shows a timeline for major events of neural development that occur during fetal and postnatal periods. These events are broadly classified by cell multiplication, cell migration, growth and differentiation and angiogenesis:

'''Cell multiplication'''
* Neurons are proliferated and generated from neural stem cells and progenitor cells (precursor cells) in a process known as neurogenesis in 2nd trimester.
* Cell death and Gliogenesis (glial cells (such as astrocytes) deriving from multipotent neural stem cells) occur in the 3rd trimester.
* Local gliogenesis continues postnatally.

'''Cell migration'''
* Neuronal migration is maximised during 2nd trimester while glial migration is maximised during 3rd trimester

'''Growth and differentiation'''
* Axonal and dendritic arborisation (fine branching structures at the end of nerve fibers) appear by the end of fetal period.
* Synaptogenesis (formation of synapses) and electrical activity is maximised in 3rd trimester (and continued postnatally).
* Cell death due to over-innervation can be observed in late fetal and postnatal period.
* Myelination occurs in late fetal and postnatal period (vast majority of postnatal growth in brain is due to myelination).

'''Angiogenesis'''
* Oxidative metabolism can be seen in late fetal period.
* Capillary networks develop postnatally.

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

'''1. cell proliferation'''

[[Image:Somatosensory cortex of E20 rat.jpeg|frame|400x400px|Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) <ref name="PMID22272298"><pubmed>22272298</pubmed></ref>]]

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

'''2. cell migration'''
[[Image:CNS_passive.jpg|frame|200x150px|Passive cell displacement and outside-to-inside spatiotemporal gradient]][[Image:CNS_active.jpg|frame|350x250px|Active cell migration and inside-to-outside spatiotemporal gradient]]

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways.

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus, hypothalamus, spinal cord, retina, dentate gyrus of the hippocampal formation and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas.

{| style="width:40%; height:170px" align="center"
|-
| [[Image:Internurons migration in cerebral cortex.jpg|frame|500x500px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex <ref name="PMID17726524"><pubmed>17726524</pubmed></ref>]]
|}

'''3. cell differentiation'''

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

=== Brain Development ===

* The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells

* By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

* The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

* Extends from the ninth gestational weeks through to the end of gestation

* Gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding

* Brain development begins rostral in GW8, proceeding caudally until it is complete at GW22 <ref><pubmed>560818</pubmed></ref>

* Formation of Secondary Sulci between GW30-35

* Formation of Tertiary Sulci begins during GW36 and into the postnatal period

* Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

* Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

* The major fibre pathways make up the brain white matter

* AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Neuron Production'''
* The human brain contains billions of neurons which are produced by mid-gestation; during fetal development <ref><pubmed>8361683</pubmed></ref>

* Processes of Neuronal production is initiated by first increasing the size of the Neural progenitor cell population within the body, these cells are mitotic in nature and are capable of forming new cells.

* Initially (from the end of gastrulation through to embryonic day 42), the neural progenitor cell population is increased greatly when the progenitor cells divide through 'symmetrical' mode of cell division. Multiple repeats of the cell division occurs throughout this period. This 'symmetrical' division method brings about the formation of 2 new identical neural progenitor cells

* Mode of cell division changes from a symmetrical cell division type to an 'asymmetrical' cell division from the beginning of E42. This asymmetrical cell division forms 2 different cell types; one Neural progenitor & one Neuron <ref><pubmed>12764028 </pubmed></ref>

* Newly formed Neural progenitor cells remains to undergo more processes of cell division whereas the newly formed neuron moves into position in the developing neocortex

'''Increase in size and weight'''

[[File:Brain ventricles and ganglia development 03.jpg|300px]]

Image of brain and ventricular development <ref name=PMID19339620><pubmed>19339620</pubmed></ref>

[[File:Brain fissure development 02.jpg|300px]]

Image of brain fissure development <ref name=PMID19339620><pubmed>19339620</pubmed></ref>

'''folding: sulcation and gyration'''

[[Image:Dev anat 01.jpg|frame|200x150px|Simplified external lateral (left) view of the brain growth]]

During the fifth and sixth month of gestation, the smooth cortex begins to fold by sulcation and gyration. <ref name=PMID21571694><pubmed>21571694</pubmed></ref>

Sulcation: This is the development of sulci, including primary and secondary. The formation of primary sulci involve the appearance of shallow grooves on the surface of the brain, which then become more deeply infolded, while the formation of secondary sulci is due to the development of side branches of the primary ones <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

Gyration: This is the development of gyrus that occurs during late during fetal development until the end of the pregnancy or after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>. This process is the formation of tertiary sulci, which is the formation of other side branches of the secondary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

{| class="wikitable"
|-
! Weeks of gestation !! Visible anatomical details
|-
| 20-21 || smooth, with the impression of "lissencephalic" brain; wide Sylvian fissures; visible interhemispheric fissure and parieto-occipital fissure
|-
| 22-23 || beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || smooth cerebral cortex surface; visible shallow grooves in the central sulci, interparietal sulci and superior temporal sulci; start of opercularization of Sylvian fissures; presence of calcarine fissures and cingular sulci
|-
| 26 || presence of central and collateral sulci
|-
| 27 || presence of marginal and precentral sulci
|-
| 28 || presence of postcentral and intraparietal sulci
|-
| 29 || presence of superior and inferior frontal sulci; narrower Sylvian fissure; clear corpus callosum; bright white matter; dark cortical ribbon
|-
| 30-31 || beginning of infolding of cortex which is first apparent in the occipital lobe; narrower ventricular system and subarachnoid spaces
|-
| 32 || presence of superior and inferior temporal sulci
|-
| 33 || presence of external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration; compactly and extensively folded cortex
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table of the process of sulcation and gyration <ref name=PMID20608424><pubmed>20608424</pubmed></ref>

=== Spinal Cord Development ===
The spinal cord is formed from parts of the neural tube during embryonic and fetal development

=== Meninges Development ===

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations
|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

{|
|-bgcolor="ECCEF5"
|
===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.

|}
{|
|-bgcolor="CED8F6"
|The following are recent studies that use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

-Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

-The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

-The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.
|}
{|
|-bgcolor="ECCEF5"
|
'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

|}
{|
|-bgcolor="CED8F6"
|
'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.
|}
{|
|-bgcolor="ECCEF5"
|
'''Cortical Overgrowth in Fetuses With Isolated Ventriculomegaly'''
<ref><pubmed> 23508710 </pubmed></ref>

* The condition fetal ventriculomegaly is characterised by dilation of lateral ventricles whilst sharing associations with other malformations. It was hypothesised that using relative brain overgrowth as marked measure of altered brain development is due to the occurrence of ventriculomegaly and to evaluate this brain overgrowth through the use of magnetic resonance imaging (MRI) of fetuses isolated with enlarged ventricles (3rd and 4th ventricles as well as cerebrospinal fluid). Furthermore, significant changes to thalamic volumes, basal ganglia and white matter did not occur between cohorts.

* The study found that there was a sufficient increase in brain volume (overgrowth) of fetuses that had ventriculomegaly in comparison to controls. Also, larger lateral ventricle volumes were yielded with fetuses with ventriculomegaly assessed via 2-dimensional movement of the atrial diameter (ultrasound and MRi) as well as a larger total brain tissue volume. This provides support for the hypothesis in that brain overgrowth can be used as a marked measure for ventriculomegaly with results showing that overgrowth was not localised in one region but across both hemispheres and thus lead to a neural deficit in children (altered neural connectivity).

* Hence, this study has assisted in the improved understanding of the effects of ventriculomegaly on cognition, language and behaviour in children.

===Future Research===

|}

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]
Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age. The most frequent cause of macrocephaly is hydrocephalus.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.
* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period) in the secondary type.

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation.

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.

===Fetal Alcohol Syndrome===
<ref><pubmed> 23809349 </pubmed></ref>

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status.

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.

{| style="width:40%; height:170px" align="center"
|-
| [[Image: Fetal alcohol syndrome.jpg|frame|250x250px|The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref> ]]
|-
| [[Image: Ethanol fetal neural.jpg|frame|350x350px|A mechanism of the effect of ethanol on neural stem cells (NSCs). Ethanol promotes asymmetrical cell division, the formation of radial glial-like cells, leading to the premature depletion of the VZ and its NSCs, and the thickening and cell proliferation in SVZ. The increased migration during early differentiation of ethanol-treated NSCs also leads to the appearance of subpial heterotopias<ref name="PMID22623924"><pubmed>22623924</pubmed></ref>.]]
|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

* All degrees of iodine deficiency (mild: 50-99 μg/day, moderate: 20-49 μg/day and severe≤20 μg/day) affect thyroid function of both mother and the neonate as well as mental development of the child. The damage increases with the degree of deficiency; overt endemic cretinism is the most severe consequence.

* Iodine deficiency disorders refer to complications that arise when the recommended dietary allowance of iodine is not met. These complications include thyroid function abnormalities and when iodine deficiency is severe, endemic goitre and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality.

* Iodine deficiency represents the world’s greatest cause of preventable brain damage and mental retardation, resulting of a loss of 10-15 IQ points globally. Therefore it is essential that the recommended dietary requirement for iodine is met, especially during pregnancy and lactation (200–300 μg/day). <ref><pubmed>10750030</pubmed></ref>

* Clinical manifestations of hypothyroidism include: Myxedematous facies (condition characterized by thickening of the skin, blunting of the senses and intellect, and laboured speech), jaundice, a puffy face and a wide posterior fontanelle with open sutures. The nasal bridge is flat. The mouth may be slightly open revealing macroglossia. Further examination would reveal bradycardia and a protuberant abdomen with a large umbilical hernia. Neurologic examination findings include hypotonia with delayed reflexes. Skin may be cool to touch and mottled in appearance due to circulatory compromise.<ref><pubmed>2903524</pubmed></ref>

===Abnormalities associated with apoptosis and migration of cells in the fetal CNS===

* The migration of cells and cell death are critically important to fetal brain and CNS development. Abnormalities in each of these processes, programmed cell death (apoptosis) in particular, have been shown to result in severe developmental abnormalities in experimental animals. Apoptosis is critically important for appropriate brain development; certain areas in brain may experience up to 50% cell death. <ref><pubmed> 11589424 </pubmed></ref>

In an experiment conducted by kuida et. al 1996, it was observed that mice that were deficient for CPP32 (a protease responsible for apoptosis), were born at a lower frequency than expected, were smaller in size compared to the normal mice and died at an early age. Brain development is significantly affected in CPP32-deficient mice resulting in a variety of hyperplasia and disorganised cell development. <ref><pubmed>8934524</pubmed></ref>

On the other hand, disrupted neuronal migration can lead to an abnormality in cell position. When this happens, the neurons are said to be heterotopic. Abnormalities in neuronal migration have been studied extensively in human cerebral cortex where these defects are associated with a variety of syndromes and diseases, ranging from behavioural disorders (including some forms of schizophrenia, dyslexia and autism) to extremely severe mental retardation and failure to thrive. <ref><pubmed>10532616</pubmed></ref>

===Neural Tube Defects===

Defects which affect the either the brain or the spinal cord in which openings remain. Grastulation occurs in week 3 of embryonic development where specialized cells (dorsal side) structurally change shape leading to the formation of the neural tube. If the neural tube does not close or fuse together properly, then openings remain which lead to various neural tube defects such as Spina bifida cystica and Spina bifida occulta.

'''Anencephaly'''

* A neural tube defect involving abnormal development of the brain and incomplete skull formation leading to high infant mortality rates with infants being stillborn or dying within a few hours after birth.

* The failure of the neural tube to close around the 23rd and 26th day into embryonic development is characteristic of this condition. As a result, the forebrain is severely affected where the cerebrum does not grow and hence partial growth occurs only. The cerebrum has a key importance in maintaining thought, consciousness and coordination whilst having no intact cerebrum rules out the probability of the affected fetus gaining consciousness .

* Increasing one's dietary intake of folic acid notably reduces the incidence of neural tube defects. Consuming 0.4mg of folic acid is sufficient to induce these results.

* Since incomplete skull formation occurs, brain tissue becomes exposed due to the absence of bone covering and therefore leading to further complications.

'''Encephaloceles'''

* Another neural tube defect in which a sac-like projections (including membrane covering) that occurs around the 3-4 week of embryonic development in which neural tube closure has not successfully occurred. The location of these protrusions varies but can be naso-frontal (nose and head), naso-ethmoidal (nose and ethmoid bone), naso-orbital (nose and eyes), meningocele (cerebrospinal fluid and membrane covering) and encephalomeningocele (meningocele with brain tissue as well).

* These sac-like protrusions lead to a variety of abnormal effects which include cerebro-spinal fluid build-up in brain, microcephaly, hydrocephaly, mental retardation, developmental problems, uncoordinated muscle movement and seizures. Consumption of folic acid again has been shown to significantly reduce the occurrence of encephaloceles in infants.

'''Hydranencephaly'''

* A very rare neural tube defect in which the cerebral hemispheres are destroyed (necrotic tissue) with the occupied space being replaced by cerebro-spinal fluid, cortex and white matter remnants within a membranous sac. Interestingly, this condition can also develop in the postnatal peroid due to viral infections or traumatic brain injury. The brain stem may remain intact and functioning in hydranencephalic infants.

* Accompanied with this condition are many effects in which include seizures, hydrocephalus, increases in head circumference,impairment in vision/ body temperature regulation and cerebral palsy. Infants affected by hydranencephaly live typically short lives being no longer than 1 year of age. Lastly, there are no viable treatment options for this condition and only supportive care is available.

'''Iniencephaly'''

* Another neural tube defect involving severe backward bending of the head (retroflexion) with subsequent spinal distortions as well. Affected infants have no neck and hence the scalp of the head is directly joined to the skin of the back (also skin of the face connected to skin of the chest). Other conditions that develop along with iniencephaly are cyclopia, cephalocele and anencephaly. The development of this condition is not solely due to one factor but from various causes (both genetic and environmental factors).

* There are specific factors that have been shown to increase the occurrence of this condition. Malnutrition, reduced folic acid intake and elevated levels of homocysteine in blood are environmental factors that increase the risk of iniencephaly <ref><pubmed> 22408660 </pubmed></ref>. Intake of certain drugs such as anti-histamines and sulphonamide/tetracycline (antibiotics) have also increases this risk <ref><pubmed> 22439066 </pubmed></ref>. Furthermore obesity has been shown to have a significant effect on the incidence of iniencephaly with 1.7-3 fold increase <ref><pubmed> 18538144 </pubmed></ref>.

* In terms of treatment, folic acid supplementation as well as avoiding certain drugs such as those outlined above significantly reduces the occurrence of this condition.

'''Spina Bifida Cystica'''

* A neural tube defect in which involves either the formation of a meningocele or myelomeningocele. Of the two, the meningocele, is the least debilitating in that a cyst-like structure forms when the neural tube does not close properly. The membrane (meninges) is pushed into openings of the vertebrae where spinal fluid builds up within the cyst. The myelomeningocele leads to severe problems as the portion of the nueral tube that is unfused allows the spinal cord to protrude through. As a result, neuronal tissue is highly exposed due to myeloschisis as well as infections and hence may lead to severe complications.

'''Spina Bifida Occulta'''

* A neural tube defect that has minimal complications in comparison to other defects. Furthermore, this defect is hidden in that a tethered spinal cord may arise as well as a thicker filum terminale and diastematomyelia (spinal cord split into two). It is also important to note that no cysts form as opposed to the other more severe spina bifida defects.

==References==

<references/>

2014 Group Project 7

2014-10-23T04:37:17Z

Z3418981: /* Development during fetal period */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, recieving and integration of information from all parts of the body, serving as the processing center of the bodies nervous system. The CNS controls all bodily functions (sensory and motor), consisting of 2 main organs; The Brain and Spinal Cord

==='''Brain'''===

The Brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

==='''Spinal Cord'''===

The Spinal Cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into

1) Ascending bundles - Transmits Sensory information from the body to the brain

2) Descending bundle - Transmits Motor function information from the brain to the body

Before fetal period, nerulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, the current research models and finding, historic findings and abnormalities that can occur in the fetal period is identified.

==Development during fetal period==

[[File:Schematic_representation_of_the_timeline_of_human_neural_development.jpg|800px]]

A simplified timeline of human neural development <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

This simplified graph shows a timeline for major events of neural development that occur during fetal and postnatal periods. These events are broadly classified by cell multiplication, cell migration, growth and differentiation and angiogenesis:

'''Cell multiplication'''
* Neurons are proliferated and generated from neural stem cells and progenitor cells (precursor cells) in a process known as neurogenesis in 2nd trimester.
* Cell death and Gliogenesis (glial cells (such as astrocytes) deriving from multipotent neural stem cells) occur in the 3rd trimester.
* Local gliogenesis continues postnatally.

'''Cell migration'''
* Neuronal migration is maximised during 2nd trimester while glial migration is maximised during 3rd trimester

'''Growth and differentiation'''
* Axonal and dendritic arborisation (fine branching structures at the end of nerve fibers) appear by the end of fetal period.
* Synaptogenesis (formation of synapses) and electrical activity is maximised in 3rd trimester (and continued postnatally).
* Cell death due to over-innervation can be observed in late fetal and postnatal period.
* Myelination occurs in late fetal and postnatal period (vast majority of postnatal growth in brain is due to myelination).

'''Angiogenesis'''
* Oxidative metabolism can be seen in late fetal period.
* Capillary networks develop postnatally.

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

'''1. cell proliferation'''

[[Image:Somatosensory cortex of E20 rat.jpeg|frame|400x400px|Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) <ref name="PMID22272298"><pubmed>22272298</pubmed></ref>]]

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

'''2. cell migration'''
[[Image:CNS_passive.jpg|frame|200x150px|Passive cell displacement and outside-to-inside spatiotemporal gradient]][[Image:CNS_active.jpg|frame|350x250px|Active cell migration and inside-to-outside spatiotemporal gradient]]

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways.

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus, hypothalamus, spinal cord, retina, dentate gyrus of the hippocampal formation and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas.

{| style="width:40%; height:170px" align="center"
|-
| [[Image:Internurons migration in cerebral cortex.jpg|frame|500x500px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex <ref name="PMID17726524"><pubmed>17726524</pubmed></ref>]]
|}

'''3. cell differentiation'''

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

=== Brain Development ===

* The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells

* By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

* The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

* Extends from the ninth gestational weeks through to the end of gestation

* Gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding

* Brain development begins rostral in GW8, proceeding caudally until it is complete at GW22 <ref><pubmed>560818</pubmed></ref>

* Formation of Secondary Sulci between GW30-35

* Formation of Tertiary Sulci begins during GW36 and into the postnatal period

* Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

* Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

* The major fibre pathways make up the brain white matter

* AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Neuron Production'''
* The human brain contains billions of neurons which are produced by mid-gestation; during fetal development <ref><pubmed>8361683</pubmed></ref>

* Processes of Neuronal production is initiated by first increasing the size of the Neural progenitor cell population within the body, these cells are mitotic in nature and are capable of forming new cells.

* Initially (from the end of gastrulation through to embryonic day 42), the neural progenitor cell population is increased greatly when the progenitor cells divide through 'symmetrical' mode of cell division. Multiple repeats of the cell division occurs throughout this period. This 'symmetrical' division method brings about the formation of 2 new identical neural progenitor cells

* Mode of cell division changes from a symmetrical cell division type to an 'asymmetrical' cell division from the beginning of E42. This asymmetrical cell division forms 2 different cell types; one Neural progenitor & one Neuron <ref><pubmed>12764028 </pubmed></ref>

* Newly formed Neural progenitor cells remains to undergo more processes of cell division whereas the newly formed neuron moves into position in the developing neocortex

'''Increase in size and weight'''

[[File:Brain ventricles and ganglia development 03.jpg|300px]]

Image of brain and ventricular development <ref name=PMID19339620><pubmed>19339620</pubmed></ref>

[[File:Brain fissure development 02.jpg|300px]]

Image of brain fissure development <ref name=PMID19339620><pubmed>19339620</pubmed></ref>

'''folding: sulcation and gyration'''

[[Image:Dev anat 01.jpg|frame|200x150px|Simplified external lateral (left) view of the brain growth]]

During the fifth and sixth month of gestation, the smooth cortex begins to fold by sulcation and gyration. <ref name=PMID21571694><pubmed>21571694</pubmed></ref>

Sulcation: This is the development of sulci, including primary and secondary. The formation of primary sulci involve the appearance of shallow grooves on the surface of the brain, which then become more deeply infolded, while the formation of secondary sulci is due to the development of side branches of the primary ones <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

Gyration: This is the development of gyrus that occurs during late during fetal development until the end of the pregnancy or after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>. This process is the formation of tertiary sulci, which is the formation of other side branches of the secondary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>.

{| class="wikitable"
|-
! Weeks of gestation !! Visible anatomical details
|-
| 20-21 || smooth, with the impression of "lissencephalic" brain; wide Sylvian fissures; visible interhemispheric fissure and parieto-occipital fissure
|-
| 22-23 || beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || smooth cerebral cortex surface; visible shallow grooves in the central sulci, interparietal sulci and superior temporal sulci; start of opercularization of Sylvian fissures; presence of calcarine fissures and cingular sulci
|-
| 26 || presence of central and collateral sulci
|-
| 27 || presence of marginal and precentral sulci
|-
| 28 || presence of postcentral and intraparietal sulci
|-
| 29 || presence of superior and inferior frontal sulci; narrower Sylvian fissure; clear corpus callosum; bright white matter; dark cortical ribbon
|-
| 30-31 || beginning of infolding of cortex which is first apparent in the occipital lobe; narrower ventricular system and subarachnoid spaces
|-
| 32 || presence of superior and inferior temporal sulci
|-
| 33 || presence of external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration; compactly and extensively folded cortex
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table of the process of sulcation and gyration <ref name=PMID20608424><pubmed>20608424</pubmed></ref>

=== Spinal Cord Development ===
The spinal cord is formed from parts of the neural tube during embryonic and fetal development

=== Meninges Development ===

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations
|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

{|
|-bgcolor="ECCEF5"
|
===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.

|}
{|
|-bgcolor="CED8F6"
|The following are recent studies that use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

-Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

-The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

-The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.
|}
{|
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'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

|}
{|
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'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.
|}
{|
|-bgcolor="ECCEF5"
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'''Cortical Overgrowth in Fetuses With Isolated Ventriculomegaly'''
<ref><pubmed> 23508710 </pubmed></ref>

* The condition fetal ventriculomegaly is characterised by dilation of lateral ventricles whilst sharing associations with other malformations. It was hypothesised that using relative brain overgrowth as marked measure of altered brain development is due to the occurrence of ventriculomegaly and to evaluate this brain overgrowth through the use of magnetic resonance imaging (MRI) of fetuses isolated with enlarged ventricles (3rd and 4th ventricles as well as cerebrospinal fluid). Furthermore, significant changes to thalamic volumes, basal ganglia and white matter did not occur between cohorts.

* The study found that there was a sufficient increase in brain volume (overgrowth) of fetuses that had ventriculomegaly in comparison to controls. Also, larger lateral ventricle volumes were yielded with fetuses with ventriculomegaly assessed via 2-dimensional movement of the atrial diameter (ultrasound and MRi) as well as a larger total brain tissue volume. This provides support for the hypothesis in that brain overgrowth can be used as a marked measure for ventriculomegaly with results showing that overgrowth was not localised in one region but across both hemispheres and thus lead to a neural deficit in children (altered neural connectivity).

* Hence, this study has assisted in the improved understanding of the effects of ventriculomegaly on cognition, language and behaviour in children.

===Future Research===

|}

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]
Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age. The most frequent cause of macrocephaly is hydrocephalus.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.
* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period) in the secondary type.

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation.

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.

===Fetal Alcohol Syndrome===
<ref><pubmed> 23809349 </pubmed></ref>

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status.

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.

{| style="width:40%; height:170px" align="center"
|-
| [[Image: Fetal alcohol syndrome.jpg|frame|250x250px|The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref> ]]
|-
| [[Image: Ethanol fetal neural.jpg|frame|350x350px|A mechanism of the effect of ethanol on neural stem cells (NSCs). Ethanol promotes asymmetrical cell division, the formation of radial glial-like cells, leading to the premature depletion of the VZ and its NSCs, and the thickening and cell proliferation in SVZ. The increased migration during early differentiation of ethanol-treated NSCs also leads to the appearance of subpial heterotopias<ref name="PMID22623924"><pubmed>22623924</pubmed></ref>.]]
|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

* All degrees of iodine deficiency (mild: 50-99 μg/day, moderate: 20-49 μg/day and severe≤20 μg/day) affect thyroid function of both mother and the neonate as well as mental development of the child. The damage increases with the degree of deficiency; overt endemic cretinism is the most severe consequence.

* Iodine deficiency disorders refer to complications that arise when the recommended dietary allowance of iodine is not met. These complications include thyroid function abnormalities and when iodine deficiency is severe, endemic goitre and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality.

* Iodine deficiency represents the world’s greatest cause of preventable brain damage and mental retardation, resulting of a loss of 10-15 IQ points globally. Therefore it is essential that the recommended dietary requirement for iodine is met, especially during pregnancy and lactation (200–300 μg/day). <ref><pubmed>10750030</pubmed></ref>

* Clinical manifestations of hypothyroidism include: Myxedematous facies (condition characterized by thickening of the skin, blunting of the senses and intellect, and laboured speech), jaundice, a puffy face and a wide posterior fontanelle with open sutures. The nasal bridge is flat. The mouth may be slightly open revealing macroglossia. Further examination would reveal bradycardia and a protuberant abdomen with a large umbilical hernia. Neurologic examination findings include hypotonia with delayed reflexes. Skin may be cool to touch and mottled in appearance due to circulatory compromise.<ref><pubmed>2903524</pubmed></ref>

===Abnormalities associated with apoptosis and migration of cells in the fetal CNS===

* The migration of cells and cell death are critically important to fetal brain and CNS development. Abnormalities in each of these processes, programmed cell death (apoptosis) in particular, have been shown to result in severe developmental abnormalities in experimental animals. Apoptosis is critically important for appropriate brain development; certain areas in brain may experience up to 50% cell death. <ref><pubmed> 11589424 </pubmed></ref>

In an experiment conducted by kuida et. al 1996, it was observed that mice that were deficient for CPP32 (a protease responsible for apoptosis), were born at a lower frequency than expected, were smaller in size compared to the normal mice and died at an early age. Brain development is significantly affected in CPP32-deficient mice resulting in a variety of hyperplasia and disorganised cell development. <ref><pubmed>8934524</pubmed></ref>

On the other hand, disrupted neuronal migration can lead to an abnormality in cell position. When this happens, the neurons are said to be heterotopic. Abnormalities in neuronal migration have been studied extensively in human cerebral cortex where these defects are associated with a variety of syndromes and diseases, ranging from behavioural disorders (including some forms of schizophrenia, dyslexia and autism) to extremely severe mental retardation and failure to thrive. <ref><pubmed>10532616</pubmed></ref>

===Neural Tube Defects===

Defects which affect the either the brain or the spinal cord in which openings remain. Grastulation occurs in week 3 of embryonic development where specialized cells (dorsal side) structurally change shape leading to the formation of the neural tube. If the neural tube does not close or fuse together properly, then openings remain which lead to various neural tube defects such as Spina bifida cystica and Spina bifida occulta.

'''Anencephaly'''

* A neural tube defect involving abnormal development of the brain and incomplete skull formation leading to high infant mortality rates with infants being stillborn or dying within a few hours after birth.

* The failure of the neural tube to close around the 23rd and 26th day into embryonic development is characteristic of this condition. As a result, the forebrain is severely affected where the cerebrum does not grow and hence partial growth occurs only. The cerebrum has a key importance in maintaining thought, consciousness and coordination whilst having no intact cerebrum rules out the probability of the affected fetus gaining consciousness .

* Increasing one's dietary intake of folic acid notably reduces the incidence of neural tube defects. Consuming 0.4mg of folic acid is sufficient to induce these results.

* Since incomplete skull formation occurs, brain tissue becomes exposed due to the absence of bone covering and therefore leading to further complications.

'''Encephaloceles'''

* Another neural tube defect in which a sac-like projections (including membrane covering) that occurs around the 3-4 week of embryonic development in which neural tube closure has not successfully occurred. The location of these protrusions varies but can be naso-frontal (nose and head), naso-ethmoidal (nose and ethmoid bone), naso-orbital (nose and eyes), meningocele (cerebrospinal fluid and membrane covering) and encephalomeningocele (meningocele with brain tissue as well).

* These sac-like protrusions lead to a variety of abnormal effects which include cerebro-spinal fluid build-up in brain, microcephaly, hydrocephaly, mental retardation, developmental problems, uncoordinated muscle movement and seizures. Consumption of folic acid again has been shown to significantly reduce the occurrence of encephaloceles in infants.

'''Hydranencephaly'''

* A very rare neural tube defect in which the cerebral hemispheres are destroyed (necrotic tissue) with the occupied space being replaced by cerebro-spinal fluid, cortex and white matter remnants within a membranous sac. Interestingly, this condition can also develop in the postnatal peroid due to viral infections or traumatic brain injury. The brain stem may remain intact and functioning in hydranencephalic infants.

* Accompanied with this condition are many effects in which include seizures, hydrocephalus, increases in head circumference,impairment in vision/ body temperature regulation and cerebral palsy. Infants affected by hydranencephaly live typically short lives being no longer than 1 year of age. Lastly, there are no viable treatment options for this condition and only supportive care is available.

'''Iniencephaly'''

* Another neural tube defect involving severe backward bending of the head (retroflexion) with subsequent spinal distortions as well. Affected infants have no neck and hence the scalp of the head is directly joined to the skin of the back (also skin of the face connected to skin of the chest). Other conditions that develop along with iniencephaly are cyclopia, cephalocele and anencephaly. The development of this condition is not solely due to one factor but from various causes (both genetic and environmental factors).

* There are specific factors that have been shown to increase the occurrence of this condition. Malnutrition, reduced folic acid intake and elevated levels of homocysteine in blood are environmental factors that increase the risk of iniencephaly <ref><pubmed> 22408660 </pubmed></ref>. Intake of certain drugs such as anti-histamines and sulphonamide/tetracycline (antibiotics) have also increases this risk <ref><pubmed> 22439066 </pubmed></ref>. Furthermore obesity has been shown to have a significant effect on the incidence of iniencephaly with 1.7-3 fold increase <ref><pubmed> 18538144 </pubmed></ref>.

* In terms of treatment, folic acid supplementation as well as avoiding certain drugs such as those outlined above significantly reduces the occurrence of this condition.

'''Spina Bifida Cystica'''

* A neural tube defect in which involves either the formation of a meningocele or myelomeningocele. Of the two, the meningocele, is the least debilitating in that a cyst-like structure forms when the neural tube does not close properly. The membrane (meninges) is pushed into openings of the vertebrae where spinal fluid builds up within the cyst. The myelomeningocele leads to severe problems as the portion of the nueral tube that is unfused allows the spinal cord to protrude through. As a result, neuronal tissue is highly exposed due to myeloschisis as well as infections and hence may lead to severe complications.

'''Spina Bifida Occulta'''

* A neural tube defect that has minimal complications in comparison to other defects. Furthermore, this defect is hidden in that a tethered spinal cord may arise as well as a thicker filum terminale and diastematomyelia (spinal cord split into two). It is also important to note that no cysts form as opposed to the other more severe spina bifida defects.

==References==

<references/>

File:Schematic representation of the timeline of human neural development.jpg

2014-10-23T04:22:53Z

Z3418981: ==A simplified timeline of human neural development== This simplified graph is modified from original version.It shows a timeline for major events of neural development that occur during fetal and postnatal periods. These events are classified by prol...

==A simplified timeline of human neural development==

This simplified graph is modified from original version.It shows a timeline for major events of neural development that occur during fetal and postnatal periods. These events are classified by proliferation, migration, differentiation and metabolism.

===Reference===
Modified from: Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.

{{Template:Student Image}}

2014 Group Project 7

2014-10-22T08:57:54Z

Z3418981: /* Introduction */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, recieving and integration of information from all parts of the body, serving as the processing center of the bodies nervous system. The CNS controls all bodily functions (sensory and motor), consisting of 2 main organs; The Brain and Spinal Cord

==='''Brain'''===

The Brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

==='''Spinal Cord'''===

The Spinal Cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into

1) Ascending bundles - Transmits Sensory information from the body to the brain

2) Descending bundle - Transmits Motor function information from the brain to the body

Before fetal period, nerulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, the current research models and finding, historic findings and abnormalities that can occur in the fetal period is identified.

==Development during fetal period==

[[File:Neural-development.jpg|800px]]

Timeline of human neural development <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

'''1. cell proliferation'''

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

[[File:Somatosensory cortex of E20 rat.jpeg|300px]]

Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) through staining <ref><pubmed>22272298</pubmed></ref>

'''2. cell migration'''

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways. [[Image:CNS_passive.jpg|frame|300x200px|Passive cell displacement and outside-to-inside spatiotemporal gradient]][[Image:CNS_active.jpg|frame|400x250px|Active cell migration and inside-to-outside spatiotemporal gradient]]

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus, hypothalamus, spinal cord, retina, dentate gyrus of the hippocampal formation and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas.
[[Image:Internurons migration in cerebral cortex.jpg|frame|200x200px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex]]

'''3. cell differentiation'''

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

== Brain Development ==

- The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells

- By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

- The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

- Extends from the ninth gestational weeks through to the end of gestation

- Gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding

- Brain development begins rostral in GW8, proceeding caudally until it is complete at GW22

- Secondary sulci emerge between GW30-35

- Formation of Tertiary sulci begins during GW36 and into the postnatal period

- Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

- Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

- The major fibre pathways make up the brain white matter

- AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Increase in size and weight'''

[[File:Brain ventricles and ganglia development 03.jpg|300px]]

Image of brain and ventricular development <ref name=PMID19339620><pubmed>19339620</pubmed></ref>

[[File:Brain fissure development 02.jpg|300px]]

Image of brain fissure development <ref name=PMID19339620><pubmed>19339620</pubmed></ref>

'''sulcation and gyration'''

Sulcation: development of sulci. Primary sulci appear as shallow grooves on the surface of the brain and become more deeply infolded. Secondary sulci are formed from the development of side branches of primary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>

Gyration: development of gyrus that occurs late during fetal development until end of the pregnancy or even later after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>

{| class="wikitable"
|-
! Weeks !! Visible anatomical details
|-
| 20-21 || smooth, "lissencephalic" brain, wide Sylvian fissures
|-
| 22-23 || corpus callosum; beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || start of opercularization of Sylvian fissures; calcarine fissures and cingular sulci
|-
| 26 || central and collateral sulci
|-
| 27 || marginal and precentral sulci
|-
| 28 || postcentral and intraparietal sulci
|-
| 29 || inferior frontal sulci; bright white matter, dark cortical ribbon
|-
| 30-31 || narrower ventricular system and subarachnoid spaces
|-
| 32 || superior and inferior temporal sulci
|-
| 33 || external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table obtained from <pubmed>20608424</pubmed> <ref><pubmed>20608424</pubmed></ref>

== Spinal Cord Development ==
The spinal cord is formed from parts of the neural tube during embryonic and fetal development

=== Meninges Development ===

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations
|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

{|
|-bgcolor="ECCEF5"
|
===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.

|}
{|
|-bgcolor="CED8F6"
|The following are recent studies that use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

-Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

-The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

-The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.
|}
{|
|-bgcolor="ECCEF5"
|
'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

|}
{|
|-bgcolor="CED8F6"
|
'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.
|}
{|
|-bgcolor="ECCEF5"
|
'''Cortical Overgrowth in Fetuses With Isolated Ventriculomegaly'''
<ref><pubmed> 23508710 </pubmed></ref>

* The condition fetal ventriculomegaly is characterised by dilation of lateral ventricles whilst sharing associations with other malformations. It was hypothesised that using relative brain overgrowth as marked measure of altered brain development is due to the occurrence of ventriculomegaly and to evaluate this brain overgrowth through the use of magnetic resonance imaging (MRI) of fetuses isolated with enlarged ventricles (3rd and 4th ventricles as well as cerebrospinal fluid). Furthermore, significant changes to thalamic volumes, basal ganglia and white matter did not occur between cohorts.

* The study found that there was a sufficient increase in brain volume (overgrowth) of fetuses that had ventriculomegaly in comparison to controls. Also, larger lateral ventricle volumes were yielded with fetuses with ventriculomegaly assessed via 2-dimensional movement of the atrial diameter (ultrasound and MRi) as well as a larger total brain tissue volume. This provides support for the hypothesis in that brain overgrowth can be used as a marked measure for ventriculomegaly with results showing that overgrowth was not localised in one region but across both hemispheres and thus lead to a neural deficit in children (altered neural connectivity).

* Hence, this study has assisted in the improved understanding of the effects of ventriculomegaly on cognition, language and behaviour in children.

===Future Research===

|}

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]
Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age. The most frequent cause of macrocephaly is hydrocephalus.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.
* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period) in the secondary type.

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation.

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.

===Fetal Alcohol Syndrome===
<ref><pubmed> 23809349 </pubmed></ref>

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status.

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.

{| style="width:40%; height:170px" align="center"
|-
| [[Image: Fetal alcohol syndrome.jpg|frame|250x250px|The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref> ]]
|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

* All degrees of iodine deficiency (mild: 50-99 μg/day, moderate: 20-49 μg/day and severe≤20 μg/day) affect thyroid function of both mother and the neonate as well as mental development of the child. The damage increases with the degree of deficiency; overt endemic cretinism is the most severe consequence.

* Iodine deficiency disorders refer to complications that arise when the recommended dietary allowance of iodine is not met. These complications include thyroid function abnormalities and when iodine deficiency is severe, endemic goitre and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality.

* Iodine deficiency represents the world’s greatest cause of preventable brain damage and mental retardation, resulting of a loss of 10-15 IQ points globally. Therefore it is essential that the recommended dietary requirement for iodine is met, especially during pregnancy and lactation (200–300 μg/day). <ref><pubmed>10750030</pubmed></ref>

* Clinical manifestations of hypothyroidism include: Myxedematous facies (condition characterized by thickening of the skin, blunting of the senses and intellect, and laboured speech), jaundice, a puffy face and a wide posterior fontanelle with open sutures. The nasal bridge is flat. The mouth may be slightly open revealing macroglossia. Further examination would reveal bradycardia and a protuberant abdomen with a large umbilical hernia. Neurologic examination findings include hypotonia with delayed reflexes. Skin may be cool to touch and mottled in appearance due to circulatory compromise.<ref><pubmed>2903524</pubmed></ref>

===Abnormalities associated with apoptosis and migration of cells in the fetal CNS===

* The migration of cells and cell death are critically important to fetal brain and CNS development. Abnormalities in each of these processes, programmed cell death (apoptosis) in particular, have been shown to result in severe developmental abnormalities in experimental animals. Apoptosis is critically important for appropriate brain development; certain areas in brain may experience up to 50% cell death. <ref><pubmed> 11589424 </pubmed></ref>

In an experiment conducted by kuida et. al 1996, it was observed that mice that were deficient for CPP32 (a protease responsible for apoptosis), were born at a lower frequency than expected, were smaller in size compared to the normal mice and died at an early age. Brain development is significantly affected in CPP32-deficient mice resulting in a variety of hyperplasia and disorganised cell development. <ref><pubmed>8934524</pubmed></ref>

On the other hand, disrupted neuronal migration can lead to an abnormality in cell position. When this happens, the neurons are said to be heterotopic. Abnormalities in neuronal migration have been studied extensively in human cerebral cortex where these defects are associated with a variety of syndromes and diseases, ranging from behavioural disorders (including some forms of schizophrenia, dyslexia and autism) to extremely severe mental retardation and failure to thrive. <ref><pubmed>10532616</pubmed></ref>

===Neural Tube Defects===

Defects which affect the either the brain or the spinal cord in which openings remain. Grastulation occurs in week 3 of embryonic development where specialized cells (dorsal side) structurally change shape leading to the formation of the neural tube. If the neural tube does not close or fuse together properly, then openings remain which lead to various neural tube defects such as Spina bifida cystica and Spina bifida occulta.

'''Anencephaly'''

* A neural tube defect involving abnormal development of the brain and incomplete skull formation leading to high infant mortality rates with infants being stillborn or dying within a few hours after birth.

* The failure of the neural tube to close around the 23rd and 26th day into embryonic development is characteristic of this condition. As a result, the forebrain is severely affected where the cerebrum does not grow and hence partial growth occurs only. The cerebrum has a key importance in maintaining thought, consciousness and coordination whilst having no intact cerebrum rules out the probability of the affected fetus gaining consciousness .

* Increasing one's dietary intake of folic acid notably reduces the incidence of neural tube defects. Consuming 0.4mg of folic acid is sufficient to induce these results.

* Since incomplete skull formation occurs, brain tissue becomes exposed due to the absence of bone covering and therefore leading to further complications.

'''Encephaloceles'''

* Another neural tube defect in which a sac-like projections (including membrane covering) that occurs around the 3-4 week of embryonic development in which neural tube closure has not successfully occurred. The location of these protrusions varies but can be naso-frontal (nose and head), naso-ethmoidal (nose and ethmoid bone), naso-orbital (nose and eyes), meningocele (cerebrospinal fluid and membrane covering) and encephalomeningocele (meningocele with brain tissue as well).

* These sac-like protrusions lead to a variety of abnormal effects which include cerebro-spinal fluid build-up in brain, microcephaly, hydrocephaly, mental retardation, developmental problems, uncoordinated muscle movement and seizures. Consumption of folic acid again has been shown to significantly reduce the occurrence of encephaloceles in infants.

'''Hydranencephaly'''

* A very rare neural tube defect in which the cerebral hemispheres are destroyed (necrotic tissue) with the occupied space being replaced by cerebro-spinal fluid, cortex and white matter remnants within a membranous sac. Interestingly, this condition can also develop in the postnatal peroid due to viral infections or traumatic brain injury. The brain stem may remain intact and functioning in hydranencephalic infants.

* Accompanied with this condition are many effects in which include seizures, hydrocephalus, increases in head circumference,impairment in vision/ body temperature regulation and cerebral palsy. Infants affected by hydranencephaly live typically short lives being no longer than 1 year of age. Lastly, there are no viable treatment options for this condition and only supportive care is available.

'''Iniencephaly'''

* Another neural tube defect involving severe backward bending of the head (retroflexion) with subsequent spinal distortions as well. Affected infants have no neck and hence the scalp of the head is directly joined to the skin of the back (also skin of the face connected to skin of the chest). Other conditions that develop along with iniencephaly are cyclopia, cephalocele and anencephaly. The development of this condition is not solely due to one factor but from various causes (both genetic and environmental factors).

* There are specific factors that have been shown to increase the occurrence of this condition. Malnutrition, reduced folic acid intake and elevated levels of homocysteine in blood are environmental factors that increase the risk of iniencephaly <ref><pubmed> 22408660 </pubmed></ref>. Intake of certain drugs such as anti-histamines and sulphonamide/tetracycline (antibiotics) have also increases this risk <ref><pubmed> 22439066 </pubmed></ref>. Furthermore obesity has been shown to have a significant effect on the incidence of iniencephaly with 1.7-3 fold increase <ref><pubmed> 18538144 </pubmed></ref>.

* In terms of treatment, folic acid supplementation as well as avoiding certain drugs such as those outlined above significantly reduces the occurrence of this condition.

'''Spina Bifida Cystica'''

* A neural tube defect in which involves either the formation of a meningocele or myelomeningocele. Of the two, the meningocele, is the least debilitating in that a cyst-like structure forms when the neural tube does not close properly. The membrane (meninges) is pushed into openings of the vertebrae where spinal fluid builds up within the cyst. The myelomeningocele leads to severe problems as the portion of the nueral tube that is unfused allows the spinal cord to protrude through. As a result, neuronal tissue is highly exposed due to myeloschisis as well as infections and hence may lead to severe complications.

'''Spina Bifida Occulta'''

* A neural tube defect that has minimal complications in comparison to other defects. Furthermore, this defect is hidden in that a tethered spinal cord may arise as well as a thicker filum terminale and diastematomyelia (spinal cord split into two). It is also important to note that no cysts form as opposed to the other more severe spina bifida defects.

==References==

<references/>

2014 Group Project 7

2014-10-22T08:55:14Z

Z3418981: /* Introduction */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==
<img id="Image-Maps-Com-image-maps-2014-10-22-044910" src="http://www.image-maps.com/m/private/0/as96cljbmobr3pklbcteov7ni4_295px-brain_human_lateral_view.svg.png" border="0" width="295" height="351" orgWidth="295" orgHeight="351" usemap="#image-maps-2014-10-22-044910" alt="" />
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The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, recieving and integration of information from all parts of the body, serving as the processing center of the bodies nervous system. The CNS controls all bodily functions (sensory and motor), consisting of 2 main organs; The Brain and Spinal Cord

==='''Brain'''===

The Brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

==='''Spinal Cord'''===

The Spinal Cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into

1) Ascending bundles - Transmits Sensory information from the body to the brain

2) Descending bundle - Transmits Motor function information from the brain to the body

Before fetal period, nerulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, the current research models and finding, historic findings and abnormalities that can occur in the fetal period is identified.

==Development during fetal period==

[[File:Neural-development.jpg|800px]]

Timeline of human neural development <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

'''1. cell proliferation'''

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

[[File:Somatosensory cortex of E20 rat.jpeg|300px]]

Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) through staining <ref><pubmed>22272298</pubmed></ref>

'''2. cell migration'''

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways. [[Image:CNS_passive.jpg|frame|300x200px|Passive cell displacement and outside-to-inside spatiotemporal gradient]][[Image:CNS_active.jpg|frame|400x250px|Active cell migration and inside-to-outside spatiotemporal gradient]]

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus, hypothalamus, spinal cord, retina, dentate gyrus of the hippocampal formation and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas.
[[Image:Internurons migration in cerebral cortex.jpg|frame|200x200px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex]]

'''3. cell differentiation'''

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

== Brain Development ==

- The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells

- By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

- The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

- Extends from the ninth gestational weeks through to the end of gestation

- Gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding

- Brain development begins rostral in GW8, proceeding caudally until it is complete at GW22

- Secondary sulci emerge between GW30-35

- Formation of Tertiary sulci begins during GW36 and into the postnatal period

- Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

- Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

- The major fibre pathways make up the brain white matter

- AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Increase in size and weight'''

[[File:Brain ventricles and ganglia development 03.jpg|300px]]

Image of brain and ventricular development <ref name=PMID19339620><pubmed>19339620</pubmed></ref>

[[File:Brain fissure development 02.jpg|300px]]

Image of brain fissure development <ref name=PMID19339620><pubmed>19339620</pubmed></ref>

'''sulcation and gyration'''

Sulcation: development of sulci. Primary sulci appear as shallow grooves on the surface of the brain and become more deeply infolded. Secondary sulci are formed from the development of side branches of primary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>

Gyration: development of gyrus that occurs late during fetal development until end of the pregnancy or even later after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>

{| class="wikitable"
|-
! Weeks !! Visible anatomical details
|-
| 20-21 || smooth, "lissencephalic" brain, wide Sylvian fissures
|-
| 22-23 || corpus callosum; beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || start of opercularization of Sylvian fissures; calcarine fissures and cingular sulci
|-
| 26 || central and collateral sulci
|-
| 27 || marginal and precentral sulci
|-
| 28 || postcentral and intraparietal sulci
|-
| 29 || inferior frontal sulci; bright white matter, dark cortical ribbon
|-
| 30-31 || narrower ventricular system and subarachnoid spaces
|-
| 32 || superior and inferior temporal sulci
|-
| 33 || external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table obtained from <pubmed>20608424</pubmed> <ref><pubmed>20608424</pubmed></ref>

== Spinal Cord Development ==
The spinal cord is formed from parts of the neural tube during embryonic and fetal development

=== Meninges Development ===

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations
|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

{|
|-bgcolor="ECCEF5"
|
===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.

|}
{|
|-bgcolor="CED8F6"
|The following are recent studies that use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

-Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

-The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

-The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.
|}
{|
|-bgcolor="ECCEF5"
|
'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

|}
{|
|-bgcolor="CED8F6"
|
'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.
|}
{|
|-bgcolor="ECCEF5"
|
'''Cortical Overgrowth in Fetuses With Isolated Ventriculomegaly'''
<ref><pubmed> 23508710 </pubmed></ref>

* The condition fetal ventriculomegaly is characterised by dilation of lateral ventricles whilst sharing associations with other malformations. It was hypothesised that using relative brain overgrowth as marked measure of altered brain development is due to the occurrence of ventriculomegaly and to evaluate this brain overgrowth through the use of magnetic resonance imaging (MRI) of fetuses isolated with enlarged ventricles (3rd and 4th ventricles as well as cerebrospinal fluid). Furthermore, significant changes to thalamic volumes, basal ganglia and white matter did not occur between cohorts.

* The study found that there was a sufficient increase in brain volume (overgrowth) of fetuses that had ventriculomegaly in comparison to controls. Also, larger lateral ventricle volumes were yielded with fetuses with ventriculomegaly assessed via 2-dimensional movement of the atrial diameter (ultrasound and MRi) as well as a larger total brain tissue volume. This provides support for the hypothesis in that brain overgrowth can be used as a marked measure for ventriculomegaly with results showing that overgrowth was not localised in one region but across both hemispheres and thus lead to a neural deficit in children (altered neural connectivity).

* Hence, this study has assisted in the improved understanding of the effects of ventriculomegaly on cognition, language and behaviour in children.

===Future Research===

|}

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]
Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age. The most frequent cause of macrocephaly is hydrocephalus.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.
* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period) in the secondary type.

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation.

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.

===Fetal Alcohol Syndrome===
<ref><pubmed> 23809349 </pubmed></ref>

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status.

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.

{| style="width:40%; height:170px" align="center"
|-
| [[Image: Fetal alcohol syndrome.jpg|frame|250x250px|The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref> ]]
|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

* All degrees of iodine deficiency (mild: 50-99 μg/day, moderate: 20-49 μg/day and severe≤20 μg/day) affect thyroid function of both mother and the neonate as well as mental development of the child. The damage increases with the degree of deficiency; overt endemic cretinism is the most severe consequence.

* Iodine deficiency disorders refer to complications that arise when the recommended dietary allowance of iodine is not met. These complications include thyroid function abnormalities and when iodine deficiency is severe, endemic goitre and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality.

* Iodine deficiency represents the world’s greatest cause of preventable brain damage and mental retardation, resulting of a loss of 10-15 IQ points globally. Therefore it is essential that the recommended dietary requirement for iodine is met, especially during pregnancy and lactation (200–300 μg/day). <ref><pubmed>10750030</pubmed></ref>

* Clinical manifestations of hypothyroidism include: Myxedematous facies (condition characterized by thickening of the skin, blunting of the senses and intellect, and laboured speech), jaundice, a puffy face and a wide posterior fontanelle with open sutures. The nasal bridge is flat. The mouth may be slightly open revealing macroglossia. Further examination would reveal bradycardia and a protuberant abdomen with a large umbilical hernia. Neurologic examination findings include hypotonia with delayed reflexes. Skin may be cool to touch and mottled in appearance due to circulatory compromise.<ref><pubmed>2903524</pubmed></ref>

===Abnormalities associated with apoptosis and migration of cells in the fetal CNS===

* The migration of cells and cell death are critically important to fetal brain and CNS development. Abnormalities in each of these processes, programmed cell death (apoptosis) in particular, have been shown to result in severe developmental abnormalities in experimental animals. Apoptosis is critically important for appropriate brain development; certain areas in brain may experience up to 50% cell death. <ref><pubmed> 11589424 </pubmed></ref>

In an experiment conducted by kuida et. al 1996, it was observed that mice that were deficient for CPP32 (a protease responsible for apoptosis), were born at a lower frequency than expected, were smaller in size compared to the normal mice and died at an early age. Brain development is significantly affected in CPP32-deficient mice resulting in a variety of hyperplasia and disorganised cell development. <ref><pubmed>8934524</pubmed></ref>

On the other hand, disrupted neuronal migration can lead to an abnormality in cell position. When this happens, the neurons are said to be heterotopic. Abnormalities in neuronal migration have been studied extensively in human cerebral cortex where these defects are associated with a variety of syndromes and diseases, ranging from behavioural disorders (including some forms of schizophrenia, dyslexia and autism) to extremely severe mental retardation and failure to thrive. <ref><pubmed>10532616</pubmed></ref>

===Neural Tube Defects===

Defects which affect the either the brain or the spinal cord in which openings remain. Grastulation occurs in week 3 of embryonic development where specialized cells (dorsal side) structurally change shape leading to the formation of the neural tube. If the neural tube does not close or fuse together properly, then openings remain which lead to various neural tube defects such as Spina bifida cystica and Spina bifida occulta.

'''Anencephaly'''

* A neural tube defect involving abnormal development of the brain and incomplete skull formation leading to high infant mortality rates with infants being stillborn or dying within a few hours after birth.

* The failure of the neural tube to close around the 23rd and 26th day into embryonic development is characteristic of this condition. As a result, the forebrain is severely affected where the cerebrum does not grow and hence partial growth occurs only. The cerebrum has a key importance in maintaining thought, consciousness and coordination whilst having no intact cerebrum rules out the probability of the affected fetus gaining consciousness .

* Increasing one's dietary intake of folic acid notably reduces the incidence of neural tube defects. Consuming 0.4mg of folic acid is sufficient to induce these results.

* Since incomplete skull formation occurs, brain tissue becomes exposed due to the absence of bone covering and therefore leading to further complications.

'''Encephaloceles'''

* Another neural tube defect in which a sac-like projections (including membrane covering) that occurs around the 3-4 week of embryonic development in which neural tube closure has not successfully occurred. The location of these protrusions varies but can be naso-frontal (nose and head), naso-ethmoidal (nose and ethmoid bone), naso-orbital (nose and eyes), meningocele (cerebrospinal fluid and membrane covering) and encephalomeningocele (meningocele with brain tissue as well).

* These sac-like protrusions lead to a variety of abnormal effects which include cerebro-spinal fluid build-up in brain, microcephaly, hydrocephaly, mental retardation, developmental problems, uncoordinated muscle movement and seizures. Consumption of folic acid again has been shown to significantly reduce the occurrence of encephaloceles in infants.

'''Hydranencephaly'''

* A very rare neural tube defect in which the cerebral hemispheres are destroyed (necrotic tissue) with the occupied space being replaced by cerebro-spinal fluid, cortex and white matter remnants within a membranous sac. Interestingly, this condition can also develop in the postnatal peroid due to viral infections or traumatic brain injury. The brain stem may remain intact and functioning in hydranencephalic infants.

* Accompanied with this condition are many effects in which include seizures, hydrocephalus, increases in head circumference,impairment in vision/ body temperature regulation and cerebral palsy. Infants affected by hydranencephaly live typically short lives being no longer than 1 year of age. Lastly, there are no viable treatment options for this condition and only supportive care is available.

'''Iniencephaly'''

* Another neural tube defect involving severe backward bending of the head (retroflexion) with subsequent spinal distortions as well. Affected infants have no neck and hence the scalp of the head is directly joined to the skin of the back (also skin of the face connected to skin of the chest). Other conditions that develop along with iniencephaly are cyclopia, cephalocele and anencephaly. The development of this condition is not solely due to one factor but from various causes (both genetic and environmental factors).

* There are specific factors that have been shown to increase the occurrence of this condition. Malnutrition, reduced folic acid intake and elevated levels of homocysteine in blood are environmental factors that increase the risk of iniencephaly <ref><pubmed> 22408660 </pubmed></ref>. Intake of certain drugs such as anti-histamines and sulphonamide/tetracycline (antibiotics) have also increases this risk <ref><pubmed> 22439066 </pubmed></ref>. Furthermore obesity has been shown to have a significant effect on the incidence of iniencephaly with 1.7-3 fold increase <ref><pubmed> 18538144 </pubmed></ref>.

* In terms of treatment, folic acid supplementation as well as avoiding certain drugs such as those outlined above significantly reduces the occurrence of this condition.

'''Spina Bifida Cystica'''

* A neural tube defect in which involves either the formation of a meningocele or myelomeningocele. Of the two, the meningocele, is the least debilitating in that a cyst-like structure forms when the neural tube does not close properly. The membrane (meninges) is pushed into openings of the vertebrae where spinal fluid builds up within the cyst. The myelomeningocele leads to severe problems as the portion of the nueral tube that is unfused allows the spinal cord to protrude through. As a result, neuronal tissue is highly exposed due to myeloschisis as well as infections and hence may lead to severe complications.

'''Spina Bifida Occulta'''

* A neural tube defect that has minimal complications in comparison to other defects. Furthermore, this defect is hidden in that a tethered spinal cord may arise as well as a thicker filum terminale and diastematomyelia (spinal cord split into two). It is also important to note that no cysts form as opposed to the other more severe spina bifida defects.

==References==

<references/>

2014 Group Project 7

2014-10-22T02:07:53Z

Z3418981: /* Current research models and findings */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, recieving and integration of information from all parts of the body, serving as the processing center of the bodies nervous system. The CNS controls all bodily functions (sensory and motor), consisting of 2 main organs; The Brain and Spinal Cord

==='''Brain'''===

The Brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

==='''Spinal Cord'''===

The Spinal Cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into

1) Ascending bundles - Transmits Sensory information from the body to the brain

2) Descending bundle - Transmits Motor function information from the brain to the body

Before fetal period, nerulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, the current research models and finding, historic findings and abnormalities that can occur in the fetal period is identified.

==Development during fetal period==

[[File:Neural-development.jpg|800px]]

Timeline of human neural development <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

'''1. cell proliferation'''

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

[[File:Somatosensory cortex of E20 rat.jpeg|300px]]

Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) through staining <ref><pubmed>22272298</pubmed></ref>

'''2. cell migration'''

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways. [[Image:CNS_passive.jpg|frame|300x200px|Passive cell displacement and outside-to-inside spatiotemporal gradient]][[Image:CNS_active.jpg|frame|400x250px|Active cell migration and inside-to-outside spatiotemporal gradient]]

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus, hypothalamus, spinal cord, retina, dentate gyrus of the hippocampal formation and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas.
[[Image:Internurons migration in cerebral cortex.jpg|frame|200x200px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex]]

'''3. cell differentiation'''

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

== Brain Development ==

- The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells

- By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

- The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

- Extends from the ninth gestational weeks through to the end of gestation

- Gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding

- Brain development begins rostral in GW8, proceeding caudally until it is complete at GW22

- Secondary sulci emerge between GW30-35

- Formation of Tertiary sulci begins during GW36 and into the postnatal period

- Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

- Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

- The major fibre pathways make up the brain white matter

- AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Increase in size and weight'''

[[File:Brain ventricles and ganglia development 03.jpg|300px]]

Image of brain and ventricular development <ref name=PMID19339620><pubmed>19339620</pubmed></ref>

[[File:Brain fissure development 02.jpg|300px]]

Image of brain fissure development <ref name=PMID19339620><pubmed>19339620</pubmed></ref>

'''sulcation and gyration'''

Sulcation: development of sulci. Primary sulci appear as shallow grooves on the surface of the brain and become more deeply infolded. Secondary sulci are formed from the development of side branches of primary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>

Gyration: development of gyrus that occurs late during fetal development until end of the pregnancy or even later after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>

{| class="wikitable"
|-
! Weeks !! Visible anatomical details
|-
| 20-21 || smooth, "lissencephalic" brain, wide Sylvian fissures
|-
| 22-23 || corpus callosum; beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || start of opercularization of Sylvian fissures; calcarine fissures and cingular sulci
|-
| 26 || central and collateral sulci
|-
| 27 || marginal and precentral sulci
|-
| 28 || postcentral and intraparietal sulci
|-
| 29 || inferior frontal sulci; bright white matter, dark cortical ribbon
|-
| 30-31 || narrower ventricular system and subarachnoid spaces
|-
| 32 || superior and inferior temporal sulci
|-
| 33 || external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table obtained from <pubmed>20608424</pubmed> <ref><pubmed>20608424</pubmed></ref>

== Spinal Cord Development ==
The spinal cord is formed from parts of the neural tube during embryonic and fetal development

=== Meninges Development ===

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations
|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

{|
|-bgcolor="ECCEF5"
|
===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.

|}
{|
|-bgcolor="CED8F6"
|The following are recent studies that use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

-Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

-The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

-The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.
|}
{|
|-bgcolor="ECCEF5"
|
'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

|}
{|
|-bgcolor="CED8F6"
|
'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.
|}
{|
|-bgcolor="ECCEF5"
|
'''Cortical Overgrowth in Fetuses With Isolated Ventriculomegaly'''
<ref><pubmed> 23508710 </pubmed></ref>

* The condition fetal ventriculomegaly is characterised by dilation of lateral ventricles whilst sharing associations with other malformations. It was hypothesised that using relative brain overgrowth as marked measure of altered brain development is due to the occurrence of ventriculomegaly and to evaluate this brain overgrowth through the use of magnetic resonance imaging (MRI) of fetuses isolated with enlarged ventricles (3rd and 4th ventricles as well as cerebrospinal fluid). Furthermore, significant changes to thalamic volumes, basal ganglia and white matter did not occur between cohorts.

* The study found that there was a sufficient increase in brain volume (overgrowth) of fetuses that had ventriculomegaly in comparison to controls. Also, larger lateral ventricle volumes were yielded with fetuses with ventriculomegaly assessed via 2-dimensional movement of the atrial diameter (ultrasound and MRi) as well as a larger total brain tissue volume. This provides support for the hypothesis in that brain overgrowth can be used as a marked measure for ventriculomegaly with results showing that overgrowth was not localised in one region but across both hemispheres and thus lead to a neural deficit in children (altered neural connectivity).

* Hence, this study has assisted in the improved understanding of the effects of ventriculomegaly on cognition, language and behaviour in children.

===Future Research===

|}

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]
Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age. The most frequent cause of macrocephaly is hydrocephalus.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.
* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period) in the secondary type.

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation.

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.

===Fetal Alcohol Syndrome===
<ref><pubmed> 23809349 </pubmed></ref>

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status.

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.

{| style="width:40%; height:170px" align="center"
|-
| [[Image: Fetal alcohol syndrome.jpg|frame|250x250px|The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref> ]]
|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

* All degrees of iodine deficiency (mild: 50-99 μg/day, moderate: 20-49 μg/day and severe≤20 μg/day) affect thyroid function of both mother and the neonate as well as mental development of the child. The damage increases with the degree of deficiency; overt endemic cretinism is the most severe consequence.

* Iodine deficiency disorders refer to complications that arise when the recommended dietary allowance of iodine is not met. These complications include thyroid function abnormalities and when iodine deficiency is severe, endemic goitre and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality.

* Iodine deficiency represents the world’s greatest cause of preventable brain damage and mental retardation, resulting of a loss of 10-15 IQ points globally. Therefore it is essential that the recommended dietary requirement for iodine is met, especially during pregnancy and lactation (200–300 μg/day). <ref><pubmed>10750030</pubmed></ref>

* Clinical manifestations of hypothyroidism include: Myxedematous facies (condition characterized by thickening of the skin, blunting of the senses and intellect, and laboured speech), jaundice, a puffy face and a wide posterior fontanelle with open sutures. The nasal bridge is flat. The mouth may be slightly open revealing macroglossia. Further examination would reveal bradycardia and a protuberant abdomen with a large umbilical hernia. Neurologic examination findings include hypotonia with delayed reflexes. Skin may be cool to touch and mottled in appearance due to circulatory compromise.<ref><pubmed>2903524</pubmed></ref>

===Abnormalities associated with apoptosis and migration of cells in the fetal CNS===

* The migration of cells and cell death are critically important to fetal brain and CNS development. Abnormalities in each of these processes, programmed cell death (apoptosis) in particular, have been shown to result in severe developmental abnormalities in experimental animals. Apoptosis is critically important for appropriate brain development; certain areas in brain may experience up to 50% cell death. <ref><pubmed> 11589424 </pubmed></ref>

In an experiment conducted by kuida et. al 1996, it was observed that mice that were deficient for CPP32 (a protease responsible for apoptosis), were born at a lower frequency than expected, were smaller in size compared to the normal mice and died at an early age. Brain development is significantly affected in CPP32-deficient mice resulting in a variety of hyperplasia and disorganised cell development. <ref><pubmed>8934524</pubmed></ref>

On the other hand, disrupted neuronal migration can lead to an abnormality in cell position. When this happens, the neurons are said to be heterotopic. Abnormalities in neuronal migration have been studied extensively in human cerebral cortex where these defects are associated with a variety of syndromes and diseases, ranging from behavioural disorders (including some forms of schizophrenia, dyslexia and autism) to extremely severe mental retardation and failure to thrive. <ref><pubmed>10532616</pubmed></ref>

===Neural Tube Defects===

Defects which affect the either the brain or the spinal cord in which openings remain. Grastulation occurs in week 3 of embryonic development where specialized cells (dorsal side) structurally change shape leading to the formation of the neural tube. If the neural tube does not close or fuse together properly, then openings remain which lead to various neural tube defects such as Spina bifida cystica and Spina bifida occulta.

'''Anencephaly'''

* A neural tube defect involving abnormal development of the brain and incomplete skull formation leading to high infant mortality rates with infants being stillborn or dying within a few hours after birth.

* The failure of the neural tube to close around the 23rd and 26th day into embryonic development is characteristic of this condition. As a result, the forebrain is severely affected where the cerebrum does not grow and hence partial growth occurs only. The cerebrum has a key importance in maintaining thought, consciousness and coordination whilst having no intact cerebrum rules out the probability of the affected fetus gaining consciousness .

* Increasing one's dietary intake of folic acid notably reduces the incidence of neural tube defects. Consuming 0.4mg of folic acid is sufficient to induce these results.

* Since incomplete skull formation occurs, brain tissue becomes exposed due to the absence of bone covering and therefore leading to further complications.

'''Encephaloceles'''

* Another neural tube defect in which a sac-like projections (including membrane covering) that occurs around the 3-4 week of embryonic development in which neural tube closure has not successfully occurred. The location of these protrusions varies but can be naso-frontal (nose and head), naso-ethmoidal (nose and ethmoid bone), naso-orbital (nose and eyes), meningocele (cerebrospinal fluid and membrane covering) and encephalomeningocele (meningocele with brain tissue as well).

* These sac-like protrusions lead to a variety of abnormal effects which include cerebro-spinal fluid build-up in brain, microcephaly, hydrocephaly, mental retardation, developmental problems, uncoordinated muscle movement and seizures. Consumption of folic acid again has been shown to significantly reduce the occurrence of encephaloceles in infants.

'''Hydranencephaly'''

* A very rare neural tube defect in which the cerebral hemispheres are destroyed (necrotic tissue) with the occupied space being replaced by cerebro-spinal fluid, cortex and white matter remnants within a membranous sac. Interestingly, this condition can also develop in the postnatal peroid due to viral infections or traumatic brain injury. The brain stem may remain intact and functioning in hydranencephalic infants.

* Accompanied with this condition are many effects in which include seizures, hydrocephalus, increases in head circumference,impairment in vision/ body temperature regulation and cerebral palsy. Infants affected by hydranencephaly live typically short lives being no longer than 1 year of age. Lastly, there are no viable treatment options for this condition and only supportive care is available.

'''Iniencephaly'''

* Another neural tube defect involving severe backward bending of the head (retroflexion) with subsequent spinal distortions as well. Affected infants have no neck and hence the scalp of the head is directly joined to the skin of the back (also skin of the face connected to skin of the chest). Other conditions that develop along with iniencephaly are cyclopia, cephalocele and anencephaly. The development of this condition is not solely due to one factor but from various causes (both genetic and environmental factors).

* There are specific factors that have been shown to increase the occurrence of this condition. Malnutrition, reduced folic acid intake and elevated levels of homocysteine in blood are environmental factors that increase the risk of iniencephaly <ref><pubmed> 22408660 </pubmed></ref>. Intake of certain drugs such as anti-histamines and sulphonamide/tetracycline (antibiotics) have also increases this risk <ref><pubmed> 22439066 </pubmed></ref>. Furthermore obesity has been shown to have a significant effect on the incidence of iniencephaly with 1.7-3 fold increase <ref><pubmed> 18538144 </pubmed></ref>.

* In terms of treatment, folic acid supplementation as well as avoiding certain drugs such as those outlined above significantly reduces the occurrence of this condition.

'''Spina Bifida Cystica'''

* A neural tube defect in which involves either the formation of a meningocele or myelomeningocele. Of the two, the meningocele, is the least debilitating in that a cyst-like structure forms when the neural tube does not close properly. The membrane (meninges) is pushed into openings of the vertebrae where spinal fluid builds up within the cyst. The myelomeningocele leads to severe problems as the portion of the nueral tube that is unfused allows the spinal cord to protrude through. As a result, neuronal tissue is highly exposed due to myeloschisis as well as infections and hence may lead to severe complications.

'''Spina Bifida Occulta'''

* A neural tube defect that has minimal complications in comparison to other defects. Furthermore, this defect is hidden in that a tethered spinal cord may arise as well as a thicker filum terminale and diastematomyelia (spinal cord split into two). It is also important to note that no cysts form as opposed to the other more severe spina bifida defects.

==References==

<references/>

2014 Group Project 7

2014-10-22T02:03:35Z

Z3418981: /* Current research models and findings */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, recieving and integration of information from all parts of the body, serving as the processing center of the bodies nervous system. The CNS controls all bodily functions (sensory and motor), consisting of 2 main organs; The Brain and Spinal Cord

==='''Brain'''===

The Brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

==='''Spinal Cord'''===

The Spinal Cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into

1) Ascending bundles - Transmits Sensory information from the body to the brain

2) Descending bundle - Transmits Motor function information from the brain to the body

Before fetal period, nerulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, the current research models and finding, historic findings and abnormalities that can occur in the fetal period is identified.

==Development during fetal period==

[[File:Neural-development.jpg|800px]]

Timeline of human neural development <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

'''1. cell proliferation'''

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

[[File:Somatosensory cortex of E20 rat.jpeg|300px]]

Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) through staining <ref><pubmed>22272298</pubmed></ref>

'''2. cell migration'''

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways. [[Image:CNS_passive.jpg|frame|300x200px|Passive cell displacement and outside-to-inside spatiotemporal gradient]][[Image:CNS_active.jpg|frame|400x250px|Active cell migration and inside-to-outside spatiotemporal gradient]]

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus, hypothalamus, spinal cord, retina, dentate gyrus of the hippocampal formation and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas.
[[Image:Internurons migration in cerebral cortex.jpg|frame|200x200px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex]]

'''3. cell differentiation'''

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

== Brain Development ==

- The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells

- By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

- The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

- Extends from the ninth gestational weeks through to the end of gestation

- Gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding

- Brain development begins rostral in GW8, proceeding caudally until it is complete at GW22

- Secondary sulci emerge between GW30-35

- Formation of Tertiary sulci begins during GW36 and into the postnatal period

- Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

- Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

- The major fibre pathways make up the brain white matter

- AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Increase in size and weight'''

[[File:Brain ventricles and ganglia development 03.jpg|300px]]

Image of brain and ventricular development <ref name=PMID19339620><pubmed>19339620</pubmed></ref>

[[File:Brain fissure development 02.jpg|300px]]

Image of brain fissure development <ref name=PMID19339620><pubmed>19339620</pubmed></ref>

'''sulcation and gyration'''

Sulcation: development of sulci. Primary sulci appear as shallow grooves on the surface of the brain and become more deeply infolded. Secondary sulci are formed from the development of side branches of primary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>

Gyration: development of gyrus that occurs late during fetal development until end of the pregnancy or even later after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>

{| class="wikitable"
|-
! Weeks !! Visible anatomical details
|-
| 20-21 || smooth, "lissencephalic" brain, wide Sylvian fissures
|-
| 22-23 || corpus callosum; beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || start of opercularization of Sylvian fissures; calcarine fissures and cingular sulci
|-
| 26 || central and collateral sulci
|-
| 27 || marginal and precentral sulci
|-
| 28 || postcentral and intraparietal sulci
|-
| 29 || inferior frontal sulci; bright white matter, dark cortical ribbon
|-
| 30-31 || narrower ventricular system and subarachnoid spaces
|-
| 32 || superior and inferior temporal sulci
|-
| 33 || external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table obtained from <pubmed>20608424</pubmed> <ref><pubmed>20608424</pubmed></ref>

== Spinal Cord Development ==
The spinal cord is formed from parts of the neural tube during embryonic and fetal development

=== Meninges Development ===

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations
|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

{|
|-bgcolor="ECCEF5"
|===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.

|}
{|
|-bgcolor="CED8F6"
|The following are recent studies that use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

-Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

-The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

-The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.

'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.

'''Cortical Overgrowth in Fetuses With Isolated Ventriculomegaly'''
<ref><pubmed> 23508710 </pubmed></ref>

* The condition fetal ventriculomegaly is characterised by dilation of lateral ventricles whilst sharing associations with other malformations. It was hypothesised that using relative brain overgrowth as marked measure of altered brain development is due to the occurrence of ventriculomegaly and to evaluate this brain overgrowth through the use of magnetic resonance imaging (MRI) of fetuses isolated with enlarged ventricles (3rd and 4th ventricles as well as cerebrospinal fluid). Furthermore, significant changes to thalamic volumes, basal ganglia and white matter did not occur between cohorts.

* The study found that there was a sufficient increase in brain volume (overgrowth) of fetuses that had ventriculomegaly in comparison to controls. Also, larger lateral ventricle volumes were yielded with fetuses with ventriculomegaly assessed via 2-dimensional movement of the atrial diameter (ultrasound and MRi) as well as a larger total brain tissue volume. This provides support for the hypothesis in that brain overgrowth can be used as a marked measure for ventriculomegaly with results showing that overgrowth was not localised in one region but across both hemispheres and thus lead to a neural deficit in children (altered neural connectivity).

* Hence, this study has assisted in the improved understanding of the effects of ventriculomegaly on cognition, language and behaviour in children.

===Future Research===

|}

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]
Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age. The most frequent cause of macrocephaly is hydrocephalus.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.
* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period) in the secondary type.

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation.

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.

===Fetal Alcohol Syndrome===
<ref><pubmed> 23809349 </pubmed></ref>

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status.

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.

{| style="width:40%; height:170px" align="center"
|-
| [[Image: Fetal alcohol syndrome.jpg|frame|250x250px|The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref> ]]
|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

* All degrees of iodine deficiency (mild: 50-99 μg/day, moderate: 20-49 μg/day and severe≤20 μg/day) affect thyroid function of both mother and the neonate as well as mental development of the child. The damage increases with the degree of deficiency; overt endemic cretinism is the most severe consequence.

* Iodine deficiency disorders refer to complications that arise when the recommended dietary allowance of iodine is not met. These complications include thyroid function abnormalities and when iodine deficiency is severe, endemic goitre and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality.

* Iodine deficiency represents the world’s greatest cause of preventable brain damage and mental retardation, resulting of a loss of 10-15 IQ points globally. Therefore it is essential that the recommended dietary requirement for iodine is met, especially during pregnancy and lactation (200–300 μg/day). <ref><pubmed>10750030</pubmed></ref>

* Clinical manifestations of hypothyroidism include: Myxedematous facies (condition characterized by thickening of the skin, blunting of the senses and intellect, and laboured speech), jaundice, a puffy face and a wide posterior fontanelle with open sutures. The nasal bridge is flat. The mouth may be slightly open revealing macroglossia. Further examination would reveal bradycardia and a protuberant abdomen with a large umbilical hernia. Neurologic examination findings include hypotonia with delayed reflexes. Skin may be cool to touch and mottled in appearance due to circulatory compromise.<ref><pubmed>2903524</pubmed></ref>

===Abnormalities associated with apoptosis and migration of cells in the fetal CNS===

* The migration of cells and cell death are critically important to fetal brain and CNS development. Abnormalities in each of these processes, programmed cell death (apoptosis) in particular, have been shown to result in severe developmental abnormalities in experimental animals. Apoptosis is critically important for appropriate brain development; certain areas in brain may experience up to 50% cell death. <ref><pubmed> 11589424 </pubmed></ref>

In an experiment conducted by kuida et. al 1996, it was observed that mice that were deficient for CPP32 (a protease responsible for apoptosis), were born at a lower frequency than expected, were smaller in size compared to the normal mice and died at an early age. Brain development is significantly affected in CPP32-deficient mice resulting in a variety of hyperplasia and disorganised cell development. <ref><pubmed>8934524</pubmed></ref>

On the other hand, disrupted neuronal migration can lead to an abnormality in cell position. When this happens, the neurons are said to be heterotopic. Abnormalities in neuronal migration have been studied extensively in human cerebral cortex where these defects are associated with a variety of syndromes and diseases, ranging from behavioural disorders (including some forms of schizophrenia, dyslexia and autism) to extremely severe mental retardation and failure to thrive. <ref><pubmed>10532616</pubmed></ref>

===Neural Tube Defects===

Defects which affect the either the brain or the spinal cord in which openings remain. Grastulation occurs in week 3 of embryonic development where specialized cells (dorsal side) structurally change shape leading to the formation of the neural tube. If the neural tube does not close or fuse together properly, then openings remain which lead to various neural tube defects such as Spina bifida cystica and Spina bifida occulta.

'''Anencephaly'''

* A neural tube defect involving abnormal development of the brain and incomplete skull formation leading to high infant mortality rates with infants being stillborn or dying within a few hours after birth.

* The failure of the neural tube to close around the 23rd and 26th day into embryonic development is characteristic of this condition. As a result, the forebrain is severely affected where the cerebrum does not grow and hence partial growth occurs only. The cerebrum has a key importance in maintaining thought, consciousness and coordination whilst having no intact cerebrum rules out the probability of the affected fetus gaining consciousness .

* Increasing one's dietary intake of folic acid notably reduces the incidence of neural tube defects. Consuming 0.4mg of folic acid is sufficient to induce these results.

* Since incomplete skull formation occurs, brain tissue becomes exposed due to the absence of bone covering and therefore leading to further complications.

'''Encephaloceles'''

* Another neural tube defect in which a sac-like projections (including membrane covering) that occurs around the 3-4 week of embryonic development in which neural tube closure has not successfully occurred. The location of these protrusions varies but can be naso-frontal (nose and head), naso-ethmoidal (nose and ethmoid bone), naso-orbital (nose and eyes), meningocele (cerebrospinal fluid and membrane covering) and encephalomeningocele (meningocele with brain tissue as well).

* These sac-like protrusions lead to a variety of abnormal effects which include cerebro-spinal fluid build-up in brain, microcephaly, hydrocephaly, mental retardation, developmental problems, uncoordinated muscle movement and seizures. Consumption of folic acid again has been shown to significantly reduce the occurrence of encephaloceles in infants.

'''Hydranencephaly'''

* A very rare neural tube defect in which the cerebral hemispheres are destroyed (necrotic tissue) with the occupied space being replaced by cerebro-spinal fluid, cortex and white matter remnants within a membranous sac. Interestingly, this condition can also develop in the postnatal peroid due to viral infections or traumatic brain injury. The brain stem may remain intact and functioning in hydranencephalic infants.

* Accompanied with this condition are many effects in which include seizures, hydrocephalus, increases in head circumference,impairment in vision/ body temperature regulation and cerebral palsy. Infants affected by hydranencephaly live typically short lives being no longer than 1 year of age. Lastly, there are no viable treatment options for this condition and only supportive care is available.

'''Iniencephaly'''

* Another neural tube defect involving severe backward bending of the head (retroflexion) with subsequent spinal distortions as well. Affected infants have no neck and hence the scalp of the head is directly joined to the skin of the back (also skin of the face connected to skin of the chest). Other conditions that develop along with iniencephaly are cyclopia, cephalocele and anencephaly. The development of this condition is not solely due to one factor but from various causes (both genetic and environmental factors).

* There are specific factors that have been shown to increase the occurrence of this condition. Malnutrition, reduced folic acid intake and elevated levels of homocysteine in blood are environmental factors that increase the risk of iniencephaly <ref><pubmed> 22408660 </pubmed></ref>. Intake of certain drugs such as anti-histamines and sulphonamide/tetracycline (antibiotics) have also increases this risk <ref><pubmed> 22439066 </pubmed></ref>. Furthermore obesity has been shown to have a significant effect on the incidence of iniencephaly with 1.7-3 fold increase <ref><pubmed> 18538144 </pubmed></ref>.

* In terms of treatment, folic acid supplementation as well as avoiding certain drugs such as those outlined above significantly reduces the occurrence of this condition.

'''Spina Bifida Cystica'''

* A neural tube defect in which involves either the formation of a meningocele or myelomeningocele. Of the two, the meningocele, is the least debilitating in that a cyst-like structure forms when the neural tube does not close properly. The membrane (meninges) is pushed into openings of the vertebrae where spinal fluid builds up within the cyst. The myelomeningocele leads to severe problems as the portion of the nueral tube that is unfused allows the spinal cord to protrude through. As a result, neuronal tissue is highly exposed due to myeloschisis as well as infections and hence may lead to severe complications.

'''Spina Bifida Occulta'''

* A neural tube defect that has minimal complications in comparison to other defects. Furthermore, this defect is hidden in that a tethered spinal cord may arise as well as a thicker filum terminale and diastematomyelia (spinal cord split into two). It is also important to note that no cysts form as opposed to the other more severe spina bifida defects.

==References==

<references/>

2014 Group Project 7

2014-10-22T01:58:31Z

Z3418981: /* Current research models and findings */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, recieving and integration of information from all parts of the body, serving as the processing center of the bodies nervous system. The CNS controls all bodily functions (sensory and motor), consisting of 2 main organs; The Brain and Spinal Cord

==='''Brain'''===

The Brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

==='''Spinal Cord'''===

The Spinal Cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into

1) Ascending bundles - Transmits Sensory information from the body to the brain

2) Descending bundle - Transmits Motor function information from the brain to the body

Before fetal period, nerulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, the current research models and finding, historic findings and abnormalities that can occur in the fetal period is identified.

==Development during fetal period==

[[File:Neural-development.jpg|800px]]

Timeline of human neural development <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

'''1. cell proliferation'''

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

[[File:Somatosensory cortex of E20 rat.jpeg|300px]]

Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) through staining <ref><pubmed>22272298</pubmed></ref>

'''2. cell migration'''

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways. [[Image:CNS_passive.jpg|frame|300x200px|Passive cell displacement and outside-to-inside spatiotemporal gradient]][[Image:CNS_active.jpg|frame|400x250px|Active cell migration and inside-to-outside spatiotemporal gradient]]

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus, hypothalamus, spinal cord, retina, dentate gyrus of the hippocampal formation and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas.
[[Image:Internurons migration in cerebral cortex.jpg|frame|200x200px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex]]

'''3. cell differentiation'''

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

== Brain Development ==

- The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells

- By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

- The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

- Extends from the ninth gestational weeks through to the end of gestation

- Gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding

- Brain development begins rostral in GW8, proceeding caudally until it is complete at GW22

- Secondary sulci emerge between GW30-35

- Formation of Tertiary sulci begins during GW36 and into the postnatal period

- Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

- Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

- The major fibre pathways make up the brain white matter

- AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Increase in size and weight'''

[[File:Brain ventricles and ganglia development 03.jpg|300px]]

Image of brain and ventricular development <ref name=PMID19339620><pubmed>19339620</pubmed></ref>

[[File:Brain fissure development 02.jpg|300px]]

Image of brain fissure development <ref name=PMID19339620><pubmed>19339620</pubmed></ref>

'''sulcation and gyration'''

Sulcation: development of sulci. Primary sulci appear as shallow grooves on the surface of the brain and become more deeply infolded. Secondary sulci are formed from the development of side branches of primary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>

Gyration: development of gyrus that occurs late during fetal development until end of the pregnancy or even later after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>

{| class="wikitable"
|-
! Weeks !! Visible anatomical details
|-
| 20-21 || smooth, "lissencephalic" brain, wide Sylvian fissures
|-
| 22-23 || corpus callosum; beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || start of opercularization of Sylvian fissures; calcarine fissures and cingular sulci
|-
| 26 || central and collateral sulci
|-
| 27 || marginal and precentral sulci
|-
| 28 || postcentral and intraparietal sulci
|-
| 29 || inferior frontal sulci; bright white matter, dark cortical ribbon
|-
| 30-31 || narrower ventricular system and subarachnoid spaces
|-
| 32 || superior and inferior temporal sulci
|-
| 33 || external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table obtained from <pubmed>20608424</pubmed> <ref><pubmed>20608424</pubmed></ref>

== Spinal Cord Development ==
The spinal cord is formed from parts of the neural tube during embryonic and fetal development

=== Meninges Development ===

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations
|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

===Current Research===

{|
|-bgcolor="ECCEF5"
|Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.

The following are recent studies that use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

-Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

-The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

-The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.

'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.

'''Cortical Overgrowth in Fetuses With Isolated Ventriculomegaly'''
<ref><pubmed> 23508710 </pubmed></ref>

* The condition fetal ventriculomegaly is characterised by dilation of lateral ventricles whilst sharing associations with other malformations. It was hypothesised that using relative brain overgrowth as marked measure of altered brain development is due to the occurrence of ventriculomegaly and to evaluate this brain overgrowth through the use of magnetic resonance imaging (MRI) of fetuses isolated with enlarged ventricles (3rd and 4th ventricles as well as cerebrospinal fluid). Furthermore, significant changes to thalamic volumes, basal ganglia and white matter did not occur between cohorts.

* The study found that there was a sufficient increase in brain volume (overgrowth) of fetuses that had ventriculomegaly in comparison to controls. Also, larger lateral ventricle volumes were yielded with fetuses with ventriculomegaly assessed via 2-dimensional movement of the atrial diameter (ultrasound and MRi) as well as a larger total brain tissue volume. This provides support for the hypothesis in that brain overgrowth can be used as a marked measure for ventriculomegaly with results showing that overgrowth was not localised in one region but across both hemispheres and thus lead to a neural deficit in children (altered neural connectivity).

* Hence, this study has assisted in the improved understanding of the effects of ventriculomegaly on cognition, language and behaviour in children.

===Future Research===

|}

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]
Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age. The most frequent cause of macrocephaly is hydrocephalus.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.
* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period) in the secondary type.

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation.

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.

===Fetal Alcohol Syndrome===
<ref><pubmed> 23809349 </pubmed></ref>

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status.

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.

{| style="width:40%; height:170px" align="center"
|-
| [[Image: Fetal alcohol syndrome.jpg|frame|250x250px|The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref> ]]
|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

* All degrees of iodine deficiency (mild: 50-99 μg/day, moderate: 20-49 μg/day and severe≤20 μg/day) affect thyroid function of both mother and the neonate as well as mental development of the child. The damage increases with the degree of deficiency; overt endemic cretinism is the most severe consequence.

* Iodine deficiency disorders refer to complications that arise when the recommended dietary allowance of iodine is not met. These complications include thyroid function abnormalities and when iodine deficiency is severe, endemic goitre and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality.

* Iodine deficiency represents the world’s greatest cause of preventable brain damage and mental retardation, resulting of a loss of 10-15 IQ points globally. Therefore it is essential that the recommended dietary requirement for iodine is met, especially during pregnancy and lactation (200–300 μg/day). <ref><pubmed>10750030</pubmed></ref>

* Clinical manifestations of hypothyroidism include: Myxedematous facies (condition characterized by thickening of the skin, blunting of the senses and intellect, and laboured speech), jaundice, a puffy face and a wide posterior fontanelle with open sutures. The nasal bridge is flat. The mouth may be slightly open revealing macroglossia. Further examination would reveal bradycardia and a protuberant abdomen with a large umbilical hernia. Neurologic examination findings include hypotonia with delayed reflexes. Skin may be cool to touch and mottled in appearance due to circulatory compromise.<ref><pubmed>2903524</pubmed></ref>

===Abnormalities associated with apoptosis and migration of cells in the fetal CNS===

* The migration of cells and cell death are critically important to fetal brain and CNS development. Abnormalities in each of these processes, programmed cell death (apoptosis) in particular, have been shown to result in severe developmental abnormalities in experimental animals. Apoptosis is critically important for appropriate brain development; certain areas in brain may experience up to 50% cell death. <ref><pubmed> 11589424 </pubmed></ref>

In an experiment conducted by kuida et. al 1996, it was observed that mice that were deficient for CPP32 (a protease responsible for apoptosis), were born at a lower frequency than expected, were smaller in size compared to the normal mice and died at an early age. Brain development is significantly affected in CPP32-deficient mice resulting in a variety of hyperplasia and disorganised cell development. <ref><pubmed>8934524</pubmed></ref>

On the other hand, disrupted neuronal migration can lead to an abnormality in cell position. When this happens, the neurons are said to be heterotopic. Abnormalities in neuronal migration have been studied extensively in human cerebral cortex where these defects are associated with a variety of syndromes and diseases, ranging from behavioural disorders (including some forms of schizophrenia, dyslexia and autism) to extremely severe mental retardation and failure to thrive. <ref><pubmed>10532616</pubmed></ref>

===Neural Tube Defects===

Defects which affect the either the brain or the spinal cord in which openings remain. Grastulation occurs in week 3 of embryonic development where specialized cells (dorsal side) structurally change shape leading to the formation of the neural tube. If the neural tube does not close or fuse together properly, then openings remain which lead to various neural tube defects such as Spina bifida cystica and Spina bifida occulta.

'''Anencephaly'''

* A neural tube defect involving abnormal development of the brain and incomplete skull formation leading to high infant mortality rates with infants being stillborn or dying within a few hours after birth.

* The failure of the neural tube to close around the 23rd and 26th day into embryonic development is characteristic of this condition. As a result, the forebrain is severely affected where the cerebrum does not grow and hence partial growth occurs only. The cerebrum has a key importance in maintaining thought, consciousness and coordination whilst having no intact cerebrum rules out the probability of the affected fetus gaining consciousness .

* Increasing one's dietary intake of folic acid notably reduces the incidence of neural tube defects. Consuming 0.4mg of folic acid is sufficient to induce these results.

* Since incomplete skull formation occurs, brain tissue becomes exposed due to the absence of bone covering and therefore leading to further complications.

'''Encephaloceles'''

* Another neural tube defect in which a sac-like projections (including membrane covering) that occurs around the 3-4 week of embryonic development in which neural tube closure has not successfully occurred. The location of these protrusions varies but can be naso-frontal (nose and head), naso-ethmoidal (nose and ethmoid bone), naso-orbital (nose and eyes), meningocele (cerebrospinal fluid and membrane covering) and encephalomeningocele (meningocele with brain tissue as well).

* These sac-like protrusions lead to a variety of abnormal effects which include cerebro-spinal fluid build-up in brain, microcephaly, hydrocephaly, mental retardation, developmental problems, uncoordinated muscle movement and seizures. Consumption of folic acid again has been shown to significantly reduce the occurrence of encephaloceles in infants.

'''Hydranencephaly'''

* A very rare neural tube defect in which the cerebral hemispheres are destroyed (necrotic tissue) with the occupied space being replaced by cerebro-spinal fluid, cortex and white matter remnants within a membranous sac. Interestingly, this condition can also develop in the postnatal peroid due to viral infections or traumatic brain injury. The brain stem may remain intact and functioning in hydranencephalic infants.

* Accompanied with this condition are many effects in which include seizures, hydrocephalus, increases in head circumference,impairment in vision/ body temperature regulation and cerebral palsy. Infants affected by hydranencephaly live typically short lives being no longer than 1 year of age. Lastly, there are no viable treatment options for this condition and only supportive care is available.

'''Iniencephaly'''

* Another neural tube defect involving severe backward bending of the head (retroflexion) with subsequent spinal distortions as well. Affected infants have no neck and hence the scalp of the head is directly joined to the skin of the back (also skin of the face connected to skin of the chest). Other conditions that develop along with iniencephaly are cyclopia, cephalocele and anencephaly. The development of this condition is not solely due to one factor but from various causes (both genetic and environmental factors).

* There are specific factors that have been shown to increase the occurrence of this condition. Malnutrition, reduced folic acid intake and elevated levels of homocysteine in blood are environmental factors that increase the risk of iniencephaly <ref><pubmed> 22408660 </pubmed></ref>. Intake of certain drugs such as anti-histamines and sulphonamide/tetracycline (antibiotics) have also increases this risk <ref><pubmed> 22439066 </pubmed></ref>. Furthermore obesity has been shown to have a significant effect on the incidence of iniencephaly with 1.7-3 fold increase <ref><pubmed> 18538144 </pubmed></ref>.

* In terms of treatment, folic acid supplementation as well as avoiding certain drugs such as those outlined above significantly reduces the occurrence of this condition.

'''Spina Bifida Cystica'''

* A neural tube defect in which involves either the formation of a meningocele or myelomeningocele. Of the two, the meningocele, is the least debilitating in that a cyst-like structure forms when the neural tube does not close properly. The membrane (meninges) is pushed into openings of the vertebrae where spinal fluid builds up within the cyst. The myelomeningocele leads to severe problems as the portion of the nueral tube that is unfused allows the spinal cord to protrude through. As a result, neuronal tissue is highly exposed due to myeloschisis as well as infections and hence may lead to severe complications.

'''Spina Bifida Occulta'''

* A neural tube defect that has minimal complications in comparison to other defects. Furthermore, this defect is hidden in that a tethered spinal cord may arise as well as a thicker filum terminale and diastematomyelia (spinal cord split into two). It is also important to note that no cysts form as opposed to the other more severe spina bifida defects.

==References==

<references/>

User:Z3418981

2014-10-22T01:18:35Z

Z3418981: /* Lab Attendance */

==Lab Attendance==
Lab 1 --[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 12:45, 6 August 2014 (EST)
http://www.ncbi.nlm.nih.gov/pubmed
[http://www.ncbi.nlm.nih.gov/pubmed PubMed]
[http://www.ncbi.nlm.nih.gov/pubmed/25084016 PMID25084016]
<pubmed>25084016</pubmed>
Lab 2 --[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 12:17, 13 August 2014 (EST)
Lab 3--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 12:58, 20 August 2014 (EST)
Lab 4--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 11:48, 27 August 2014 (EST)
Lab 5--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 11:42, 3 September 2014 (EST)
Lab 6--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 11:51, 10 September 2014 (EST)
Lab 7--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 11:17, 17 September 2014 (EST)
Lab 8--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 12:30, 24 September 2014 (EST)
Lab 9--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 12:22, 8 October 2014 (EST)
Lab 10--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 12:11, 15 October 2014 (EST)
Lab 11--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 12:18, 22 October 2014 (EST)

==Individual Assessments==
===Lab 1 Assessment===
'''Reference''': [http://www.ncbi.nlm.nih.gov/pubmed/24726222 PMID24726222]

<pubmed>24726222</pubmed>

'''Summary of the Method'''

In this study, genomic DNA was extracted from the umbilical cord blood of a total of 185 newborn females. Patients included 60 infants conceived by intracytoplasmic sperm injection (ICSI) and 73 infants conceived by in vitro fertilization (IVF) all recruited from a number of IVF centers across Canada. In addition, 52 naturally conceived patients were recruited from hospitals across the Lower Mainland in British Columbia, Canada. A karyotype or comparative genomic hybridization (CGH) analysis of the chromosomes was performed for all newborn cases. Cases were not included if congenital and/or chromosome abnormalities were present.

The X-chromosome inactivation (XCI) assay was performed to determine the XCI skewing of different tissues in different parts of the placenta by assaying allelic ratio of methylated alleles at the androgen receptor(AR), fragile X mental retardation 1 (FMR1), and DXS6673E loci. Fisher's exact test was a statistical method used to compare the frequency of mildly skewed (≥75%) and extremely skewed (≥90%) XCI in the patients. The parental nature of the skewed allele was determined by automated fluorescence analysis which was used to measure the AR alleles of the maternal decidua of the placenta.

'''Summary of the Results'''

There was no statistically significant difference between the ICSI, IVF and NC populations in the frequency of skewing ≥75% (7.0% vs. 5.7% vs. 2.0%, respectively; P=.523) or ≥ 90% (0 vs. 1.4% vs. 2.0%, respectively; P=.747). The mean level of skewing between the ICSI, IVF, and ICSI groups also was not significantly different (63.7% vs. 61.8% vs. 60.7%, respectively). Only two samples were found to have extremely skewed cases (≥90% skewing): one IVF (89.6%) and one NC (90.6%). The parental origin of the preferentially inactivated X chromosome in these extremely skewed cases was maternal for IVF and paternal for NC case.

'''Reference:''' [http://www.ncbi.nlm.nih.gov/pubmed/24399508 PMID24399508]

<pubmed>24399508</pubmed>

'''Summary of the Method'''

All of the pregnancies conceived by in vitro fertilization in Denmark from 1995 to 2005 (n = 18 787) was included in this study using the data reported to the National In Vitro Fertilisation register (IVF register). Information about the pregnancy outcomes as well as cycle-specific information on the type and date of treatment, and the occurrence of pregnancy, abortions and deliveries was also obtained from IVF.

A study published by Virkus et al. on venous thromboembolism in pregnant and puerperal women in Denmark was used as a reference (Virkus et al., 2011). This study was used as a reference since the population used in this study (727 VTE patients among the 805 464 pregnancies recorded in the Danish National Patient Registry from 1995 to 2005) is ideal and comparable to the present study. Consequently, venous thrombosis incidence rates in pregnancies conceived by in vitro fertilization were compared with venous thrombosis incidence rates in reference pregnancies, by calculating incidence rate ratios.

'''Summary of the Results'''

The venous thrombosis incidence was significantly increased in pregnancies after in vitro fertilization. The overall ratio of venous thrombosis incidence rate during in vitro fertilization pregnancies to reference pregnancies was 3.0 (95% CI 2.1–4.3). The overall venous thrombosis incidence rate was 28.6 per 10 000 pregnancy-years (95% confidence interval (CI) 20.6–39.6) for pregnancies after in vitro fertilization compared to 10.7 per 10 000 woman-years in reference pregnancies.

Reference used in the "Summary of the Method" section:

<pubmed>21713323</pubmed>

--[[User:Z8600021|Mark Hill]] These articles are well summarised and relevant. Please do not use all capitals in sub-headings and follow the site formatting. (5/5)

===Lab 2 Assessment===
[[File:An overview of the process of fertilisation in mutant C. elegans.jpeg|300px]]

Image showing the process of fertilisation in mutant C. elegans<ref><pubmed>15086962</pubmed>|[http://www.biomedcentral.com/1471-213X/4/3 BMC Developmental Biology]</ref>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 16:19, 21 August 2014 (EST) This is all correct. The image is very large (1.15 MB), perhaps a smaller image version could have been uploaded. You can adjust the resolution and size in most image editing programs. (5/5)

<references/>

===Lab 3 Assessment===

====Abnormalities associated with neural development====
<pubmed>12454899</pubmed>
<pubmed>25007063</pubmed>
<pubmed>16530991</pubmed>
<pubmed>7504639</pubmed>
<pubmed>19651588</pubmed>
<pubmed>25135350</pubmed>
<pubmed>25128525</pubmed>
<pubmed>24397701</pubmed>

--[[User:Z8600021|Mark Hill]] These are all relevant references, and a sentence description for selection would also help. (4/5)

===Lab 4 Assessment===

'''1. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.'''

<pubmed>24104453</pubmed>

The inhibitory effect of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) on the growth of C6 glioma cells was investigated in this study. Initially C6 cells were cultured with different concentrations of hUC-MSCs in order to examine whether the hUC-MSCs inhibition of glioma cell growth was mediated by soluble factors. It was found that hUCMSCs-CM exhibited a concentration-dependent inhibitory effect on C6 cell growth which in turn suggested that soluble factors in the conditioned media from hUC-MSCs were responsible for the inhibition of C6 glioma cells. Subsequently, flow cytometric analysis was used to test the effect of the soluble factors derived from hUCMSCs-CM on the cell cycle of glioma cells. Using this method, cell cycle status of C6 cells treated with different concentrations of hUCMSCs-CM was identified. It was observed that C6 cells treated with hUCMSCs-CM showed increases in the G0/G1 phase and reductions in the S phase compared to the control group (0 % hUCMSCs). These results suggested that hUC-MSCs could potentially inhibit the growth of C6 glioma cells and stop the cell cycle at the G0/G1 phase by secreting some soluble factors.

Western blot analysis was then performed and it was observed that the expression levels of β-catenin and c-Myc in C6 cells were reduced in the conditioned media derived from hUC-MSCs. These results indicated that some soluble factors secreted from hUCMSCs-CM may play a role in the inhibition of Wnt signaling pathway in C6 cells. Further investigations demonstrated that the secretion levels of dickkopf-1 (DKK1) were positively correlated with the concentrations of hUCMSCs-CM. Subsequently, the hypothesis that stem cells secreted Wnt inhibitors, such as DKK1, which could inhibit the Wnt signaling in tumor cells, was made.

Neutralizing antibody against DKK1 was then added to the hUCMSCs-CM in order to further confirm that DKK1 is a key factor in the inhibitory effect of hUCMSCs on C6 cell proliferation. It was observed that the inhibitory effect of hUC-MSCs on C6 cells was decreased when DKK1 was neutralized by anti-DKK1 antibody. Moreover, it was found that conditioned media from hUC-MSCs transfection with siRNA targeting DKK1 mRNA altered the regulation of the Wnt signaling in C6 cells. Therefore, it was concluded that hUC-MSCs inhibited C6 glioma cell growth by secreting DKK1, an inhibitor of Wnt pathway.

'''2.There are a number of developmental vascular "shunts" present in the embryo, that are closed postnatally. Identify these shunts and their anatomical location.'''

There are three developmental vascular "shunts" present in the embryo that are closed postnatally:

Foramen ovale (Foramen Botalli)

Foramen ovale is an opening in the inter-atrial septum which allows blood from the right atrium to enter the left atrium during foetal development. Foramen ovale allows blood to bypass the non-functional foetal lungs while the foetus obtains its oxygen from the placenta. A layer of cells exist over the foramen ovale during fetal development which acts as a valve and is known as septum primum. After birth, increased pulmonary blood flow and pulmonary venous return to left heart causes the pressure in the left atrium to be higher than the pressure in the right atrium. The increased left atrial pressure results in the closure of foramen ovale after birth.

Ductus venosus

In the foetus, the ductus venosus shunts blood from the left umbilical vein directly to the inferior vena cava and therefore allows oxygenated blood from the placenta to bypass the liver. Ductus venosus plays an important role in shunting oxygenated blood to the fetal brain.The ligamentum venosum which is usually attached to the left branch of the portal vein is the fibrous remnant of the ductus venosus

Ductus arteriosus (Ductus Botalli)

Ductus arteriosus connects the pulmonary artery to the proximal descending aorta. Ductus arteriosus prevents the output of the right ventricle from entering the unexpanded, fluid-filled and non-functional foetal lung. Therefore only enough blood reaches the foetal lungs to maintain the developing lung tissue. Ductus arteriosus becomes the ligamentum arteriosum after closing at birth.

===Lab 5 Assessment===

'''Azygos Lobe'''

Azygos lobe (also known as Adam's lobe) is a congenital malformation of the lung due to an alteration in the embryonic development of the azygos vein. Azygos lobe is a common congenital anomaly with an incidence of 1 in 100-200 of anatomical samples and 0.4-0.5% of chest radiographs. In general, azygos lobe means accessory lobe or supernumerary lobe of lung. There are three main types of azygos lobes: upper azygos lobe, lower azygos lobe and the lobe of azygos vein. The upper and lower azygos lobes are of very little clinical significance compared to the lobe of azygos vein.

During normal fetal development, the right posterior cardinal vein (precursor of the thoracic segment of the azygos vein) migrates over the apex of the right upper lung to occupy a medial mediastinal position. In the case of azygos lobe, an abnormal migration of this vein occurs and it penetrates into the right upper lobe. The right posterior cardinal vein carries the parietal and visceral layers of pleura with it and forms an accessory fissure made up of a total of four pleural layers called mesoazygos. The lung parenchyma located medial to the accessory fissure is called the azygos lobe.

Subsequently in the case of azygos lobe, the abnormal azygos vein crosses the apex of lung instead of its border and forms a fissure which separates the apex of the lung into medial and lateral parts. The medial part of the ruptured apex forms the lobe of azygos vein. Therefore the azygos lobe is a variably separated portion of the right lung and not an independent segment. Moreover, some course variability of the phrenic nerve have also been observed in the presence of an azygos lobe which is of importance when performing surgery.

'''References'''

<pubmed>16333920</pubmed>
<pubmed>23705047</pubmed>

===Lab 7 Assessment===

1. Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.

<pubmed>14561778 </pubmed>

In this study, the functional characterization of ''Arx'', a gene encoding homeodomain-containing proteins that are potentially involved in endocrine pancreas development is being investigated. To study the role of this gene in pancreas development, loss-of-function mutant mice were generated by targeting the genes in mice embryonic stem cells. Arx-deficient mice developed severe and early-onset hypoglycaemia, dehydration and weakness and died only two days after birth. Immunohistochemical analysis of Arx mutant pancreas then revealed an absence of mature endocrine α cells and an increased number of β and δ cells. However, islet morphology and the total number of endocrine cells remained intact. These results suggested a requirement of Arx transcription factor for α-cell fate acquirement and a repressive action on β-and δ-cell destiny, which is exactly the opposite of the phenotype observed in Pax4-deficient mice.

Therefore, the results of this study suggest that a mutual cross-regulatory inhibition of these factors exist so that Arx promotes α-cell cycle and prevents β- and δ-cell proliferation whereas Pax4 favours β- and δ-cell fate and inhibits α-cell proliferation. It was demonstrated using multiplex reverse transcriptase PCR (RT-PCR) that Pax4 and Arx transcripts accumulate in Arx and Pax4 mutant mice, respectively. These results further suggest that the antagonistic functions of Arx and Pax4 for proper islet cell specification are based on the pancreatic levels of the respective transcripts.

2. Identify the embryonic layers and tissues that contribute to the developing teeth.

a) Neural-crest-derived mesenchymal cells that differentiate under the influence of the enamel epithelium form odontoblasts. Odontoblasts secrete predentin which calcifies to form dentin.

b) Epithelial cells give rise to ameloblasts that produce the enamel of the tooth.

c) Periodontal ligament is a special connective tissue structure that holds the tooth in place and surrounds the tooth root coating of cementum.

===Lab 8 Assessment===

1. Provide a brief time course and overview of embryonic development of either the human testis or ovary. (2-3 paragraphs)

'''Embryonic Development of Ovaries'''

The gonads are developed from mesothelium lining the posterior abdominal wall, underlying mesenchyme and primordial germ cells. The initial stages of gonadal development are the same in males and females and occur during the fifth week with the formation of the gonadal ridge, a bulge on the medial side of the mesonephros. Finger like epithelial cords then grow into the underlying mesenchyme forming the gonadal cords. In females (XX), the cortex of the indifferent gonad differentiates into an ovary, and the medulla regresses.

Primordial germ cells are the first population of cells that migrate through the primitive streak in early gastrulation. These cells then lie at the hindgut yolk sac junctional region and subsequently migrate into the gonadal ridge in early embryonic development. The primordial germ cells enter the underlying mesenchyme during week 6 and are incorporated in the gonadal cords.

The gonads of males and females are identical before week 7 and are called indifferent gonads. Germ cells migrate into the indifferent gonads. The ovaries (females, XX) or testis (males, XY) then begin to develop and the successive structure of germ cells differentiates for each of the two sexes. In females with XX, genes on X-chromosome (such as Wnt-4 and DAX-1) along with an autosomal gene are necessary for initiation of female pathway. Ovary development is a slow process in female embryos and the ovary is not histologically identifiable until week 10.

[http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00012-6--s0095&isbn=978-1-4377-2002-0&uniqId=466385578-2 Moore: The Developing Human, 9th ed. Chapter 12]

2. Include an image from the historic genital embryology section of the online notes in your description.

[[File:Bailey330.jpg|500px]]

'''Image showing a section through the ovary of a human foetus of 4 months.'''

===Lab 9 Assessment===

'''Group 1 (Respiratory System)'''

The introduction is written well and it provides sufficient background information on the anatomy and development of respiratory system. It is also well-divided into the two conducting and respiratory zones. However it lacks to provide information on what is included in the page such as current research and abnormalities. In addition, this assignment is aimed to describe the fetal development but fetal period does not seem to be the focus in this project. I understand that it is difficult to focus on fetal period, especially for the respiratory system but if that is the case, you can mention why you’re also including information on embryonic and postnatal periods in your introduction. There are also a few spelling errors within the text that should be corrected (such as ‘id’ instead of ‘is’). The images of the histological sections are relevant but there is no caption for any of the photos and it is difficult to understand what they are trying to show. There is no information provided on the summary of the image either and one of the images is missing copyright information. In addition, the text as well as the images in the introduction needs to be referenced on the page.
The table of lung development stages is simple and very well summarised. The content of this section relates to the learning objectives of embryology however there is not enough explanation considering that this section is the main part of the project. In order to aid with understanding of the development of lungs, simple diagrams could be drawn that show different developmental stages. You can then explain more on what happens in each stage.

The first paragraph of the current research and findings about the conducting system and functional unit is already discussed in the introduction and therefore there is no need to include it again in this section. Try to include more precise information on the findings of each study and also talk about the new models that have aided in understanding of the development of this system. For example you can elaborate more on the three geometrical models that are proposed in the review study in 2013(there is no information under the “current models” subheading at the moment- you can put this information there). Also it is a good idea to organise the research findings in chronological order so that new advancements are found in more recent studies (2011 must come before 2013).The two alveolar cell types under current research is irrelevant – I would put them under introduction. Also I don’t understand why the image of lung diseases is under current research (maybe put that image under abnormalities?)

The historic findings section is very informative, especially the “surfactant” section. You can also tabulate the data to make it look neater. However from my understanding, in this section we also need to provide information on the history and stages of fetal lung development. I know it is hard to find this information but maybe try looking for review articles that summarise the findings of past studies in this area. The abnormality section is well written and thorough with so many abnormalities named and described. The only suggestion is to include more images.

Overall, this web page shows a very effective team work and it is clear that work has been allocated with each person working on a different subheading. You only need to pay attention to minor issues mentioned above. Also in terms of referencing, there are many in-text references missing in different sections. It is very important to format these references correctly under one ‘references’ subheading at the end of the page (instead of having a separate reference list for each section).

'''Group 2 (Renal System)'''

Introduction is very well-written with a precise background on the renal system anatomy and function. There is also a brief introduction on the development of renal system in both embryonic and fetal period as well as the abnormalities that can be associated with the development of this system. Therefore the reader can gain an expectation of what is going to be included in the wiki-page by reading the introduction first. In-cite referencing is also used to support the information provided. I suggest including an image of the anatomy of organs in the renal system to make the introduction even more perfect.

The developmental timeline is a very good way to start the development section; however your timeline is missing some of the important features such as when the ureter and urethra develop. I would also recommend tabulating the data so that it looks neater. I also recommend placing the “current research models” section after the sections describing the development of different organs so that the timeline is located right before the section explaining the development of “kidney”. Dividing the development into different organs and the subheadings used (especially under the heading of “kidney”) are very appropriate and are evidence of significant research that has been done for this project. The information provided is very comprehensive; however it is all formatted in paragraphs. I would suggest using dot points or adding your own diagrams and figures to summarise the text and make it more interesting to the readers. For example the diagram used to illustrate the anatomical position is very helpful and effectively summarises the information to readers. You should also make sure that you remove the image used for the development of kidney since it cannot be used due to copyright. In addition, most images are missing the ‘student template’ so make sure the template is added.
There isn’t any information under the heading ‘historic findings’. I understand that this section is a bit more difficult than the rest. A suggestion I can make is to search for old articles in PubMed (by adjusting the year) which can include key historical events. Review articles that summarise historic findings related to renal development may also be helpful.

The content under “current research” is very interesting and relevant. A minor spelling error exists (“buy” instead of “by”). To further improve this section, I suggest searching for recent models that aid in better understanding of kidney development. The abnormalities section is very informative. Each disease is explained thoroughly and concisely. The images are also very helpful with the understanding of clinical manifestations. To improve this section, I suggest using dot-points and using more images. Make sure you include information for “Horseshoe Kidney” as well.

Overall, the content used in this project was very relevant and showed extensive research and understanding. The use of headings and subheadings was very appropriate which showed that the work has been well-divided among members. The use of in-cite referencing is also very good and references are all listed under one subheading; however, some references are used more than once, this can be fixed and they can be all combined under one number.

'''Group 3 (GIT)'''

Introduction is good with brief background information on the anatomy of the GIT which is an appropriate starting point for the readers. Fetal development is also described in the introduction, however I suggest including more information on embryonic period and how that leads to fetal development so that the rest of the page can focus more on the fetal stages. I also suggest including parts of each of the major subheadings in the introduction such as the common abnormalities and the recent finding. An image illustrating different organs of GIT can also help with better understanding of the anatomy. There is no referencing in the introduction to support the information provided.
Regarding the timeline section, the information needs to be tabulated in order to make it easier to compare between organs. Another alternative is to include a small timeline for each of the organs at the beginning of each section. It is very good that each stage of the timeline has been separately referenced; this shows the extensive research that has been conducted.

The recent finding section focuses on only one study in 2006 on hedge-hog signalling pathway. There are a lot of interesting and more recent studies that can be included in this section. As a starting point, you can search for recent models that help in better understanding of GIT development.
The information under each of the foregut, midgut and hindgut is very detailed and comprehensive; however the structure does not flow through the whole page with mid-gut including different subheadings and diagrams. In my opinion you should break up the foregut and hindgut sections into smaller subheadings and use diagrams like the ones used for midgut. Potential images can also be used in these sections. Additionally, the anorectal deformities under the ‘hindgut’ section can be placed under the deformities section. The “Midgut” section includes very good information and the drawings are helpful in understanding the concept however they need to be captioned.

This project does not include historic findings. I understand that this section is a bit more difficult as it is hard to find information on it. A suggestion I can make is to search for old articles in PubMed (by adjusting the year) which can include key historical events. Review articles that summarise historic findings related to GIT development may also be helpful. The abnormalities are precisely discussed and are relevant to the topic but as mentioned before, I suggest putting all the abnormalities under one subheading to make it easier for the viewers to navigate.

Overall, the main key points are addressed in this project and the content demonstrates extensive research and a good understanding of the concept. In order to facilitate learning and to make it more interesting and understandable for viewers, some of the text can be summarised in diagrams. Dot -points can also be used in some parts instead of paragraphs. The use of hand written drawings was creative and aided in understanding however I would suggest stating that the drawing is handwritten in your page. If the drawing is copied from another image, then the source of that image needs to be included as well. Also a more complete description of the image will make it easier to understand.

'''Group 4 (Genital System)'''

An introduction is recommended as it is usually a good starting point. I suggest starting by giving background information on the anatomy of male and female genital systems. You can then talk about the embryonic period and give a brief summary of how this period is different to fetal period. You can then briefly mention the significant events that occur during fetal period and the sections you are including in your project (including abnormalities and research findings).

The table in the system development is a good summary however it looks a bit messy at this stage. I suggest having two different tables for male and female, avoid using all capital letters and bold texts in the table. I also suggest starting the development section with a brief paragraph on early stages of development. The image included under ‘system development” is a very good summary but it needs to be captioned and referenced. I also recommend re-uploading the image in a smaller size to improve the quality. The use of the video is also very creative. Well done for finding this helpful video!! It would be perfect if you could reference the video and maybe include a few sentences on what it is showing. Overall, the development section is very good with the use of different methods to help in learning. To make this section perfect, you can add some details in paragraphs to explain more on different stages of development.

There is a lot of information under “current models” which shows extensive research, however I find this section hard to follow. Using paragraphs instead of dot points will result in a more coherent flow. Also the studies need to be referenced appropriately; it would be a good idea to include the name and year of the article in the text. The division into “current research” and “current models” is a smart thing to do however in both sections the amount of information provided for male is much more than female therefore more research needs to be done for female. I like how a self-drawn image is used; it would be a good idea to include a description for the image (rather than “alt text”). Also make sure that all the references are listed at the end under one reference subheading instead of having different references for each section. Also, great job for historic findings! This is the most difficult section but you have managed to include detailed information. Similar to current research section however, most of the information found is for the development of male system. Try to add to historic findings on female system if possible.

Abnormalities section includes a significant number of abnormalities with causes and treatment of each abnormality addressed precisely. I also like how you divided this section into female, male and both. Information is well referenced and helpful images are included. Make sure that your images are referenced. If self-drawn images are used, then you can briefly mention that in your text. I would also recommend adding more images for other diseases to illustrate the clinical manifestations of each disease. Overall this group has done an extensive research and the methods used (such as drawings and videos) are very creative and helpful. Well done!

'''Group 5 (Integumentary System)'''

The presentation of this page is very well with multiple images being used and text organised into tables and dot points. The introduction is short however includes necessary information regarding what is being included in the project. I recommend adding background information on anatomy of the skin (explaining on different layers) and other structures as well as a brief summary on the embryonic development of the system so that fetal development can be further expanded throughout the project.

The development overview section is done very well and is divided into different sections each explaining the development of a different structure. The use of table, images and bullet points has made the page look very interesting. The table of the timeline in the ‘Development Overview’ is done very well and the use of histological images is excellent as it helps in visualising the anatomy at each stage. There is however no proper referencing, copyright information or student template for any of the images. The table under “teeth” is also a very good summary of events during fetal period. I recommend including self-drawn diagram as well, since this is the only feature missing from your project. You can include a drawing of the different layers of skin (possibly in the introduction section). I also suggest putting all the references under one reference list at the end of the page instead of having references at the end of each section.

The “some research finding” section is presented well with a different background colour to other sections (it is similar to recent findings in mark’s wiki pages). This makes the page look very visually appealing! You have elaborated on two out of four research papers which is very good. However I recommend describing the other two papers as well and even including more papers (It would be perfect if you could provide research papers for different structures). I like how the “more research papers” can be expanded for anyone interested.

Historic findings section is very well researched considering it is difficult to find information for this section. The ‘Abnormalities’ section is also perfect and complete with all four diseases having sufficient information and appropriate references. The images are also relevant and illustrate the clinical manifestations well. Overall this page is very well-organised and only minor issues mentioned above need to be fixed.

'''Group 6 (Endocrine System)'''

The endocrine system is made up of different glands and there is so much information that could be provided regarding the the anatomy and development of each gland so very well done for working on the difficult system! I like how you have divided the page into different glands; I can imagine having the four major headings (development, historic findings, current research and abnormalities) and then subdividing it into different organs would be more confusing. Just try to follow the same structure for each organ; I recommend doing a brief introduction, anatomy, function, timeline, development, historic findings, current research and abnormalities for each organ. It is important that your page has a coherent flow by following the same structure for each subheading. An overall introduction on endocrine system might also be very useful. You can then include in the introduction how you are planning to structure your page.

The content and number of references show that extensive research has been conducted. It would be great if you could use in-text referencing and place all the references under one subheading at the end of the page. Arranging the information into tables is a great idea but you need to complete your tables for pineal gland, hypothalamus and placenta. You also need to include more images in your page (you can include at least one image for the abnormality associated with each organ). There are a few images included at the moment and they are well done and appropriately referenced. You can also try to draw your own diagrams. In my opinion, a timeline showing the development of all the systems would be a great way to compare the different stages in development of different endocrine glands. Maybe think about including this in a table after you finished all the sections; it is a good way to connect the information provided separately for each organ. Overall the content of this page is very good but it needs to be formatted so that it can have a coherent flow. Also there is no information for introduction, historic findings and development of placenta, make sure you include those.

'''Group 8 (Musculoskeletal System)'''

In this project the development section is well-researched however introduction, historical findings, current models and abnormalities still need some work. The development section is very informative with appropriate use of in-text referencing. However, to prevent having bulks of text, you can create diagrams and flow charts or use bullet points. It would also be great if you could provide a timeline under “muscle development general timeline” section. Background embryonic development section is very helpful but we do not need this much information on embryonic period for this project. You can summarise this information in introduction, so that it provides a starting point and fetal development can be further expanded through the project. The rest of the information regarding system development seems to cover the important points; however it still needs work (for e.g. “second trimester muscular development” section is clearly missing some bits).

The abnormality section only includes one abnormality (Duchenne Muscular Dystrophy). This abnormality is well described but it needs to be referenced. An image of the clinical manifestation of the disease can clearly help with understanding. There are lots of other abnormalities that you can include in this section (We learnt from the musculoskeletal development lecture that musculoskeletal conditions form 20% of all abnormalities at birth). You can also refer to “limb development lecture” to find information on musculoskeletal abnormalities.

Finding information on historic findings might be a little challenging. A suggestion I can make is to search for old articles in PubMed (by adjusting the year). These articles can include key historical events. Review articles that summarise historic findings related to musculoskeletal development may also be helpful. You also need to find information on current research.

Finally, you should add an introduction to your project. It seems like you are more focused on muscular development rather than “musculoskeletal” so you can mention that in your introduction. You can also show creativity by drawing your own diagrams, adding images, and tabulating timeline data. You should also fix the references by putting all the references under one subheading in the bottom of the page.

===Lab 10 Assessment===

'''Research article- The Involvement of Neural Retina Pax6 in Lens Fiber Differentiation'''

<pubmed>15855760</pubmed>

Specific interactions that occur between neural and ectodermal tissues as a result of regulated gene expression and controlled signalling events are necessary for proper eye formation. The homeobox gene Pax6 is proved to be essential for eye development in both vertebrates and invertebrates. Pax6 expression for the retina anlage has been revealed to be crucial in the development of different retinal cells. In this study, lab techniques such as plasmid construction, in ovo microelectroporation, in situ hybridization and section immunostaining were performed to examine the expression of several transcription factors in the lens of Pax6-negative optic vesicle eye in chick embryos. Initially, it was shown that the expression of a negative version of Pax6 isoform in developing optic vesicles of chick embryos prevents proper lens development at the lens vesicle stage as well as resulting in optic cup deformation. Following this finding, the molecular events underlying deformed lens formation were further explored.

A Pax6-EnR gene which effectively repressed endogenous Pax6 activity in neurons was used to examine the role of Pax6 in optic cup formation and lens differentiation. It was observed that overexpression of Pax6-EnR in optic vesicle results in abnormal optic cup formation. In addition, a severely deformed lens was formed in the Pax6-negative optic vesicle eye. The development of the lens was significantly delayed at stage 24 and the lens was dramatically smaller than the control lens. It was concluded from these findings that Pax6 expression plays an important role in lens development.

The remaining part of this study was focused on determining the molecular pathways underlying the previous findings. Initially, the expression of L-Maf (a transcription factor that has a crucial role in lens differentiation) was investigated. There was almost no reactivity for L-Maf in the deformed lens while the contralateral lens showed normal L-Maf expression. The expression of c-Maf was investigated afterwards. C-Maf is a transcription factor that is strongly expressed in both epithelial and fiber cells. Unlike L-Maf, C-Maf transcripts were normally expressed in both control and malformed lens. This result suggests that the function of Pax6 is not required for c-Maf expression in the lens at stage 24.

Finally, to illustrate how the Pax6-EnR effect is coupled to the down-regulation of L-Maf, the expression of fibroblast growth factor FGF8, a diffusible factor that was shown to activate L-Maf in non-lens cells was investigated. It was found that FGF8 is down-regulated in the neural tissue. This finding suggests that Pax6 in neural retina regulates FGF8 expression, which may maintain L-Maf expression in the lens to be essential for subsequent lens fiber differentiation.

[https://embryology.med.unsw.edu.au/embryology/index.php/Sensory_-_Vision_Development#Lens Sensory-Vision development Wiki page]

2014 Group Project 7

2014-10-22T01:02:52Z

Z3418981: /* Current Research */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, recieving and integration of information from all parts of the body, serving as the processing center of the bodies nervous system. The CNS controls all bodily functions (sensory and motor), consisting of 2 main organs; The Brain and Spinal Cord

==='''Brain'''===

The Brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

==='''Spinal Cord'''===

The Spinal Cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into

1) Ascending bundles - Transmits Sensory information from the body to the brain

2) Descending bundle - Transmits Motor function information from the brain to the body

Before fetal period, nerulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, the current research models and finding, historic findings and abnormalities that can occur in the fetal period is identified.

==Development during fetal period==

[[File:Neural-development.jpg|800px]]

Timeline of human neural development <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

'''1. cell proliferation'''

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

[[File:Somatosensory cortex of E20 rat.jpeg|300px]]

Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) through staining <ref><pubmed>22272298</pubmed></ref>

'''2. cell migration'''

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways. [[Image:CNS_passive.jpg|frame|300x200px|Passive cell displacement and outside-to-inside spatiotemporal gradient]][[Image:CNS_active.jpg|frame|400x250px|Active cell migration and inside-to-outside spatiotemporal gradient]]

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus, hypothalamus, spinal cord, retina, dentate gyrus of the hippocampal formation and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas.
[[Image:Internurons migration in cerebral cortex.jpg|frame|200x200px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex]]

'''3. cell differentiation'''

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

== Brain Development ==

- The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells

- By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

- The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

- Extends from the ninth gestational weeks through to the end of gestation

- Gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding

- Brain development begins rostral in GW8, proceeding caudally until it is complete at GW22

- Secondary sulci emerge between GW30-35

- Formation of Tertiary sulci begins during GW36 and into the postnatal period

- Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

- Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

- The major fibre pathways make up the brain white matter

- AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Increase in size and weight'''

[[File:Brain ventricles and ganglia development 03.jpg|300px]]

Image of brain and ventricular development <ref name=PMID19339620><pubmed>19339620</pubmed></ref>

[[File:Brain fissure development 02.jpg|300px]]

Image of brain fissure development <ref name=PMID19339620><pubmed>19339620</pubmed></ref>

'''sulcation and gyration'''

Sulcation: development of sulci. Primary sulci appear as shallow grooves on the surface of the brain and become more deeply infolded. Secondary sulci are formed from the development of side branches of primary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>

Gyration: development of gyrus that occurs late during fetal development until end of the pregnancy or even later after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>

{| class="wikitable"
|-
! Weeks !! Visible anatomical details
|-
| 20-21 || smooth, "lissencephalic" brain, wide Sylvian fissures
|-
| 22-23 || corpus callosum; beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || start of opercularization of Sylvian fissures; calcarine fissures and cingular sulci
|-
| 26 || central and collateral sulci
|-
| 27 || marginal and precentral sulci
|-
| 28 || postcentral and intraparietal sulci
|-
| 29 || inferior frontal sulci; bright white matter, dark cortical ribbon
|-
| 30-31 || narrower ventricular system and subarachnoid spaces
|-
| 32 || superior and inferior temporal sulci
|-
| 33 || external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table obtained from <pubmed>20608424</pubmed> <ref><pubmed>20608424</pubmed></ref>

== Spinal Cord Development ==
The spinal cord is formed from parts of the neural tube during embryonic and fetal development

=== Meninges Development ===

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations
|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

File:Cortical growth rate patterns (redrawn diagram).JPG
[[Image:Cortical_growth_rate_patterns_(redrawn_diagram).JPG|frame|right|middle|300x250px|This is a redrawn diagram illustrating a lateral view of T statistic map of the model of cortical plate volume increases. Red indicates regions that have a significantly higher growth rate compared to average cerebral growth rate. Growth rate decreases in yellow, black and blue regions respectively. Redrawn from <ref name=PMID21414909><pubmed>21414909</pubmed></ref>]]

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.

The following are recent studies that use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

-Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

-The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

-The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.

'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.

'''Cortical Overgrowth in Fetuses With Isolated Ventriculomegaly'''
<ref><pubmed> 23508710 </pubmed></ref>

* The condition fetal ventriculomegaly is characterised by dilation of lateral ventricles whilst sharing associations with other malformations. It was hypothesised that using relative brain overgrowth as marked measure of altered brain development is due to the occurrence of ventriculomegaly and to evaluate this brain overgrowth through the use of magnetic resonance imaging (MRI) of fetuses isolated with enlarged ventricles (3rd and 4th ventricles as well as cerebrospinal fluid). Furthermore, significant changes to thalamic volumes, basal ganglia and white matter did not occur between cohorts.

* The study found that there was a sufficient increase in brain volume (overgrowth) of fetuses that had ventriculomegaly in comparison to controls. Also, larger lateral ventricle volumes were yielded with fetuses with ventriculomegaly assessed via 2-dimensional movement of the atrial diameter (ultrasound and MRi) as well as a larger total brain tissue volume. This provides support for the hypothesis in that brain overgrowth can be used as a marked measure for ventriculomegaly with results showing that overgrowth was not localised in one region but across both hemispheres and thus lead to a neural deficit in children (altered neural connectivity).

* Hence, this study has assisted in the improved understanding of the effects of ventriculomegaly on cognition, language and behaviour in children.

===Future Research===

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]
Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age. The most frequent cause of macrocephaly is hydrocephalus.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.
* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period) in the secondary type.

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation.

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.

===Fetal Alcohol Syndrome===
<ref><pubmed> 23809349 </pubmed></ref>

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status.

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.

{| style="width:40%; height:170px" align="center"
|-
| [[Image: Fetal alcohol syndrome.jpg|frame|250x250px|The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref> ]]
|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

* All degrees of iodine deficiency (mild: 50-99 μg/day, moderate: 20-49 μg/day and severe≤20 μg/day) affect thyroid function of both mother and the neonate as well as mental development of the child. The damage increases with the degree of deficiency; overt endemic cretinism is the most severe consequence.

* Iodine deficiency disorders refer to complications that arise when the recommended dietary allowance of iodine is not met. These complications include thyroid function abnormalities and when iodine deficiency is severe, endemic goitre and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality.

* Iodine deficiency represents the world’s greatest cause of preventable brain damage and mental retardation, resulting of a loss of 10-15 IQ points globally. Therefore it is essential that the recommended dietary requirement for iodine is met, especially during pregnancy and lactation (200–300 μg/day). <ref><pubmed>10750030</pubmed></ref>

* Clinical manifestations of hypothyroidism include: Myxedematous facies (condition characterized by thickening of the skin, blunting of the senses and intellect, and laboured speech), jaundice, a puffy face and a wide posterior fontanelle with open sutures. The nasal bridge is flat. The mouth may be slightly open revealing macroglossia. Further examination would reveal bradycardia and a protuberant abdomen with a large umbilical hernia. Neurologic examination findings include hypotonia with delayed reflexes. Skin may be cool to touch and mottled in appearance due to circulatory compromise.<ref><pubmed>2903524</pubmed></ref>

===Abnormalities associated with apoptosis and migration of cells in the fetal CNS===

* The migration of cells and cell death are critically important to fetal brain and CNS development. Abnormalities in each of these processes, programmed cell death (apoptosis) in particular, have been shown to result in severe developmental abnormalities in experimental animals. Apoptosis is critically important for appropriate brain development; certain areas in brain may experience up to 50% cell death. <ref><pubmed> 11589424 </pubmed></ref>

In an experiment conducted by kuida et. al 1996, it was observed that mice that were deficient for CPP32 (a protease responsible for apoptosis), were born at a lower frequency than expected, were smaller in size compared to the normal mice and died at an early age. Brain development is significantly affected in CPP32-deficient mice resulting in a variety of hyperplasia and disorganised cell development. <ref><pubmed>8934524</pubmed></ref>

On the other hand, disrupted neuronal migration can lead to an abnormality in cell position. When this happens, the neurons are said to be heterotopic. Abnormalities in neuronal migration have been studied extensively in human cerebral cortex where these defects are associated with a variety of syndromes and diseases, ranging from behavioural disorders (including some forms of schizophrenia, dyslexia and autism) to extremely severe mental retardation and failure to thrive. <ref><pubmed>10532616</pubmed></ref>

===Neural Tube Defects===

Defects which affect the either the brain or the spinal cord in which openings remain. Grastulation occurs in week 3 of embryonic development where specialized cells (dorsal side) structurally change shape leading to the formation of the neural tube. If the neural tube does not close or fuse together properly, then openings remain which lead to various neural tube defects such as Spina bifida cystica and Spina bifida occulta.

'''Anencephaly'''

* A neural tube defect involving abnormal development of the brain and incomplete skull formation leading to high infant mortality rates with infants being stillborn or dying within a few hours after birth.

* The failure of the neural tube to close around the 23rd and 26th day into embryonic development is characteristic of this condition. As a result, the forebrain is severely affected where the cerebrum does not grow and hence partial growth occurs only. The cerebrum has a key importance in maintaining thought, consciousness and coordination whilst having no intact cerebrum rules out the probability of the affected fetus gaining consciousness .

* Increasing one's dietary intake of folic acid notably reduces the incidence of neural tube defects. Consuming 0.4mg of folic acid is sufficient to induce these results.

* Since incomplete skull formation occurs, brain tissue becomes exposed due to the absence of bone covering and therefore leading to further complications.

'''Encephaloceles'''

* Another neural tube defect in which a sac-like projections (including membrane covering) that occurs around the 3-4 week of embryonic development in which neural tube closure has not successfully occurred. The location of these protrusions varies but can be naso-frontal (nose and head), naso-ethmoidal (nose and ethmoid bone), naso-orbital (nose and eyes), meningocele (cerebrospinal fluid and membrane covering) and encephalomeningocele (meningocele with brain tissue as well).

* These sac-like protrusions lead to a variety of abnormal effects which include cerebro-spinal fluid build-up in brain, microcephaly, hydrocephaly, mental retardation, developmental problems, uncoordinated muscle movement and seizures. Consumption of folic acid again has been shown to significantly reduce the occurrence of encephaloceles in infants.

'''Hydranencephaly'''

* A very rare neural tube defect in which the cerebral hemispheres are destroyed (necrotic tissue) with the occupied space being replaced by cerebro-spinal fluid, cortex and white matter remnants within a membranous sac. Interestingly, this condition can also develop in the postnatal peroid due to viral infections or traumatic brain injury. The brain stem may remain intact and functioning in hydranencephalic infants.

* Accompanied with this condition are many effects in which include seizures, hydrocephalus, increases in head circumference,impairment in vision/ body temperature regulation and cerebral palsy. Infants affected by hydranencephaly live typically short lives being no longer than 1 year of age. Lastly, there are no viable treatment options for this condition and only supportive care is available.

'''Iniencephaly'''

* Another neural tube defect involving severe backward bending of the head (retroflexion) with subsequent spinal distortions as well. Affected infants have no neck and hence the scalp of the head is directly joined to the skin of the back (also skin of the face connected to skin of the chest). Other conditions that develop along with iniencephaly are cyclopia, cephalocele and anencephaly. The development of this condition is not solely due to one factor but from various causes (both genetic and environmental factors).

* There are specific factors that have been shown to increase the occurrence of this condition. Malnutrition, reduced folic acid intake and elevated levels of homocysteine in blood are environmental factors that increase the risk of iniencephaly <ref><pubmed> 22408660 </pubmed></ref>. Intake of certain drugs such as anti-histamines and sulphonamide/tetracycline (antibiotics) have also increases this risk <ref><pubmed> 22439066 </pubmed></ref>. Furthermore obesity has been shown to have a significant effect on the incidence of iniencephaly with 1.7-3 fold increase <ref><pubmed> 18538144 </pubmed></ref>.

* In terms of treatment, folic acid supplementation as well as avoiding certain drugs such as those outlined above significantly reduces the occurrence of this condition.

'''Spina Bifida Cystica'''

* A neural tube defect in which involves either the formation of a meningocele or myelomeningocele. Of the two, the meningocele, is the least debilitating in that a cyst-like structure forms when the neural tube does not close properly. The membrane (meninges) is pushed into openings of the vertebrae where spinal fluid builds up within the cyst. The myelomeningocele leads to severe problems as the portion of the nueral tube that is unfused allows the spinal cord to protrude through. As a result, neuronal tissue is highly exposed due to myeloschisis as well as infections and hence may lead to severe complications.

'''Spina Bifida Occulta'''

* A neural tube defect that has minimal complications in comparison to other defects. Furthermore, this defect is hidden in that a tethered spinal cord may arise as well as a thicker filum terminale and diastematomyelia (spinal cord split into two). It is also important to note that no cysts form as opposed to the other more severe spina bifida defects.

==References==

<references/>

2014 Group Project 7

2014-10-22T00:55:46Z

Z3418981: /* Current research models and findings */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, recieving and integration of information from all parts of the body, serving as the processing center of the bodies nervous system. The CNS controls all bodily functions (sensory and motor), consisting of 2 main organs; The Brain and Spinal Cord

==='''Brain'''===

The Brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

==='''Spinal Cord'''===

The Spinal Cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into

1) Ascending bundles - Transmits Sensory information from the body to the brain

2) Descending bundle - Transmits Motor function information from the brain to the body

Before fetal period, nerulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, the current research models and finding, historic findings and abnormalities that can occur in the fetal period is identified.

==Development during fetal period==

[[File:Neural-development.jpg|800px]]

Timeline of human neural development <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

'''1. cell proliferation'''

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

[[File:Somatosensory cortex of E20 rat.jpeg|300px]]

Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) through staining <ref><pubmed>22272298</pubmed></ref>

'''2. cell migration'''

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways. [[Image:CNS_passive.jpg|frame|300x200px|Passive cell displacement and outside-to-inside spatiotemporal gradient]][[Image:CNS_active.jpg|frame|400x250px|Active cell migration and inside-to-outside spatiotemporal gradient]]

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus, hypothalamus, spinal cord, retina, dentate gyrus of the hippocampal formation and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas.
[[Image:Internurons migration in cerebral cortex.jpg|frame|200x200px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex]]

'''3. cell differentiation'''

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

== Brain Development ==

- The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells

- By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

- The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

- Extends from the ninth gestational weeks through to the end of gestation

- Gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding

- Brain development begins rostral in GW8, proceeding caudally until it is complete at GW22

- Secondary sulci emerge between GW30-35

- Formation of Tertiary sulci begins during GW36 and into the postnatal period

- Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

- Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

- The major fibre pathways make up the brain white matter

- AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Increase in size and weight'''

[[File:Brain ventricles and ganglia development 03.jpg|300px]]

Image of brain and ventricular development <ref name=PMID19339620><pubmed>19339620</pubmed></ref>

[[File:Brain fissure development 02.jpg|300px]]

Image of brain fissure development <ref name=PMID19339620><pubmed>19339620</pubmed></ref>

'''sulcation and gyration'''

Sulcation: development of sulci. Primary sulci appear as shallow grooves on the surface of the brain and become more deeply infolded. Secondary sulci are formed from the development of side branches of primary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>

Gyration: development of gyrus that occurs late during fetal development until end of the pregnancy or even later after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>

{| class="wikitable"
|-
! Weeks !! Visible anatomical details
|-
| 20-21 || smooth, "lissencephalic" brain, wide Sylvian fissures
|-
| 22-23 || corpus callosum; beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || start of opercularization of Sylvian fissures; calcarine fissures and cingular sulci
|-
| 26 || central and collateral sulci
|-
| 27 || marginal and precentral sulci
|-
| 28 || postcentral and intraparietal sulci
|-
| 29 || inferior frontal sulci; bright white matter, dark cortical ribbon
|-
| 30-31 || narrower ventricular system and subarachnoid spaces
|-
| 32 || superior and inferior temporal sulci
|-
| 33 || external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table obtained from <pubmed>20608424</pubmed> <ref><pubmed>20608424</pubmed></ref>

== Spinal Cord Development ==
The spinal cord is formed from parts of the neural tube during embryonic and fetal development

=== Meninges Development ===

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations
|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''<ref name=PMID21414909><pubmed>21414909</pubmed></ref>

File:Cortical growth rate patterns (redrawn diagram).JPG
[[Image:Cortical_growth_rate_patterns_(redrawn_diagram).JPG|frame|right|middle|300x250px|This is a redrawn diagram illustrating a lateral view of T statistic map of the model of cortical plate volume increases. Red indicates regions that have a significantly higher growth rate compared to average cerebral growth rate. Growth rate decreases in yellow, black and blue regions respectively. Redrawn from <ref name=PMID21414909><pubmed>21414909</pubmed></ref>

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.

The following are recent studies that use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

-Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

-The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

-The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.

'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.

'''Cortical Overgrowth in Fetuses With Isolated Ventriculomegaly'''
<ref><pubmed> 23508710 </pubmed></ref>

* The condition fetal ventriculomegaly is characterised by dilation of lateral ventricles whilst sharing associations with other malformations. It was hypothesised that using relative brain overgrowth as marked measure of altered brain development is due to the occurrence of ventriculomegaly and to evaluate this brain overgrowth through the use of magnetic resonance imaging (MRI) of fetuses isolated with enlarged ventricles (3rd and 4th ventricles as well as cerebrospinal fluid). Furthermore, significant changes to thalamic volumes, basal ganglia and white matter did not occur between cohorts.

* The study found that there was a sufficient increase in brain volume (overgrowth) of fetuses that had ventriculomegaly in comparison to controls. Also, larger lateral ventricle volumes were yielded with fetuses with ventriculomegaly assessed via 2-dimensional movement of the atrial diameter (ultrasound and MRi) as well as a larger total brain tissue volume. This provides support for the hypothesis in that brain overgrowth can be used as a marked measure for ventriculomegaly with results showing that overgrowth was not localised in one region but across both hemispheres and thus lead to a neural deficit in children (altered neural connectivity).

* Hence, this study has assisted in the improved understanding of the effects of ventriculomegaly on cognition, language and behaviour in children.

===Future Research===

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]
Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age. The most frequent cause of macrocephaly is hydrocephalus.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.
* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period) in the secondary type.

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation.

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.

===Fetal Alcohol Syndrome===
<ref><pubmed> 23809349 </pubmed></ref>

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status.

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.

{| style="width:40%; height:170px" align="center"
|-
| [[Image: Fetal alcohol syndrome.jpg|frame|250x250px|The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref> ]]
|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

* All degrees of iodine deficiency (mild: 50-99 μg/day, moderate: 20-49 μg/day and severe≤20 μg/day) affect thyroid function of both mother and the neonate as well as mental development of the child. The damage increases with the degree of deficiency; overt endemic cretinism is the most severe consequence.

* Iodine deficiency disorders refer to complications that arise when the recommended dietary allowance of iodine is not met. These complications include thyroid function abnormalities and when iodine deficiency is severe, endemic goitre and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality.

* Iodine deficiency represents the world’s greatest cause of preventable brain damage and mental retardation, resulting of a loss of 10-15 IQ points globally. Therefore it is essential that the recommended dietary requirement for iodine is met, especially during pregnancy and lactation (200–300 μg/day). <ref><pubmed>10750030</pubmed></ref>

* Clinical manifestations of hypothyroidism include: Myxedematous facies (condition characterized by thickening of the skin, blunting of the senses and intellect, and laboured speech), jaundice, a puffy face and a wide posterior fontanelle with open sutures. The nasal bridge is flat. The mouth may be slightly open revealing macroglossia. Further examination would reveal bradycardia and a protuberant abdomen with a large umbilical hernia. Neurologic examination findings include hypotonia with delayed reflexes. Skin may be cool to touch and mottled in appearance due to circulatory compromise.<ref><pubmed>2903524</pubmed></ref>

===Abnormalities associated with apoptosis and migration of cells in the fetal CNS===

* The migration of cells and cell death are critically important to fetal brain and CNS development. Abnormalities in each of these processes, programmed cell death (apoptosis) in particular, have been shown to result in severe developmental abnormalities in experimental animals. Apoptosis is critically important for appropriate brain development; certain areas in brain may experience up to 50% cell death. <ref><pubmed> 11589424 </pubmed></ref>

In an experiment conducted by kuida et. al 1996, it was observed that mice that were deficient for CPP32 (a protease responsible for apoptosis), were born at a lower frequency than expected, were smaller in size compared to the normal mice and died at an early age. Brain development is significantly affected in CPP32-deficient mice resulting in a variety of hyperplasia and disorganised cell development. <ref><pubmed>8934524</pubmed></ref>

On the other hand, disrupted neuronal migration can lead to an abnormality in cell position. When this happens, the neurons are said to be heterotopic. Abnormalities in neuronal migration have been studied extensively in human cerebral cortex where these defects are associated with a variety of syndromes and diseases, ranging from behavioural disorders (including some forms of schizophrenia, dyslexia and autism) to extremely severe mental retardation and failure to thrive. <ref><pubmed>10532616</pubmed></ref>

===Neural Tube Defects===

Defects which affect the either the brain or the spinal cord in which openings remain. Grastulation occurs in week 3 of embryonic development where specialized cells (dorsal side) structurally change shape leading to the formation of the neural tube. If the neural tube does not close or fuse together properly, then openings remain which lead to various neural tube defects such as Spina bifida cystica and Spina bifida occulta.

'''Anencephaly'''

* A neural tube defect involving abnormal development of the brain and incomplete skull formation leading to high infant mortality rates with infants being stillborn or dying within a few hours after birth.

* The failure of the neural tube to close around the 23rd and 26th day into embryonic development is characteristic of this condition. As a result, the forebrain is severely affected where the cerebrum does not grow and hence partial growth occurs only. The cerebrum has a key importance in maintaining thought, consciousness and coordination whilst having no intact cerebrum rules out the probability of the affected fetus gaining consciousness .

* Increasing one's dietary intake of folic acid notably reduces the incidence of neural tube defects. Consuming 0.4mg of folic acid is sufficient to induce these results.

* Since incomplete skull formation occurs, brain tissue becomes exposed due to the absence of bone covering and therefore leading to further complications.

'''Encephaloceles'''

* Another neural tube defect in which a sac-like projections (including membrane covering) that occurs around the 3-4 week of embryonic development in which neural tube closure has not successfully occurred. The location of these protrusions varies but can be naso-frontal (nose and head), naso-ethmoidal (nose and ethmoid bone), naso-orbital (nose and eyes), meningocele (cerebrospinal fluid and membrane covering) and encephalomeningocele (meningocele with brain tissue as well).

* These sac-like protrusions lead to a variety of abnormal effects which include cerebro-spinal fluid build-up in brain, microcephaly, hydrocephaly, mental retardation, developmental problems, uncoordinated muscle movement and seizures. Consumption of folic acid again has been shown to significantly reduce the occurrence of encephaloceles in infants.

'''Hydranencephaly'''

* A very rare neural tube defect in which the cerebral hemispheres are destroyed (necrotic tissue) with the occupied space being replaced by cerebro-spinal fluid, cortex and white matter remnants within a membranous sac. Interestingly, this condition can also develop in the postnatal peroid due to viral infections or traumatic brain injury. The brain stem may remain intact and functioning in hydranencephalic infants.

* Accompanied with this condition are many effects in which include seizures, hydrocephalus, increases in head circumference,impairment in vision/ body temperature regulation and cerebral palsy. Infants affected by hydranencephaly live typically short lives being no longer than 1 year of age. Lastly, there are no viable treatment options for this condition and only supportive care is available.

'''Iniencephaly'''

* Another neural tube defect involving severe backward bending of the head (retroflexion) with subsequent spinal distortions as well. Affected infants have no neck and hence the scalp of the head is directly joined to the skin of the back (also skin of the face connected to skin of the chest). Other conditions that develop along with iniencephaly are cyclopia, cephalocele and anencephaly. The development of this condition is not solely due to one factor but from various causes (both genetic and environmental factors).

* There are specific factors that have been shown to increase the occurrence of this condition. Malnutrition, reduced folic acid intake and elevated levels of homocysteine in blood are environmental factors that increase the risk of iniencephaly <ref><pubmed> 22408660 </pubmed></ref>. Intake of certain drugs such as anti-histamines and sulphonamide/tetracycline (antibiotics) have also increases this risk <ref><pubmed> 22439066 </pubmed></ref>. Furthermore obesity has been shown to have a significant effect on the incidence of iniencephaly with 1.7-3 fold increase <ref><pubmed> 18538144 </pubmed></ref>.

* In terms of treatment, folic acid supplementation as well as avoiding certain drugs such as those outlined above significantly reduces the occurrence of this condition.

'''Spina Bifida Cystica'''

* A neural tube defect in which involves either the formation of a meningocele or myelomeningocele. Of the two, the meningocele, is the least debilitating in that a cyst-like structure forms when the neural tube does not close properly. The membrane (meninges) is pushed into openings of the vertebrae where spinal fluid builds up within the cyst. The myelomeningocele leads to severe problems as the portion of the nueral tube that is unfused allows the spinal cord to protrude through. As a result, neuronal tissue is highly exposed due to myeloschisis as well as infections and hence may lead to severe complications.

'''Spina Bifida Occulta'''

* A neural tube defect that has minimal complications in comparison to other defects. Furthermore, this defect is hidden in that a tethered spinal cord may arise as well as a thicker filum terminale and diastematomyelia (spinal cord split into two). It is also important to note that no cysts form as opposed to the other more severe spina bifida defects.

==References==

<references/>

2014 Group Project 7

2014-10-22T00:47:41Z

Z3418981: /* Brain Development */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, recieving and integration of information from all parts of the body, serving as the processing center of the bodies nervous system. The CNS controls all bodily functions (sensory and motor), consisting of 2 main organs; The Brain and Spinal Cord

==='''Brain'''===

The Brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

==='''Spinal Cord'''===

The Spinal Cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into

1) Ascending bundles - Transmits Sensory information from the body to the brain

2) Descending bundle - Transmits Motor function information from the brain to the body

Before fetal period, nerulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, the current research models and finding, historic findings and abnormalities that can occur in the fetal period is identified.

==Development during fetal period==

[[File:Neural-development.jpg|800px]]

Timeline of human neural development <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

'''1. cell proliferation'''

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

[[File:Somatosensory cortex of E20 rat.jpeg|300px]]

Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) through staining <ref><pubmed>22272298</pubmed></ref>

'''2. cell migration'''

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways. [[Image:CNS_passive.jpg|frame|300x200px|Passive cell displacement and outside-to-inside spatiotemporal gradient]][[Image:CNS_active.jpg|frame|400x250px|Active cell migration and inside-to-outside spatiotemporal gradient]]

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus, hypothalamus, spinal cord, retina, dentate gyrus of the hippocampal formation and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas.
[[Image:Internurons migration in cerebral cortex.jpg|frame|200x200px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex]]

'''3. cell differentiation'''

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

== Brain Development ==

- The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells

- By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

- The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

- Extends from the ninth gestational weeks through to the end of gestation

- Gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding

- Brain development begins rostral in GW8, proceeding caudally until it is complete at GW22

- Secondary sulci emerge between GW30-35

- Formation of Tertiary sulci begins during GW36 and into the postnatal period

- Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

- Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

- The major fibre pathways make up the brain white matter

- AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Increase in size and weight'''

[[File:Brain ventricles and ganglia development 03.jpg|300px]]

Image of brain and ventricular development <ref name=PMID19339620><pubmed>19339620</pubmed></ref>

[[File:Brain fissure development 02.jpg|300px]]

Image of brain fissure development <ref name=PMID19339620><pubmed>19339620</pubmed></ref>

'''sulcation and gyration'''

Sulcation: development of sulci. Primary sulci appear as shallow grooves on the surface of the brain and become more deeply infolded. Secondary sulci are formed from the development of side branches of primary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>

Gyration: development of gyrus that occurs late during fetal development until end of the pregnancy or even later after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>

{| class="wikitable"
|-
! Weeks !! Visible anatomical details
|-
| 20-21 || smooth, "lissencephalic" brain, wide Sylvian fissures
|-
| 22-23 || corpus callosum; beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || start of opercularization of Sylvian fissures; calcarine fissures and cingular sulci
|-
| 26 || central and collateral sulci
|-
| 27 || marginal and precentral sulci
|-
| 28 || postcentral and intraparietal sulci
|-
| 29 || inferior frontal sulci; bright white matter, dark cortical ribbon
|-
| 30-31 || narrower ventricular system and subarachnoid spaces
|-
| 32 || superior and inferior temporal sulci
|-
| 33 || external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table obtained from <pubmed>20608424</pubmed> <ref><pubmed>20608424</pubmed></ref>

== Spinal Cord Development ==
The spinal cord is formed from parts of the neural tube during embryonic and fetal development

=== Meninges Development ===

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations
|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''
<ref><pubmed> 21414909 </pubmed></ref>

File:Cortical growth rate patterns (redrawn diagram).JPG
[[Image:Cortical_growth_rate_patterns_(redrawn_diagram).JPG|frame|right|middle|300x250px|This is a redrawn diagram illustrating a lateral view of T statistic map of the model of cortical plate volume increases. Red indicates regions that have a significantly higher growth rate compared to average cerebral growth rate. Growth rate decreases in yellow, black and blue regions respectively. Redrawn from <ref><pubmed>21414909</pubmed></ref>]]

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.

The following are recent studies that use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

-Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

-The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

-The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.

'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.

'''Cortical Overgrowth in Fetuses With Isolated Ventriculomegaly'''
<ref><pubmed> 23508710 </pubmed></ref>

* The condition fetal ventriculomegaly is characterised by dilation of lateral ventricles whilst sharing associations with other malformations. It was hypothesised that using relative brain overgrowth as marked measure of altered brain development is due to the occurrence of ventriculomegaly and to evaluate this brain overgrowth through the use of magnetic resonance imaging (MRI) of fetuses isolated with enlarged ventricles (3rd and 4th ventricles as well as cerebrospinal fluid). Furthermore, significant changes to thalamic volumes, basal ganglia and white matter did not occur between cohorts.

* The study found that there was a sufficient increase in brain volume (overgrowth) of fetuses that had ventriculomegaly in comparison to controls. Also, larger lateral ventricle volumes were yielded with fetuses with ventriculomegaly assessed via 2-dimensional movement of the atrial diameter (ultrasound and MRi) as well as a larger total brain tissue volume. This provides support for the hypothesis in that brain overgrowth can be used as a marked measure for ventriculomegaly with results showing that overgrowth was not localised in one region but across both hemispheres and thus lead to a neural deficit in children (altered neural connectivity).

* Hence, this study has assisted in the improved understanding of the effects of ventriculomegaly on cognition, language and behaviour in children.

===Future Research===

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]
Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age. The most frequent cause of macrocephaly is hydrocephalus.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.
* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period) in the secondary type.

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation.

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.

===Fetal Alcohol Syndrome===
<ref><pubmed> 23809349 </pubmed></ref>

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status.

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.

{| style="width:40%; height:170px" align="center"
|-
| [[Image: Fetal alcohol syndrome.jpg|frame|250x250px|The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref> ]]
|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

* All degrees of iodine deficiency (mild: 50-99 μg/day, moderate: 20-49 μg/day and severe≤20 μg/day) affect thyroid function of both mother and the neonate as well as mental development of the child. The damage increases with the degree of deficiency; overt endemic cretinism is the most severe consequence.

* Iodine deficiency disorders refer to complications that arise when the recommended dietary allowance of iodine is not met. These complications include thyroid function abnormalities and when iodine deficiency is severe, endemic goitre and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality.

* Iodine deficiency represents the world’s greatest cause of preventable brain damage and mental retardation, resulting of a loss of 10-15 IQ points globally. Therefore it is essential that the recommended dietary requirement for iodine is met, especially during pregnancy and lactation (200–300 μg/day). <ref><pubmed>10750030</pubmed></ref>

* Clinical manifestations of hypothyroidism include: Myxedematous facies (condition characterized by thickening of the skin, blunting of the senses and intellect, and laboured speech), jaundice, a puffy face and a wide posterior fontanelle with open sutures. The nasal bridge is flat. The mouth may be slightly open revealing macroglossia. Further examination would reveal bradycardia and a protuberant abdomen with a large umbilical hernia. Neurologic examination findings include hypotonia with delayed reflexes. Skin may be cool to touch and mottled in appearance due to circulatory compromise.<ref><pubmed>2903524</pubmed></ref>

===Abnormalities associated with apoptosis and migration of cells in the fetal CNS===

* The migration of cells and cell death are critically important to fetal brain and CNS development. Abnormalities in each of these processes, programmed cell death (apoptosis) in particular, have been shown to result in severe developmental abnormalities in experimental animals. Apoptosis is critically important for appropriate brain development; certain areas in brain may experience up to 50% cell death. <ref><pubmed> 11589424 </pubmed></ref>

In an experiment conducted by kuida et. al 1996, it was observed that mice that were deficient for CPP32 (a protease responsible for apoptosis), were born at a lower frequency than expected, were smaller in size compared to the normal mice and died at an early age. Brain development is significantly affected in CPP32-deficient mice resulting in a variety of hyperplasia and disorganised cell development. <ref><pubmed>8934524</pubmed></ref>

On the other hand, disrupted neuronal migration can lead to an abnormality in cell position. When this happens, the neurons are said to be heterotopic. Abnormalities in neuronal migration have been studied extensively in human cerebral cortex where these defects are associated with a variety of syndromes and diseases, ranging from behavioural disorders (including some forms of schizophrenia, dyslexia and autism) to extremely severe mental retardation and failure to thrive. <ref><pubmed>10532616</pubmed></ref>

===Neural Tube Defects===

Defects which affect the either the brain or the spinal cord in which openings remain. Grastulation occurs in week 3 of embryonic development where specialized cells (dorsal side) structurally change shape leading to the formation of the neural tube. If the neural tube does not close or fuse together properly, then openings remain which lead to various neural tube defects such as Spina bifida cystica and Spina bifida occulta.

'''Anencephaly'''

* A neural tube defect involving abnormal development of the brain and incomplete skull formation leading to high infant mortality rates with infants being stillborn or dying within a few hours after birth.

* The failure of the neural tube to close around the 23rd and 26th day into embryonic development is characteristic of this condition. As a result, the forebrain is severely affected where the cerebrum does not grow and hence partial growth occurs only. The cerebrum has a key importance in maintaining thought, consciousness and coordination whilst having no intact cerebrum rules out the probability of the affected fetus gaining consciousness .

* Increasing one's dietary intake of folic acid notably reduces the incidence of neural tube defects. Consuming 0.4mg of folic acid is sufficient to induce these results.

* Since incomplete skull formation occurs, brain tissue becomes exposed due to the absence of bone covering and therefore leading to further complications.

'''Encephaloceles'''

* Another neural tube defect in which a sac-like projections (including membrane covering) that occurs around the 3-4 week of embryonic development in which neural tube closure has not successfully occurred. The location of these protrusions varies but can be naso-frontal (nose and head), naso-ethmoidal (nose and ethmoid bone), naso-orbital (nose and eyes), meningocele (cerebrospinal fluid and membrane covering) and encephalomeningocele (meningocele with brain tissue as well).

* These sac-like protrusions lead to a variety of abnormal effects which include cerebro-spinal fluid build-up in brain, microcephaly, hydrocephaly, mental retardation, developmental problems, uncoordinated muscle movement and seizures. Consumption of folic acid again has been shown to significantly reduce the occurrence of encephaloceles in infants.

'''Hydranencephaly'''

* A very rare neural tube defect in which the cerebral hemispheres are destroyed (necrotic tissue) with the occupied space being replaced by cerebro-spinal fluid, cortex and white matter remnants within a membranous sac. Interestingly, this condition can also develop in the postnatal peroid due to viral infections or traumatic brain injury. The brain stem may remain intact and functioning in hydranencephalic infants.

* Accompanied with this condition are many effects in which include seizures, hydrocephalus, increases in head circumference,impairment in vision/ body temperature regulation and cerebral palsy. Infants affected by hydranencephaly live typically short lives being no longer than 1 year of age. Lastly, there are no viable treatment options for this condition and only supportive care is available.

'''Iniencephaly'''

* Another neural tube defect involving severe backward bending of the head (retroflexion) with subsequent spinal distortions as well. Affected infants have no neck and hence the scalp of the head is directly joined to the skin of the back (also skin of the face connected to skin of the chest). Other conditions that develop along with iniencephaly are cyclopia, cephalocele and anencephaly. The development of this condition is not solely due to one factor but from various causes (both genetic and environmental factors).

* There are specific factors that have been shown to increase the occurrence of this condition. Malnutrition, reduced folic acid intake and elevated levels of homocysteine in blood are environmental factors that increase the risk of iniencephaly <ref><pubmed> 22408660 </pubmed></ref>. Intake of certain drugs such as anti-histamines and sulphonamide/tetracycline (antibiotics) have also increases this risk <ref><pubmed> 22439066 </pubmed></ref>. Furthermore obesity has been shown to have a significant effect on the incidence of iniencephaly with 1.7-3 fold increase <ref><pubmed> 18538144 </pubmed></ref>.

* In terms of treatment, folic acid supplementation as well as avoiding certain drugs such as those outlined above significantly reduces the occurrence of this condition.

'''Spina Bifida Cystica'''

* A neural tube defect in which involves either the formation of a meningocele or myelomeningocele. Of the two, the meningocele, is the least debilitating in that a cyst-like structure forms when the neural tube does not close properly. The membrane (meninges) is pushed into openings of the vertebrae where spinal fluid builds up within the cyst. The myelomeningocele leads to severe problems as the portion of the nueral tube that is unfused allows the spinal cord to protrude through. As a result, neuronal tissue is highly exposed due to myeloschisis as well as infections and hence may lead to severe complications.

'''Spina Bifida Occulta'''

* A neural tube defect that has minimal complications in comparison to other defects. Furthermore, this defect is hidden in that a tethered spinal cord may arise as well as a thicker filum terminale and diastematomyelia (spinal cord split into two). It is also important to note that no cysts form as opposed to the other more severe spina bifida defects.

==References==

<references/>

2014 Group Project 7

2014-10-22T00:44:59Z

Z3418981: /* Brain Development */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, recieving and integration of information from all parts of the body, serving as the processing center of the bodies nervous system. The CNS controls all bodily functions (sensory and motor), consisting of 2 main organs; The Brain and Spinal Cord

==='''Brain'''===

The Brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

==='''Spinal Cord'''===

The Spinal Cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into

1) Ascending bundles - Transmits Sensory information from the body to the brain

2) Descending bundle - Transmits Motor function information from the brain to the body

Before fetal period, nerulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, the current research models and finding, historic findings and abnormalities that can occur in the fetal period is identified.

==Development during fetal period==

[[File:Neural-development.jpg|800px]]

Timeline of human neural development <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

'''1. cell proliferation'''

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

[[File:Somatosensory cortex of E20 rat.jpeg|300px]]

Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) through staining <ref><pubmed>22272298</pubmed></ref>

'''2. cell migration'''

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways. [[Image:CNS_passive.jpg|frame|300x200px|Passive cell displacement and outside-to-inside spatiotemporal gradient]][[Image:CNS_active.jpg|frame|400x250px|Active cell migration and inside-to-outside spatiotemporal gradient]]

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus, hypothalamus, spinal cord, retina, dentate gyrus of the hippocampal formation and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas.
[[Image:Internurons migration in cerebral cortex.jpg|frame|200x200px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex]]

'''3. cell differentiation'''

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

== Brain Development ==

- The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells

- By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

- The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

- Extends from the ninth gestational weeks through to the end of gestation

- Gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding

- Brain development begins rostral in GW8, proceeding caudally until it is complete at GW22

- Secondary sulci emerge between GW30-35

- Formation of Tertiary sulci begins during GW36 and into the postnatal period

- Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

- Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

- The major fibre pathways make up the brain white matter

- AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Increase in size and weight'''

[[File:Brain ventricles and ganglia development 03.jpg|300px]]

Image of brain and ventricular development <ref name=PMID19339620><ref><pubmed>19339620</pubmed></ref>

[[File:Brain fissure development 02.jpg|300px]]

Image of brain fissure development <ref name=PMID19339620><ref><pubmed>19339620</pubmed></ref>

'''sulcation and gyration'''

Sulcation: development of sulci. Primary sulci appear as shallow grooves on the surface of the brain and become more deeply infolded. Secondary sulci are formed from the development of side branches of primary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>

Gyration: development of gyrus that occurs late during fetal development until end of the pregnancy or even later after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>

{| class="wikitable"
|-
! Weeks !! Visible anatomical details
|-
| 20-21 || smooth, "lissencephalic" brain, wide Sylvian fissures
|-
| 22-23 || corpus callosum; beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || start of opercularization of Sylvian fissures; calcarine fissures and cingular sulci
|-
| 26 || central and collateral sulci
|-
| 27 || marginal and precentral sulci
|-
| 28 || postcentral and intraparietal sulci
|-
| 29 || inferior frontal sulci; bright white matter, dark cortical ribbon
|-
| 30-31 || narrower ventricular system and subarachnoid spaces
|-
| 32 || superior and inferior temporal sulci
|-
| 33 || external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table obtained from <pubmed>20608424</pubmed> <ref><pubmed>20608424</pubmed></ref>

== Spinal Cord Development ==
The spinal cord is formed from parts of the neural tube during embryonic and fetal development

=== Meninges Development ===

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations
|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''
<ref><pubmed> 21414909 </pubmed></ref>

File:Cortical growth rate patterns (redrawn diagram).JPG
[[Image:Cortical_growth_rate_patterns_(redrawn_diagram).JPG|frame|right|middle|300x250px|This is a redrawn diagram illustrating a lateral view of T statistic map of the model of cortical plate volume increases. Red indicates regions that have a significantly higher growth rate compared to average cerebral growth rate. Growth rate decreases in yellow, black and blue regions respectively. Redrawn from <ref><pubmed>21414909</pubmed></ref>]]

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.

The following are recent studies that use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

-Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

-The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

-The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.

'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.

'''Cortical Overgrowth in Fetuses With Isolated Ventriculomegaly'''
<ref><pubmed> 23508710 </pubmed></ref>

* The condition fetal ventriculomegaly is characterised by dilation of lateral ventricles whilst sharing associations with other malformations. It was hypothesised that using relative brain overgrowth as marked measure of altered brain development is due to the occurrence of ventriculomegaly and to evaluate this brain overgrowth through the use of magnetic resonance imaging (MRI) of fetuses isolated with enlarged ventricles (3rd and 4th ventricles as well as cerebrospinal fluid). Furthermore, significant changes to thalamic volumes, basal ganglia and white matter did not occur between cohorts.

* The study found that there was a sufficient increase in brain volume (overgrowth) of fetuses that had ventriculomegaly in comparison to controls. Also, larger lateral ventricle volumes were yielded with fetuses with ventriculomegaly assessed via 2-dimensional movement of the atrial diameter (ultrasound and MRi) as well as a larger total brain tissue volume. This provides support for the hypothesis in that brain overgrowth can be used as a marked measure for ventriculomegaly with results showing that overgrowth was not localised in one region but across both hemispheres and thus lead to a neural deficit in children (altered neural connectivity).

* Hence, this study has assisted in the improved understanding of the effects of ventriculomegaly on cognition, language and behaviour in children.

===Future Research===

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]
Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age. The most frequent cause of macrocephaly is hydrocephalus.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.
* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period) in the secondary type.

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation.

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.

===Fetal Alcohol Syndrome===
<ref><pubmed> 23809349 </pubmed></ref>

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status.

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.

{| style="width:40%; height:170px" align="center"
|-
| [[Image: Fetal alcohol syndrome.jpg|frame|250x250px|The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref> ]]
|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

* All degrees of iodine deficiency (mild: 50-99 μg/day, moderate: 20-49 μg/day and severe≤20 μg/day) affect thyroid function of both mother and the neonate as well as mental development of the child. The damage increases with the degree of deficiency; overt endemic cretinism is the most severe consequence.

* Iodine deficiency disorders refer to complications that arise when the recommended dietary allowance of iodine is not met. These complications include thyroid function abnormalities and when iodine deficiency is severe, endemic goitre and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality.

* Iodine deficiency represents the world’s greatest cause of preventable brain damage and mental retardation, resulting of a loss of 10-15 IQ points globally. Therefore it is essential that the recommended dietary requirement for iodine is met, especially during pregnancy and lactation (200–300 μg/day). <ref><pubmed>10750030</pubmed></ref>

* Clinical manifestations of hypothyroidism include: Myxedematous facies (condition characterized by thickening of the skin, blunting of the senses and intellect, and laboured speech), jaundice, a puffy face and a wide posterior fontanelle with open sutures. The nasal bridge is flat. The mouth may be slightly open revealing macroglossia. Further examination would reveal bradycardia and a protuberant abdomen with a large umbilical hernia. Neurologic examination findings include hypotonia with delayed reflexes. Skin may be cool to touch and mottled in appearance due to circulatory compromise.<ref><pubmed>2903524</pubmed></ref>

===Abnormalities associated with apoptosis and migration of cells in the fetal CNS===

* The migration of cells and cell death are critically important to fetal brain and CNS development. Abnormalities in each of these processes, programmed cell death (apoptosis) in particular, have been shown to result in severe developmental abnormalities in experimental animals. Apoptosis is critically important for appropriate brain development; certain areas in brain may experience up to 50% cell death. <ref><pubmed> 11589424 </pubmed></ref>

In an experiment conducted by kuida et. al 1996, it was observed that mice that were deficient for CPP32 (a protease responsible for apoptosis), were born at a lower frequency than expected, were smaller in size compared to the normal mice and died at an early age. Brain development is significantly affected in CPP32-deficient mice resulting in a variety of hyperplasia and disorganised cell development. <ref><pubmed>8934524</pubmed></ref>

On the other hand, disrupted neuronal migration can lead to an abnormality in cell position. When this happens, the neurons are said to be heterotopic. Abnormalities in neuronal migration have been studied extensively in human cerebral cortex where these defects are associated with a variety of syndromes and diseases, ranging from behavioural disorders (including some forms of schizophrenia, dyslexia and autism) to extremely severe mental retardation and failure to thrive. <ref><pubmed>10532616</pubmed></ref>

===Neural Tube Defects===

Defects which affect the either the brain or the spinal cord in which openings remain. Grastulation occurs in week 3 of embryonic development where specialized cells (dorsal side) structurally change shape leading to the formation of the neural tube. If the neural tube does not close or fuse together properly, then openings remain which lead to various neural tube defects such as Spina bifida cystica and Spina bifida occulta.

'''Anencephaly'''

* A neural tube defect involving abnormal development of the brain and incomplete skull formation leading to high infant mortality rates with infants being stillborn or dying within a few hours after birth.

* The failure of the neural tube to close around the 23rd and 26th day into embryonic development is characteristic of this condition. As a result, the forebrain is severely affected where the cerebrum does not grow and hence partial growth occurs only. The cerebrum has a key importance in maintaining thought, consciousness and coordination whilst having no intact cerebrum rules out the probability of the affected fetus gaining consciousness .

* Increasing one's dietary intake of folic acid notably reduces the incidence of neural tube defects. Consuming 0.4mg of folic acid is sufficient to induce these results.

* Since incomplete skull formation occurs, brain tissue becomes exposed due to the absence of bone covering and therefore leading to further complications.

'''Encephaloceles'''

* Another neural tube defect in which a sac-like projections (including membrane covering) that occurs around the 3-4 week of embryonic development in which neural tube closure has not successfully occurred. The location of these protrusions varies but can be naso-frontal (nose and head), naso-ethmoidal (nose and ethmoid bone), naso-orbital (nose and eyes), meningocele (cerebrospinal fluid and membrane covering) and encephalomeningocele (meningocele with brain tissue as well).

* These sac-like protrusions lead to a variety of abnormal effects which include cerebro-spinal fluid build-up in brain, microcephaly, hydrocephaly, mental retardation, developmental problems, uncoordinated muscle movement and seizures. Consumption of folic acid again has been shown to significantly reduce the occurrence of encephaloceles in infants.

'''Hydranencephaly'''

* A very rare neural tube defect in which the cerebral hemispheres are destroyed (necrotic tissue) with the occupied space being replaced by cerebro-spinal fluid, cortex and white matter remnants within a membranous sac. Interestingly, this condition can also develop in the postnatal peroid due to viral infections or traumatic brain injury. The brain stem may remain intact and functioning in hydranencephalic infants.

* Accompanied with this condition are many effects in which include seizures, hydrocephalus, increases in head circumference,impairment in vision/ body temperature regulation and cerebral palsy. Infants affected by hydranencephaly live typically short lives being no longer than 1 year of age. Lastly, there are no viable treatment options for this condition and only supportive care is available.

'''Iniencephaly'''

* Another neural tube defect involving severe backward bending of the head (retroflexion) with subsequent spinal distortions as well. Affected infants have no neck and hence the scalp of the head is directly joined to the skin of the back (also skin of the face connected to skin of the chest). Other conditions that develop along with iniencephaly are cyclopia, cephalocele and anencephaly. The development of this condition is not solely due to one factor but from various causes (both genetic and environmental factors).

* There are specific factors that have been shown to increase the occurrence of this condition. Malnutrition, reduced folic acid intake and elevated levels of homocysteine in blood are environmental factors that increase the risk of iniencephaly <ref><pubmed> 22408660 </pubmed></ref>. Intake of certain drugs such as anti-histamines and sulphonamide/tetracycline (antibiotics) have also increases this risk <ref><pubmed> 22439066 </pubmed></ref>. Furthermore obesity has been shown to have a significant effect on the incidence of iniencephaly with 1.7-3 fold increase <ref><pubmed> 18538144 </pubmed></ref>.

* In terms of treatment, folic acid supplementation as well as avoiding certain drugs such as those outlined above significantly reduces the occurrence of this condition.

'''Spina Bifida Cystica'''

* A neural tube defect in which involves either the formation of a meningocele or myelomeningocele. Of the two, the meningocele, is the least debilitating in that a cyst-like structure forms when the neural tube does not close properly. The membrane (meninges) is pushed into openings of the vertebrae where spinal fluid builds up within the cyst. The myelomeningocele leads to severe problems as the portion of the nueral tube that is unfused allows the spinal cord to protrude through. As a result, neuronal tissue is highly exposed due to myeloschisis as well as infections and hence may lead to severe complications.

'''Spina Bifida Occulta'''

* A neural tube defect that has minimal complications in comparison to other defects. Furthermore, this defect is hidden in that a tethered spinal cord may arise as well as a thicker filum terminale and diastematomyelia (spinal cord split into two). It is also important to note that no cysts form as opposed to the other more severe spina bifida defects.

==References==

<references/>

2014 Group Project 7

2014-10-22T00:41:23Z

Z3418981: /* Brain Development */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, recieving and integration of information from all parts of the body, serving as the processing center of the bodies nervous system. The CNS controls all bodily functions (sensory and motor), consisting of 2 main organs; The Brain and Spinal Cord

==='''Brain'''===

The Brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

==='''Spinal Cord'''===

The Spinal Cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into

1) Ascending bundles - Transmits Sensory information from the body to the brain

2) Descending bundle - Transmits Motor function information from the brain to the body

Before fetal period, nerulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, the current research models and finding, historic findings and abnormalities that can occur in the fetal period is identified.

==Development during fetal period==

[[File:Neural-development.jpg|800px]]

Timeline of human neural development <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

'''1. cell proliferation'''

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

[[File:Somatosensory cortex of E20 rat.jpeg|300px]]

Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) through staining <ref><pubmed>22272298</pubmed></ref>

'''2. cell migration'''

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways. [[Image:CNS_passive.jpg|frame|300x200px|Passive cell displacement and outside-to-inside spatiotemporal gradient]][[Image:CNS_active.jpg|frame|400x250px|Active cell migration and inside-to-outside spatiotemporal gradient]]

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus, hypothalamus, spinal cord, retina, dentate gyrus of the hippocampal formation and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas.
[[Image:Internurons migration in cerebral cortex.jpg|frame|200x200px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex]]

'''3. cell differentiation'''

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

== Brain Development ==

- The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells

- By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

- The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

- Extends from the ninth gestational weeks through to the end of gestation

- Gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding

- Brain development begins rostral in GW8, proceeding caudally until it is complete at GW22

- Secondary sulci emerge between GW30-35

- Formation of Tertiary sulci begins during GW36 and into the postnatal period

- Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

- Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

- The major fibre pathways make up the brain white matter

- AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Increase in size and weight'''

[[File:Brain ventricles and ganglia development 03.jpg|300px]]

Image of brain and ventricular development <ref><pubmed>19339620</pubmed></ref>

[[File:Brain fissure development 02.jpg|300px]]

Image of brain fissure development <ref><pubmed>19339620</pubmed></ref>

'''sulcation and gyration'''

Sulcation: development of sulci. Primary sulci appear as shallow grooves on the surface of the brain and become more deeply infolded. Secondary sulci are formed from the development of side branches of primary sulci <ref name=PMID11158907><pubmed>11158907</pubmed></ref>

Gyration: development of gyrus that occurs late during fetal development until end of the pregnancy or even later after birth <ref name=PMID11158907><pubmed>11158907</pubmed></ref>

{| class="wikitable"
|-
! Weeks !! Visible anatomical details
|-
| 20-21 || smooth, "lissencephalic" brain, wide Sylvian fissures
|-
| 22-23 || corpus callosum; beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || start of opercularization of Sylvian fissures; calcarine fissures and cingular sulci
|-
| 26 || central and collateral sulci
|-
| 27 || marginal and precentral sulci
|-
| 28 || postcentral and intraparietal sulci
|-
| 29 || inferior frontal sulci; bright white matter, dark cortical ribbon
|-
| 30-31 || narrower ventricular system and subarachnoid spaces
|-
| 32 || superior and inferior temporal sulci
|-
| 33 || external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table obtained from <pubmed>20608424</pubmed> <ref><pubmed>20608424</pubmed></ref>

== Spinal Cord Development ==
The spinal cord is formed from parts of the neural tube during embryonic and fetal development

=== Meninges Development ===

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations
|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''
<ref><pubmed> 21414909 </pubmed></ref>

File:Cortical growth rate patterns (redrawn diagram).JPG
[[Image:Cortical_growth_rate_patterns_(redrawn_diagram).JPG|frame|right|middle|300x250px|This is a redrawn diagram illustrating a lateral view of T statistic map of the model of cortical plate volume increases. Red indicates regions that have a significantly higher growth rate compared to average cerebral growth rate. Growth rate decreases in yellow, black and blue regions respectively. Redrawn from <ref><pubmed>21414909</pubmed></ref>]]

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.

The following are recent studies that use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

-Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

-The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

-The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.

'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.

'''Cortical Overgrowth in Fetuses With Isolated Ventriculomegaly'''
<ref><pubmed> 23508710 </pubmed></ref>

* The condition fetal ventriculomegaly is characterised by dilation of lateral ventricles whilst sharing associations with other malformations. It was hypothesised that using relative brain overgrowth as marked measure of altered brain development is due to the occurrence of ventriculomegaly and to evaluate this brain overgrowth through the use of magnetic resonance imaging (MRI) of fetuses isolated with enlarged ventricles (3rd and 4th ventricles as well as cerebrospinal fluid). Furthermore, significant changes to thalamic volumes, basal ganglia and white matter did not occur between cohorts.

* The study found that there was a sufficient increase in brain volume (overgrowth) of fetuses that had ventriculomegaly in comparison to controls. Also, larger lateral ventricle volumes were yielded with fetuses with ventriculomegaly assessed via 2-dimensional movement of the atrial diameter (ultrasound and MRi) as well as a larger total brain tissue volume. This provides support for the hypothesis in that brain overgrowth can be used as a marked measure for ventriculomegaly with results showing that overgrowth was not localised in one region but across both hemispheres and thus lead to a neural deficit in children (altered neural connectivity).

* Hence, this study has assisted in the improved understanding of the effects of ventriculomegaly on cognition, language and behaviour in children.

===Future Research===

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]
Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age. The most frequent cause of macrocephaly is hydrocephalus.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.
* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period) in the secondary type.

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation.

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.

===Fetal Alcohol Syndrome===
<ref><pubmed> 23809349 </pubmed></ref>

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status.

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.

{| style="width:40%; height:170px" align="center"
|-
| [[Image: Fetal alcohol syndrome.jpg|frame|250x250px|The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref> ]]
|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

* All degrees of iodine deficiency (mild: 50-99 μg/day, moderate: 20-49 μg/day and severe≤20 μg/day) affect thyroid function of both mother and the neonate as well as mental development of the child. The damage increases with the degree of deficiency; overt endemic cretinism is the most severe consequence.

* Iodine deficiency disorders refer to complications that arise when the recommended dietary allowance of iodine is not met. These complications include thyroid function abnormalities and when iodine deficiency is severe, endemic goitre and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality.

* Iodine deficiency represents the world’s greatest cause of preventable brain damage and mental retardation, resulting of a loss of 10-15 IQ points globally. Therefore it is essential that the recommended dietary requirement for iodine is met, especially during pregnancy and lactation (200–300 μg/day). <ref><pubmed>10750030</pubmed></ref>

* Clinical manifestations of hypothyroidism include: Myxedematous facies (condition characterized by thickening of the skin, blunting of the senses and intellect, and laboured speech), jaundice, a puffy face and a wide posterior fontanelle with open sutures. The nasal bridge is flat. The mouth may be slightly open revealing macroglossia. Further examination would reveal bradycardia and a protuberant abdomen with a large umbilical hernia. Neurologic examination findings include hypotonia with delayed reflexes. Skin may be cool to touch and mottled in appearance due to circulatory compromise.<ref><pubmed>2903524</pubmed></ref>

===Abnormalities associated with apoptosis and migration of cells in the fetal CNS===

* The migration of cells and cell death are critically important to fetal brain and CNS development. Abnormalities in each of these processes, programmed cell death (apoptosis) in particular, have been shown to result in severe developmental abnormalities in experimental animals. Apoptosis is critically important for appropriate brain development; certain areas in brain may experience up to 50% cell death. <ref><pubmed> 11589424 </pubmed></ref>

In an experiment conducted by kuida et. al 1996, it was observed that mice that were deficient for CPP32 (a protease responsible for apoptosis), were born at a lower frequency than expected, were smaller in size compared to the normal mice and died at an early age. Brain development is significantly affected in CPP32-deficient mice resulting in a variety of hyperplasia and disorganised cell development. <ref><pubmed>8934524</pubmed></ref>

On the other hand, disrupted neuronal migration can lead to an abnormality in cell position. When this happens, the neurons are said to be heterotopic. Abnormalities in neuronal migration have been studied extensively in human cerebral cortex where these defects are associated with a variety of syndromes and diseases, ranging from behavioural disorders (including some forms of schizophrenia, dyslexia and autism) to extremely severe mental retardation and failure to thrive. <ref><pubmed>10532616</pubmed></ref>

===Neural Tube Defects===

Defects which affect the either the brain or the spinal cord in which openings remain. Grastulation occurs in week 3 of embryonic development where specialized cells (dorsal side) structurally change shape leading to the formation of the neural tube. If the neural tube does not close or fuse together properly, then openings remain which lead to various neural tube defects such as Spina bifida cystica and Spina bifida occulta.

'''Anencephaly'''

* A neural tube defect involving abnormal development of the brain and incomplete skull formation leading to high infant mortality rates with infants being stillborn or dying within a few hours after birth.

* The failure of the neural tube to close around the 23rd and 26th day into embryonic development is characteristic of this condition. As a result, the forebrain is severely affected where the cerebrum does not grow and hence partial growth occurs only. The cerebrum has a key importance in maintaining thought, consciousness and coordination whilst having no intact cerebrum rules out the probability of the affected fetus gaining consciousness .

* Increasing one's dietary intake of folic acid notably reduces the incidence of neural tube defects. Consuming 0.4mg of folic acid is sufficient to induce these results.

* Since incomplete skull formation occurs, brain tissue becomes exposed due to the absence of bone covering and therefore leading to further complications.

'''Encephaloceles'''

* Another neural tube defect in which a sac-like projections (including membrane covering) that occurs around the 3-4 week of embryonic development in which neural tube closure has not successfully occurred. The location of these protrusions varies but can be naso-frontal (nose and head), naso-ethmoidal (nose and ethmoid bone), naso-orbital (nose and eyes), meningocele (cerebrospinal fluid and membrane covering) and encephalomeningocele (meningocele with brain tissue as well).

* These sac-like protrusions lead to a variety of abnormal effects which include cerebro-spinal fluid build-up in brain, microcephaly, hydrocephaly, mental retardation, developmental problems, uncoordinated muscle movement and seizures. Consumption of folic acid again has been shown to significantly reduce the occurrence of encephaloceles in infants.

'''Hydranencephaly'''

* A very rare neural tube defect in which the cerebral hemispheres are destroyed (necrotic tissue) with the occupied space being replaced by cerebro-spinal fluid, cortex and white matter remnants within a membranous sac. Interestingly, this condition can also develop in the postnatal peroid due to viral infections or traumatic brain injury. The brain stem may remain intact and functioning in hydranencephalic infants.

* Accompanied with this condition are many effects in which include seizures, hydrocephalus, increases in head circumference,impairment in vision/ body temperature regulation and cerebral palsy. Infants affected by hydranencephaly live typically short lives being no longer than 1 year of age. Lastly, there are no viable treatment options for this condition and only supportive care is available.

'''Iniencephaly'''

* Another neural tube defect involving severe backward bending of the head (retroflexion) with subsequent spinal distortions as well. Affected infants have no neck and hence the scalp of the head is directly joined to the skin of the back (also skin of the face connected to skin of the chest). Other conditions that develop along with iniencephaly are cyclopia, cephalocele and anencephaly. The development of this condition is not solely due to one factor but from various causes (both genetic and environmental factors).

* There are specific factors that have been shown to increase the occurrence of this condition. Malnutrition, reduced folic acid intake and elevated levels of homocysteine in blood are environmental factors that increase the risk of iniencephaly <ref><pubmed> 22408660 </pubmed></ref>. Intake of certain drugs such as anti-histamines and sulphonamide/tetracycline (antibiotics) have also increases this risk <ref><pubmed> 22439066 </pubmed></ref>. Furthermore obesity has been shown to have a significant effect on the incidence of iniencephaly with 1.7-3 fold increase <ref><pubmed> 18538144 </pubmed></ref>.

* In terms of treatment, folic acid supplementation as well as avoiding certain drugs such as those outlined above significantly reduces the occurrence of this condition.

'''Spina Bifida Cystica'''

* A neural tube defect in which involves either the formation of a meningocele or myelomeningocele. Of the two, the meningocele, is the least debilitating in that a cyst-like structure forms when the neural tube does not close properly. The membrane (meninges) is pushed into openings of the vertebrae where spinal fluid builds up within the cyst. The myelomeningocele leads to severe problems as the portion of the nueral tube that is unfused allows the spinal cord to protrude through. As a result, neuronal tissue is highly exposed due to myeloschisis as well as infections and hence may lead to severe complications.

'''Spina Bifida Occulta'''

* A neural tube defect that has minimal complications in comparison to other defects. Furthermore, this defect is hidden in that a tethered spinal cord may arise as well as a thicker filum terminale and diastematomyelia (spinal cord split into two). It is also important to note that no cysts form as opposed to the other more severe spina bifida defects.

==References==

<references/>

2014 Group Project 7

2014-10-22T00:38:30Z

Z3418981: /* Current research models and findings */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, recieving and integration of information from all parts of the body, serving as the processing center of the bodies nervous system. The CNS controls all bodily functions (sensory and motor), consisting of 2 main organs; The Brain and Spinal Cord

==='''Brain'''===

The Brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

==='''Spinal Cord'''===

The Spinal Cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into

1) Ascending bundles - Transmits Sensory information from the body to the brain

2) Descending bundle - Transmits Motor function information from the brain to the body

Before fetal period, nerulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, the current research models and finding, historic findings and abnormalities that can occur in the fetal period is identified.

==Development during fetal period==

[[File:Neural-development.jpg|800px]]

Timeline of human neural development <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

'''1. cell proliferation'''

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

[[File:Somatosensory cortex of E20 rat.jpeg|300px]]

Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) through staining <ref><pubmed>22272298</pubmed></ref>

'''2. cell migration'''

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways. [[Image:CNS_passive.jpg|frame|300x200px|Passive cell displacement and outside-to-inside spatiotemporal gradient]][[Image:CNS_active.jpg|frame|400x250px|Active cell migration and inside-to-outside spatiotemporal gradient]]

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus, hypothalamus, spinal cord, retina, dentate gyrus of the hippocampal formation and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas.
[[Image:Internurons migration in cerebral cortex.jpg|frame|200x200px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex]]

'''3. cell differentiation'''

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

== Brain Development ==

- The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells

- By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

- The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

- Extends from the ninth gestational weeks through to the end of gestation

- Gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding

- Brain development begins rostral in GW8, proceeding caudally until it is complete at GW22

- Secondary sulci emerge between GW30-35

- Formation of Tertiary sulci begins during GW36 and into the postnatal period

- Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

- Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

- The major fibre pathways make up the brain white matter

- AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Increase in size and weight'''

[[File:Brain ventricles and ganglia development 03.jpg|300px]]

Image of brain and ventricular development <ref><pubmed>19339620</pubmed></ref>

[[File:Brain fissure development 02.jpg|300px]]

Image of brain fissure development <ref><pubmed>19339620</pubmed></ref>

'''sulcation and gyration'''

Sulcation: development of sulci. Primary sulci appear as shallow grooves on the surface of the brain and become more deeply infolded. Secondary sulci are formed from the development of side branches of primary sulci <ref name=”PMID11158907”><pubmed>11158907</pubmed></ref>

Gyration: development of gyrus that occurs late during fetal development until end of the pregnancy or even later after birth <ref name=”PMID11158907”><pubmed>11158907</pubmed></ref>

{| class="wikitable"
|-
! Weeks !! Visible anatomical details
|-
| 20-21 || smooth, "lissencephalic" brain, wide Sylvian fissures
|-
| 22-23 || corpus callosum; beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || start of opercularization of Sylvian fissures; calcarine fissures and cingular sulci
|-
| 26 || central and collateral sulci
|-
| 27 || marginal and precentral sulci
|-
| 28 || postcentral and intraparietal sulci
|-
| 29 || inferior frontal sulci; bright white matter, dark cortical ribbon
|-
| 30-31 || narrower ventricular system and subarachnoid spaces
|-
| 32 || superior and inferior temporal sulci
|-
| 33 || external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table obtained from <pubmed>20608424</pubmed> <ref><pubmed>20608424</pubmed></ref>

== Spinal Cord Development ==
The spinal cord is formed from parts of the neural tube during embryonic and fetal development

=== Meninges Development ===

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations
|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==

===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''
<ref><pubmed> 21414909 </pubmed></ref>

File:Cortical growth rate patterns (redrawn diagram).JPG
[[Image:Cortical_growth_rate_patterns_(redrawn_diagram).JPG|frame|right|middle|300x250px|This is a redrawn diagram illustrating a lateral view of T statistic map of the model of cortical plate volume increases. Red indicates regions that have a significantly higher growth rate compared to average cerebral growth rate. Growth rate decreases in yellow, black and blue regions respectively. Redrawn from <ref><pubmed>21414909</pubmed></ref>]]

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.

The following are recent studies that use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

-Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

-The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

-The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.

'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.

'''Cortical Overgrowth in Fetuses With Isolated Ventriculomegaly'''
<ref><pubmed> 23508710 </pubmed></ref>

* The condition fetal ventriculomegaly is characterised by dilation of lateral ventricles whilst sharing associations with other malformations. It was hypothesised that using relative brain overgrowth as marked measure of altered brain development is due to the occurrence of ventriculomegaly and to evaluate this brain overgrowth through the use of magnetic resonance imaging (MRI) of fetuses isolated with enlarged ventricles (3rd and 4th ventricles as well as cerebrospinal fluid). Furthermore, significant changes to thalamic volumes, basal ganglia and white matter did not occur between cohorts.

* The study found that there was a sufficient increase in brain volume (overgrowth) of fetuses that had ventriculomegaly in comparison to controls. Also, larger lateral ventricle volumes were yielded with fetuses with ventriculomegaly assessed via 2-dimensional movement of the atrial diameter (ultrasound and MRi) as well as a larger total brain tissue volume. This provides support for the hypothesis in that brain overgrowth can be used as a marked measure for ventriculomegaly with results showing that overgrowth was not localised in one region but across both hemispheres and thus lead to a neural deficit in children (altered neural connectivity).

* Hence, this study has assisted in the improved understanding of the effects of ventriculomegaly on cognition, language and behaviour in children.

===Future Research===

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]
Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age. The most frequent cause of macrocephaly is hydrocephalus.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.
* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period) in the secondary type.

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation.

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.

===Fetal Alcohol Syndrome===
<ref><pubmed> 23809349 </pubmed></ref>

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status.

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.

{| style="width:40%; height:170px" align="center"
|-
| [[Image: Fetal alcohol syndrome.jpg|frame|250x250px|The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref> ]]
|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

* All degrees of iodine deficiency (mild: 50-99 μg/day, moderate: 20-49 μg/day and severe≤20 μg/day) affect thyroid function of both mother and the neonate as well as mental development of the child. The damage increases with the degree of deficiency; overt endemic cretinism is the most severe consequence.

* Iodine deficiency disorders refer to complications that arise when the recommended dietary allowance of iodine is not met. These complications include thyroid function abnormalities and when iodine deficiency is severe, endemic goitre and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality.

* Iodine deficiency represents the world’s greatest cause of preventable brain damage and mental retardation, resulting of a loss of 10-15 IQ points globally. Therefore it is essential that the recommended dietary requirement for iodine is met, especially during pregnancy and lactation (200–300 μg/day). <ref><pubmed>10750030</pubmed></ref>

* Clinical manifestations of hypothyroidism include: Myxedematous facies (condition characterized by thickening of the skin, blunting of the senses and intellect, and laboured speech), jaundice, a puffy face and a wide posterior fontanelle with open sutures. The nasal bridge is flat. The mouth may be slightly open revealing macroglossia. Further examination would reveal bradycardia and a protuberant abdomen with a large umbilical hernia. Neurologic examination findings include hypotonia with delayed reflexes. Skin may be cool to touch and mottled in appearance due to circulatory compromise.<ref><pubmed>2903524</pubmed></ref>

===Abnormalities associated with apoptosis and migration of cells in the fetal CNS===

* The migration of cells and cell death are critically important to fetal brain and CNS development. Abnormalities in each of these processes, programmed cell death (apoptosis) in particular, have been shown to result in severe developmental abnormalities in experimental animals. Apoptosis is critically important for appropriate brain development; certain areas in brain may experience up to 50% cell death. <ref><pubmed> 11589424 </pubmed></ref>

In an experiment conducted by kuida et. al 1996, it was observed that mice that were deficient for CPP32 (a protease responsible for apoptosis), were born at a lower frequency than expected, were smaller in size compared to the normal mice and died at an early age. Brain development is significantly affected in CPP32-deficient mice resulting in a variety of hyperplasia and disorganised cell development. <ref><pubmed>8934524</pubmed></ref>

On the other hand, disrupted neuronal migration can lead to an abnormality in cell position. When this happens, the neurons are said to be heterotopic. Abnormalities in neuronal migration have been studied extensively in human cerebral cortex where these defects are associated with a variety of syndromes and diseases, ranging from behavioural disorders (including some forms of schizophrenia, dyslexia and autism) to extremely severe mental retardation and failure to thrive. <ref><pubmed>10532616</pubmed></ref>

===Neural Tube Defects===

Defects which affect the either the brain or the spinal cord in which openings remain. Grastulation occurs in week 3 of embryonic development where specialized cells (dorsal side) structurally change shape leading to the formation of the neural tube. If the neural tube does not close or fuse together properly, then openings remain which lead to various neural tube defects such as Spina bifida cystica and Spina bifida occulta.

'''Anencephaly'''

* A neural tube defect involving abnormal development of the brain and incomplete skull formation leading to high infant mortality rates with infants being stillborn or dying within a few hours after birth.

* The failure of the neural tube to close around the 23rd and 26th day into embryonic development is characteristic of this condition. As a result, the forebrain is severely affected where the cerebrum does not grow and hence partial growth occurs only. The cerebrum has a key importance in maintaining thought, consciousness and coordination whilst having no intact cerebrum rules out the probability of the affected fetus gaining consciousness .

* Increasing one's dietary intake of folic acid notably reduces the incidence of neural tube defects. Consuming 0.4mg of folic acid is sufficient to induce these results.

* Since incomplete skull formation occurs, brain tissue becomes exposed due to the absence of bone covering and therefore leading to further complications.

'''Encephaloceles'''

* Another neural tube defect in which a sac-like projections (including membrane covering) that occurs around the 3-4 week of embryonic development in which neural tube closure has not successfully occurred. The location of these protrusions varies but can be naso-frontal (nose and head), naso-ethmoidal (nose and ethmoid bone), naso-orbital (nose and eyes), meningocele (cerebrospinal fluid and membrane covering) and encephalomeningocele (meningocele with brain tissue as well).

* These sac-like protrusions lead to a variety of abnormal effects which include cerebro-spinal fluid build-up in brain, microcephaly, hydrocephaly, mental retardation, developmental problems, uncoordinated muscle movement and seizures. Consumption of folic acid again has been shown to significantly reduce the occurrence of encephaloceles in infants.

'''Hydranencephaly'''

* A very rare neural tube defect in which the cerebral hemispheres are destroyed (necrotic tissue) with the occupied space being replaced by cerebro-spinal fluid, cortex and white matter remnants within a membranous sac. Interestingly, this condition can also develop in the postnatal peroid due to viral infections or traumatic brain injury. The brain stem may remain intact and functioning in hydranencephalic infants.

* Accompanied with this condition are many effects in which include seizures, hydrocephalus, increases in head circumference,impairment in vision/ body temperature regulation and cerebral palsy. Infants affected by hydranencephaly live typically short lives being no longer than 1 year of age. Lastly, there are no viable treatment options for this condition and only supportive care is available.

'''Iniencephaly'''

* Another neural tube defect involving severe backward bending of the head (retroflexion) with subsequent spinal distortions as well. Affected infants have no neck and hence the scalp of the head is directly joined to the skin of the back (also skin of the face connected to skin of the chest). Other conditions that develop along with iniencephaly are cyclopia, cephalocele and anencephaly. The development of this condition is not solely due to one factor but from various causes (both genetic and environmental factors).

* There are specific factors that have been shown to increase the occurrence of this condition. Malnutrition, reduced folic acid intake and elevated levels of homocysteine in blood are environmental factors that increase the risk of iniencephaly <ref><pubmed> 22408660 </pubmed></ref>. Intake of certain drugs such as anti-histamines and sulphonamide/tetracycline (antibiotics) have also increases this risk <ref><pubmed> 22439066 </pubmed></ref>. Furthermore obesity has been shown to have a significant effect on the incidence of iniencephaly with 1.7-3 fold increase <ref><pubmed> 18538144 </pubmed></ref>.

* In terms of treatment, folic acid supplementation as well as avoiding certain drugs such as those outlined above significantly reduces the occurrence of this condition.

'''Spina Bifida Cystica'''

* A neural tube defect in which involves either the formation of a meningocele or myelomeningocele. Of the two, the meningocele, is the least debilitating in that a cyst-like structure forms when the neural tube does not close properly. The membrane (meninges) is pushed into openings of the vertebrae where spinal fluid builds up within the cyst. The myelomeningocele leads to severe problems as the portion of the nueral tube that is unfused allows the spinal cord to protrude through. As a result, neuronal tissue is highly exposed due to myeloschisis as well as infections and hence may lead to severe complications.

'''Spina Bifida Occulta'''

* A neural tube defect that has minimal complications in comparison to other defects. Furthermore, this defect is hidden in that a tethered spinal cord may arise as well as a thicker filum terminale and diastematomyelia (spinal cord split into two). It is also important to note that no cysts form as opposed to the other more severe spina bifida defects.

==References==

<references/>

2014 Group Project 7

2014-10-22T00:34:14Z

Z3418981: /* Brain Development */

{{ANAT2341Project2014header}}
=Neural - CNS=

==Introduction==

The Central Nervous System (CNS) is a complex network of neurons which are responsible for the sending, recieving and integration of information from all parts of the body, serving as the processing center of the bodies nervous system. The CNS controls all bodily functions (sensory and motor), consisting of 2 main organs; The Brain and Spinal Cord

==='''Brain'''===

The Brain is the body's control center consisting of 3 main components; Forebrain, Midbrain and Hindbrain. The forebrain functions in receiving and processing sensory information, thinking, perception, and control of motor functions as well as containing essential structures; Hypothalamus and Thalamus, which are responsible in motor control, autonomic function control and the relaying of sensory information. The Midbrain along with the Hindbrain together form the brain-stem and are both important in auditory and visual responses

==='''Spinal Cord'''===

The Spinal Cord is a cylindrical shaped structure composes of nerve fiber bundles which is connected to the brain via the brain-stalk formed from the Midbrain and Hindbrain, running through the spinal canal in the vertebrae (in animals) from the neck to the lower back. The spinal cord plays the important role of transmitting information from bodily organs and external stimuli to the brain and acts as a channel to send important signals to other parts of the body. The nerve bundles in the Spinal cord are divided into

1) Ascending bundles - Transmits Sensory information from the body to the brain

2) Descending bundle - Transmits Motor function information from the brain to the body

Before fetal period, nerulation occurs that ectoderm forms initial structure of the CNS and folds upon itself to form neural tube towards the end of week 3. The head portion becomes the brain, which further differentiates into forebrain, midbrain and hindbrain, while the middle portion becomes the brain stem. Around week 5, neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain). By week 7, the prosencephalon divides into the telencephalon and the diencephalon, while the rhombencephalon divides into the metencephalon and the myelencephalon. The formation of these 2 additional structures creates 5 primary units that will become the mature brain.

In this website, CNS development during the fetal period, the current research models and finding, historic findings and abnormalities that can occur in the fetal period is identified.

==Development during fetal period==

[[File:Neural-development.jpg|800px]]

Timeline of human neural development <ref>Report of the Workshop on Acute Perinatal Asphyxia in Term Infants, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Child Health and Human Development, [http://www.nichd.nih.gov/publications/pubs/acute/acute.cfm NIH Publication No. 96-3823], March 1996.</ref>

===Cellular process===

In developing CNS, there are 4 major cellular processes, including cell proliferation, cell migration, cell differentiation and cell death. They are a cascade of events that the earlier occurring process may influence the subsequently occurring ones, but a late-occurring event cannot influence the earlier ones.

'''1. cell proliferation'''

* This process is responsible for the formation of neurons and glia.

* Begins around 40th embryonic day and is almost complete around the 6th month of gestation <ref><pubmed>4203033</pubmed></ref>

* Location: occurs in germinal matrix that comprised of ventricular and subventricular proliferative zones of cells.

# Ventricular zone: This is the proliferative zone that appears first which is a pseudostratified columnar epithelium <ref><pubmed>5414696</pubmed></ref>. In some part if the developing CNS, this is the only proliferative zone and therefore it is assume that ventricular zone produces all of the cell types. For example, in the hippocampus, all of the neurons of the major subdivisions (areas CA1, CA2 and CA3) are derived from the ventricular zone. There is substantial movement of the nuclei as they move through the cell cycle <ref><pubmed>7204662</pubmed></ref>. The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone <ref><pubmed>12764033</pubmed></ref>.
# Subventricular zone: This is the second proliferative zone that appears in some parts of the developing CNS. Most of the glia for most of the brain are produced in this zone, therefore it is important to the adult brain <ref><pubmed>8523077</pubmed></ref>. In some parts of the brain, there is the production of a significant number of neurons in this zone <ref><pubmed>9712307</pubmed></ref>. For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain <ref><pubmed>1713238</pubmed></ref>. In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.

[[File:Somatosensory cortex of E20 rat.jpeg|300px]]

Image of coronal sections of somatosensory cortex of E20 rat showing boundaries between the ventricular zone (VZ), inner subventricular zone (iSVZ) and outer SVZ (oSVZ) through staining <ref><pubmed>22272298</pubmed></ref>

'''2. cell migration'''

* This is the process that influences the final cell position by migrating the cells produced from the two ventricular zones.

* The postmitotic young neurons migrate from the proliferation site to their ultimate position in two different ways. [[Image:CNS_passive.jpg|frame|300x200px|Passive cell displacement and outside-to-inside spatiotemporal gradient]][[Image:CNS_active.jpg|frame|400x250px|Active cell migration and inside-to-outside spatiotemporal gradient]]

# Passive cell displacement: Moving of cells in this way does not require active locomotor activity. In some parts of the developing CNS, the postmitotic neurons that only move a very short distance from the border of proliferative zone are displaced outward by newly produced cells (figure). This results in an “outside-to-inside” spatiotemporal gradient that the earliest generated neurons are located farthest away from the proliferative zone, where the youngest generated ones are located closest to the zone. This pattern can be found in the thalamus, hypothalamus, spinal cord, retina, dentate gyrus of the hippocampal formation and many regions of the brainstem.
# Active migration: This requires the active participation of the moving cell for its displacement which neurons move at a greater distance and the migrating young neuron bypasses the previously generated cell (figure). This results in an “inside-to-outside” spatiotemporal gradient. This pattern can be found in well-laminated structure including cerebral cortex and several subcortical areas.
[[Image:Internurons migration in cerebral cortex.jpg|frame|200x200px|Image of interneurons migration and interactions with radial glia in the developing cerebral cortex]]

'''3. cell differentiation'''

* This is the process begins after the migration of neuronal and glial cells to the final positions and it is responsible for the generation of a wide variety of cells in the adult CNS. During the differentiation, each neuron grows out its axon and dendrites.

* Time: starts about the 25th month of gestation until adolescence

* The axons do not grow directly to their final targets, but they transiently innervate areas and cells in two ways that the connections cannot be found in adult brain. These two types of transient connections are not mutually exclusive and can be found within a single population of cells.

#Divergent transient connections: one neuron innervates more cells than normal which will be eliminated by the reduction of projection area.
#Convergent transient connections: several neurons innervate one target neuron where only one of these neuronal connections is found in adult.

'''4. cell death (apoptosis)'''

* This is the process where elimination of transient connections occurs and two mechanisms, axonal retraction and neuronal pruning <ref><pubmed>10532616</pubmed></ref>, are involved.

# Axonal retraction: The transient connections are removed by the recession of the collaterals of the neuron’s axon or by the shrinking of the terminal arborisation of the axon.
# Neuronal pruning: The transient connections are removed through a selective cell death that neurons die due to the failing to establish projections.

* Critical for appropriate brain development

 

== Brain Development ==

- The human brain development begins in the 3rd gestational week with the start marked by differentiation of the neural progenitor cells

- By the end of the embryonic period in gestation week 9 (GW9), the basic structures of the brain and CNS are established as well as the major parts of the Central and Peripheral nervous systems being defined <ref><pubmed>21042938</pubmed></ref>

- The early fetal period (mid-gestation) is a critical period in the development of the neocortex, as well as the formation of vital cortical neurons which are vital in the brain processing information

'''During Fetal Period'''

- Extends from the ninth gestational weeks through to the end of gestation

- Gross morphology of the developing brain undergoes striking change during this time, beginning as a smooth structure and gradually developing the characteristic mature pattern of gyral and sulcal folding

- Brain development begins rostral in GW8, proceeding caudally until it is complete at GW22

- Secondary sulci emerge between GW30-35

- Formation of Tertiary sulci begins during GW36 and into the postnatal period

- Different population of neurons form grey matter structures in many regions of the brain including hindbrain and spinal column, cerebellum, midbrain structure and the neocortex

- Neurons, after production, migrate away from the proliferative regions of the VZ, the neurons that will form the neocortex migrate in an orderly fashion forming the 6 layered neocortical mantle

- The major fibre pathways make up the brain white matter

- AS development proceeds, the brain becomes larger and the primary mode of neuronal migration from the VZ changes.

'''Increase in size and weight'''

[[File:Brain ventricles and ganglia development 03.jpg|300px]]

Image of brain and ventricular development <ref><pubmed>19339620</pubmed></ref>

[[File:Brain fissure development 02.jpg|300px]]

Image of brain fissure development <ref><pubmed>19339620</pubmed></ref>

'''sulcation and gyration'''

Sulcation: development of sulci. Primary sulci appear as shallow grooves on the surface of the brain and become more deeply infolded. Secondary sulci are formed from the development of side branches of primary sulci <ref name=”PMID11158907”><pubmed>11158907</pubmed></ref>

Gyration: development of gyrus that occurs late during fetal development until end of the pregnancy or even later after birth <ref name=”PMID11158907”><pubmed>11158907</pubmed></ref>

{| class="wikitable"
|-
! Weeks !! Visible anatomical details
|-
| 20-21 || smooth, "lissencephalic" brain, wide Sylvian fissures
|-
| 22-23 || corpus callosum; beginning of calcarine and hippocampal fissures and of callosal sulci
|-
| 24-25 || start of opercularization of Sylvian fissures; calcarine fissures and cingular sulci
|-
| 26 || central and collateral sulci
|-
| 27 || marginal and precentral sulci
|-
| 28 || postcentral and intraparietal sulci
|-
| 29 || inferior frontal sulci; bright white matter, dark cortical ribbon
|-
| 30-31 || narrower ventricular system and subarachnoid spaces
|-
| 32 || superior and inferior temporal sulci
|-
| 33 || external occipitotemporal sulci
|-
| 34-35 || close to final shape of gyration
|-
| 36-37 || completed opercularization of Sylvian fissures; narrow pericerebral fluid spaces; dark subcortical fibres and corona radiata
|-
| 38-40 || dark posterior limbs of internal capsules
|}

table obtained from <pubmed>20608424</pubmed> <ref><pubmed>20608424</pubmed></ref>

== Spinal Cord Development ==
The spinal cord is formed from parts of the neural tube during embryonic and fetal development

=== Meninges Development ===

== Historical Research and Findings ==

Historical knowledge, predating when modern research techniques were made available, in understanding and studying the Central Nervous structure of humans and other animals were gathered by various investigations by Pathologists, Anatomists, Physiologists from the early 1800’s.

{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1824 || Luigi Rolando first discovered a method to study Central Nervous system structures via cutting chemically hardened pieces of brain tissue into thin sections for microscopical observations
|-
| 1833 || Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar
|-
| 1842 || Rolando’s method of observing CNS structures was perfected by Benedikt Stilling by cutting series of consecutive slices of the same tissue, this allowed the ability to trace nerve tracts and establish spacial relations
|-
| 1858 || Joseph von Gerlach brings forth a new process to differentiate between the different microstructures in the brain by treating the sample to a solution of ‘Carmine’.
This solution made the sample no longer appear homogenous under the lens but able to be differentiable to its components
|-
| 1889 || Camille Golgi comes forth with the procedure of impregnating hardened brain tissues with silver nitrate solution which resulted in the staining of nerve cells.
Possibility to trace cellular prolongations definitely to their termini now present.
Ramon y Cajal announces his discoveries.

Old theory of union of nerve cells into an endless mesh-work is discarded altogether, the new theory of isolated nerve elements ‘theory of neurons’ is fully established in its place <Ref><Pubmed>17490748</pubmed></ref>

|}

'''HOW DO WE REFERENCE BOOKS?'''
A History of Science by Henry Smith Williams, M.D., LL.D. assisted by Edward H. Williams, M.D. (1904)

==Current research models and findings==
<pubmed>19786578</pubmed>
<pubmed>21501576</pubmed>
<pubmed>21492152</pubmed>
<pubmed>24664314</pubmed>
<pubmed>24639464</pubmed>
<pubmed>24284205</pubmed>
<pubmed>24177053</pubmed>
<pubmed>24051984</pubmed>
<pubmed>24996922</pubmed>

===Current Research===

Most previous studies describe overall growth of brain based upon ''in utero'' imaging studies with the use of magnetic resonance imaging (MRI) and ultrasound; however, complicated folding of the cortex in adult brain is due to different rates of regional tissue growth. In the following study, maps of local variation in tissue expansion are created for the first time in the living fetal human brain, in order to examine how structural complexity emerges in fetal brain.

'''Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero'''
<ref><pubmed> 21414909 </pubmed></ref>

File:Cortical growth rate patterns (redrawn diagram).JPG
[[Image:Cortical_growth_rate_patterns_(redrawn_diagram).JPG|frame|right|middle|300x250px|This is a redrawn diagram illustrating a lateral view of T statistic map of the model of cortical plate volume increases. Red indicates regions that have a significantly higher growth rate compared to average cerebral growth rate. Growth rate decreases in yellow, black and blue regions respectively. Redrawn from <ref><pubmed>21414909</pubmed></ref>]]

Recent development in fetal MRI motion correction and computational image analysis techniques were employed in this study to help with the understanding of the patterns of local tissue growth. These techniques were applied to 40 normal fetal human brains in the period of primary sulcal formation (20–28 gestational weeks). This time period covers a developmental stage from the point at which only few primary sulci have developed until the time at which most of the primary sulci have formed, but before the emergence of secondary sulci on MRI. This developmental period is also important clinically, since the clinical MRI scans are also performed at this gestational age. Therefore it is important to describe the normal growth patterns in this period in order to be able to recognise abnormalities in the formation of sulci and gyri.

Techniques mentioned previously were utilised to quantify tissue locations in order to map the tissues that were expanding with a higher or lower growth rate than the overall cerebral growth rate. It was found that relatively higher growth rates were detected in the formation of precentral and postcentral gyri, right superior temporal gyrus, and opercula whereas slower growth rates were found in the germinal matrix and ventricles. Additionally, analysis of the cortex illustrated greater volume increases in parietal and occipital regions compared to the frontal lobe. It was also found that gyrification was more active after 24 gestational weeks. These maps of the fetal brain were used to create a three-dimensional model of developmental biomarkers with which abnormal development in human brain can be compared.

The following are recent studies that use a similar model to what was described above:

'''Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age'''
<ref><pubmed> 23307634 </pubmed></ref>

* In this study longitudinal cortical hemispheric asymmetries were mapped in infants using surface-based morphometry of magnetic resonance images

* Some of the findings of this study:

-Sexual dimorphisms of cortical asymmetries are present at birth with males having larger sizes of asymmetries.

-The left supra marginal gyrus is much more posterior compared to the right supra marginal gyrus at birth and this position difference increases for both males and females by 2 years of age.

-The right superior temporal parieto-occipital sulci are significantly larger and deeper than those in the left hemisphere while the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages.

* It was concluded in this study that early hemispheric structural asymmetries are inherent and gender related.

'''Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia'''
<ref><pubmed> 23307635 </pubmed></ref>

* In this study, they investigate the geometry of inter-hemispheric white matter connections in patients with schizophrenia with a particular focus on sexual differences in white matter connection.

* They find a correlation between the sex-dependent abnormality in the geometry of white matter connecting the two hemispheres and the severity of schizophrenia

'''Asymmetry of White Matter Pathways in Developing Human Brains'''
<ref><pubmed> 24812082 </pubmed></ref>

* The use of high-angular resolution diffusion imaging tractography has allowed the above article to investigate the emergence of asymmetry of white matter pathways in fetal brains typically being less than 3 years of age comparable to adult brains over 40 years of age. Furthermore, the high spatial resolution generated from the use of this imaging technique provides a detailed image in order to shed some light on the irregular spatial pattern of white matter systems and whether primary associative functions form before higher cognitive functions. This is essentially important in the application of learning difficulties at a youthful age due to improved and revised understanding on cognitive development in children.

* It was found that the emergence of asymmetry of white matter pathways in children less than 3 years of age specifically the association of higher order cognitive functions (arcuate fasciculus) was not observed however the emergence of the ILF pathway in FA occurred. Hence asymmetry while present in prenatal development, a more resilient and sturdy asymmetry develops at a later age.

* The study however was unable to use a wider range of age intervals for brains obtained (only up to 3 years) and hence was unable to investigate the asymmetry of white matter pathways during important periods further.

'''Cortical Overgrowth in Fetuses With Isolated Ventriculomegaly'''
<ref><pubmed> 23508710 </pubmed></ref>

* The condition fetal ventriculomegaly is characterised by dilation of lateral ventricles whilst sharing associations with other malformations. It was hypothesised that using relative brain overgrowth as marked measure of altered brain development is due to the occurrence of ventriculomegaly and to evaluate this brain overgrowth through the use of magnetic resonance imaging (MRI) of fetuses isolated with enlarged ventricles (3rd and 4th ventricles as well as cerebrospinal fluid). Furthermore, significant changes to thalamic volumes, basal ganglia and white matter did not occur between cohorts.

* The study found that there was a sufficient increase in brain volume (overgrowth) of fetuses that had ventriculomegaly in comparison to controls. Also, larger lateral ventricle volumes were yielded with fetuses with ventriculomegaly assessed via 2-dimensional movement of the atrial diameter (ultrasound and MRi) as well as a larger total brain tissue volume. This provides support for the hypothesis in that brain overgrowth can be used as a marked measure for ventriculomegaly with results showing that overgrowth was not localised in one region but across both hemispheres and thus lead to a neural deficit in children (altered neural connectivity).

* Hence, this study has assisted in the improved understanding of the effects of ventriculomegaly on cognition, language and behaviour in children.

===Future Research===

==Abnormalities==

===Microcephaly, Macrocephaly and Hydrocephalus===

[[Image: Occipital encephalocele associated with microcephaly.jpg|frame|right|middle|300x250px|Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia. <ref><pubmed>3271622</pubmed></ref>]]
Microcephaly and macrocephaly refer to abnormal head size. These abnormalities are seen in less than 2% of all newborns. Learning abnormalities and neurophysiological malfunctioning associated with these abnormalities are dependent on etiology, severity and patient’s age. The most frequent cause of macrocephaly is hydrocephalus.

'''Microcephaly'''

* Noticeable reduction in the size of brain is observed due to factors that kill the dividing cells in the ventricular germinal zone. These dividing cells give rise to brain cells (both neurons and glia).

* Microcephaly is specifically defined as a head size more than two standard deviations below the mean for age, gender and race.There are two diagnostic types of '''primary''' and '''secondary''' microcephaly.

* Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.
* Secondary Microcephaly: Abnormal development occurs during the last 2 months of gestation (prenatal period) in the secondary type.

* Microcephaly is caused by various factors that prevent normal proliferation and migration of cells during CNS development. These factors are divided into physical (irradiation, raised maternal temperature), chemical (anticancer drugs) and biological (infection of uterus due to rubella, cytomegalovirus and herpes simplex virus).

* Genetic defects and chromosomal disorders can also play a role.All of these factors result in destruction of the brain tissue (encephalopathy) with multiple areas of scarring and cyst formation.

'''Macrocephaly'''

* In patients with macrocephaly the head is enlarged.

* Macrocephaly is specifically defined as a head size more than two standard deviations above the mean for age, gender and race.

* Macrocephaly is a syndrome of diverse etiologies rather than a disease and the most frequent cause is hydrocephalus.

'''Hydrocephalus'''

[[Image: Arachnoid_cyst_with_hydrocephalus.jpg|frame|right|middle|300x250px|Magnetic Resonance image showing Arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>]]

* Progressive enlargement of head due to accumulation of cerebrospinal fluid in ventricles is known as hydrocephalus.

* Excessive accumulation of cerebrospinal fluid is due to an imbalance between the formation and absorption of cerebrospinal fluid (communicating hydrocephalus) or obstruction of circulation of cerebrospinal fluid (non-communicating hydrocephalus).

* Multiple abnormalities such as brain tumours, congenital malformations and inflammatory lesions are associated with hydrocephalus.

* In a patient with hydrocephalus, cerebrospinal fluid accumulation results in raised intracranial pressure which in turn results in enlarged ventricles and skull. Raised intracranial pressure is further associated with behavioural change, headache, papilloedema (oedema of the optic nerve) and herniation syndromes (subfalcine, uncal and cerebellar).

* Enlargement of cranial sutures, progressive thinning of cerebral walls and lamination of cerebral cortex are all manifestations of hydrocephalus. Symptoms include significant deficits in motor skills (damage to pyramidal tracts) and cognitive functioning.

* The extent of brain damage depends on the underlying factor and developmental stage in which damage occurs. Hydrocephalus can be treated by shunting the excess fluid from the lateral ventricles into the heart or peritoneal cavity.

===Fetal Alcohol Syndrome===
<ref><pubmed> 23809349 </pubmed></ref>

* Severe alcohol consumption during pregnancy and especially at critical stages of development (i.e. just after neural tube closure) can result in fetal alcohol syndrome (FAS).

* FAS is the most severe form of a spectrum of physical, cognitive and behavioural disabilities, collectively known as fetal alcohol spectrum disorders (FASD).

* Mental retardation is the most serious abnormality associated with FAS. In addition, FAS is typically associated with central nervous system abnormalities, impaired sensation, impaired motor skills and lack of coordination.

* Patients diagnosed with FAS have a small head size relative to height, and demonstrate minor abnormalities of the face, eye, heart, joints, and external genitalia. (image)

* Ethanol in alcohol directly damages neurons by acting as an agonist for GABA receptors in the brain as well as interfering with many other receptors. Ethanol can also alter body’s metabolism by an indirect effect on neurons that modulate the secretion of hormones. In addition, it is postulated that malnutrition intensified by alcohol abuse is another cause of FAS since FAS is more common in individuals with low socioeconomic status.

* Nutritional deficiency and alcohol abuse inhibit the metabolism of folate, choline and vitamin A which are necessary for neurodevelopment. Therefore supplementation of these three nutrients to mothers with Disorder Binge drinking or low socioeconomic status may reduce the severity of FAS.

* Consequently, pregnant mothers need to be aware of the risk associated with consuming even small amounts of alcohol. FASD and FAS represent a serious problem for both the individuals and society but are easily preventable.

{| style="width:40%; height:170px" align="center"
|-
| [[Image: Fetal alcohol syndrome.jpg|frame|250x250px|The standard facial features of individuals with FAS include microcephaly (decreased cranial size at birth), flat mid-face with short palpebral fissures, short nose with a low bridge, long smooth or flat phylum with a narrow vermilion of the upper lip [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756137/figure/f1-arh-34-1-4/]</ref> ]]
|}

===Iodine deficiency===

[[Image:Infant with congenital hypothyroidism.jpg|frame|right|middle|300x250px|A) A three- month old infant with untreated congenital hypothyroidism. Image illustrates hypotonic posture, myxedematous facies., macroglossia, and umbilical hernia. B) Same infant- close-up of the face, showing myxedematous facies, macroglossia, and skin mottling. C) Same infant- close up showing abdominal distension and umbilical hernia. <ref><pubmed>2903524</pubmed></ref>]]

* Iodine is required for the synthesis of thyroid hormones. Thyroid hormones play an important role in the regulation of metabolism of an organism. Additionally, thyroid hormones take part in early growth and development of most organs particularly the brain, during fetal and early post-natal development. <ref><pubmed> 11264481 </pubmed></ref>

* The physiological role of thyroid hormones is to coordinate the time of different developmental events through specific effects on the rate of cell differentiation and gene expression during fetal and early postnatal development. Iodine deficiency may affect thyroid hormone synthesis during this critical period which will further result in hypothyroidism and brain damage. The clinical outcome is mental retardation. <ref><pubmed>7581959</pubmed></ref>

* All degrees of iodine deficiency (mild: 50-99 μg/day, moderate: 20-49 μg/day and severe≤20 μg/day) affect thyroid function of both mother and the neonate as well as mental development of the child. The damage increases with the degree of deficiency; overt endemic cretinism is the most severe consequence.

* Iodine deficiency disorders refer to complications that arise when the recommended dietary allowance of iodine is not met. These complications include thyroid function abnormalities and when iodine deficiency is severe, endemic goitre and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality.

* Iodine deficiency represents the world’s greatest cause of preventable brain damage and mental retardation, resulting of a loss of 10-15 IQ points globally. Therefore it is essential that the recommended dietary requirement for iodine is met, especially during pregnancy and lactation (200–300 μg/day). <ref><pubmed>10750030</pubmed></ref>

* Clinical manifestations of hypothyroidism include: Myxedematous facies (condition characterized by thickening of the skin, blunting of the senses and intellect, and laboured speech), jaundice, a puffy face and a wide posterior fontanelle with open sutures. The nasal bridge is flat. The mouth may be slightly open revealing macroglossia. Further examination would reveal bradycardia and a protuberant abdomen with a large umbilical hernia. Neurologic examination findings include hypotonia with delayed reflexes. Skin may be cool to touch and mottled in appearance due to circulatory compromise.<ref><pubmed>2903524</pubmed></ref>

===Abnormalities associated with apoptosis and migration of cells in the fetal CNS===

* The migration of cells and cell death are critically important to fetal brain and CNS development. Abnormalities in each of these processes, programmed cell death (apoptosis) in particular, have been shown to result in severe developmental abnormalities in experimental animals. Apoptosis is critically important for appropriate brain development; certain areas in brain may experience up to 50% cell death. <ref><pubmed> 11589424 </pubmed></ref>

In an experiment conducted by kuida et. al 1996, it was observed that mice that were deficient for CPP32 (a protease responsible for apoptosis), were born at a lower frequency than expected, were smaller in size compared to the normal mice and died at an early age. Brain development is significantly affected in CPP32-deficient mice resulting in a variety of hyperplasia and disorganised cell development. <ref><pubmed>8934524</pubmed></ref>

On the other hand, disrupted neuronal migration can lead to an abnormality in cell position. When this happens, the neurons are said to be heterotopic. Abnormalities in neuronal migration have been studied extensively in human cerebral cortex where these defects are associated with a variety of syndromes and diseases, ranging from behavioural disorders (including some forms of schizophrenia, dyslexia and autism) to extremely severe mental retardation and failure to thrive. <ref><pubmed>10532616</pubmed></ref>

===Neural Tube Defects===

Defects which affect the either the brain or the spinal cord in which openings remain. Grastulation occurs in week 3 of embryonic development where specialized cells (dorsal side) structurally change shape leading to the formation of the neural tube. If the neural tube does not close or fuse together properly, then openings remain which lead to various neural tube defects such as Spina bifida cystica and Spina bifida occulta.

'''Anencephaly'''

* A neural tube defect involving abnormal development of the brain and incomplete skull formation leading to high infant mortality rates with infants being stillborn or dying within a few hours after birth.

* The failure of the neural tube to close around the 23rd and 26th day into embryonic development is characteristic of this condition. As a result, the forebrain is severely affected where the cerebrum does not grow and hence partial growth occurs only. The cerebrum has a key importance in maintaining thought, consciousness and coordination whilst having no intact cerebrum rules out the probability of the affected fetus gaining consciousness .

* Increasing one's dietary intake of folic acid notably reduces the incidence of neural tube defects. Consuming 0.4mg of folic acid is sufficient to induce these results.

* Since incomplete skull formation occurs, brain tissue becomes exposed due to the absence of bone covering and therefore leading to further complications.

'''Encephaloceles'''

* Another neural tube defect in which a sac-like projections (including membrane covering) that occurs around the 3-4 week of embryonic development in which neural tube closure has not successfully occurred. The location of these protrusions varies but can be naso-frontal (nose and head), naso-ethmoidal (nose and ethmoid bone), naso-orbital (nose and eyes), meningocele (cerebrospinal fluid and membrane covering) and encephalomeningocele (meningocele with brain tissue as well).

* These sac-like protrusions lead to a variety of abnormal effects which include cerebro-spinal fluid build-up in brain, microcephaly, hydrocephaly, mental retardation, developmental problems, uncoordinated muscle movement and seizures. Consumption of folic acid again has been shown to significantly reduce the occurrence of encephaloceles in infants.

'''Hydranencephaly'''

* A very rare neural tube defect in which the cerebral hemispheres are destroyed (necrotic tissue) with the occupied space being replaced by cerebro-spinal fluid, cortex and white matter remnants within a membranous sac. Interestingly, this condition can also develop in the postnatal peroid due to viral infections or traumatic brain injury. The brain stem may remain intact and functioning in hydranencephalic infants.

* Accompanied with this condition are many effects in which include seizures, hydrocephalus, increases in head circumference,impairment in vision/ body temperature regulation and cerebral palsy. Infants affected by hydranencephaly live typically short lives being no longer than 1 year of age. Lastly, there are no viable treatment options for this condition and only supportive care is available.

'''Iniencephaly'''

* Another neural tube defect involving severe backward bending of the head (retroflexion) with subsequent spinal distortions as well. Affected infants have no neck and hence the scalp of the head is directly joined to the skin of the back (also skin of the face connected to skin of the chest). Other conditions that develop along with iniencephaly are cyclopia, cephalocele and anencephaly. The development of this condition is not solely due to one factor but from various causes (both genetic and environmental factors).

* There are specific factors that have been shown to increase the occurrence of this condition. Malnutrition, reduced folic acid intake and elevated levels of homocysteine in blood are environmental factors that increase the risk of iniencephaly <ref><pubmed> 22408660 </pubmed></ref>. Intake of certain drugs such as anti-histamines and sulphonamide/tetracycline (antibiotics) have also increases this risk <ref><pubmed> 22439066 </pubmed></ref>. Furthermore obesity has been shown to have a significant effect on the incidence of iniencephaly with 1.7-3 fold increase <ref><pubmed> 18538144 </pubmed></ref>.

* In terms of treatment, folic acid supplementation as well as avoiding certain drugs such as those outlined above significantly reduces the occurrence of this condition.

'''Spina Bifida Cystica'''

* A neural tube defect in which involves either the formation of a meningocele or myelomeningocele. Of the two, the meningocele, is the least debilitating in that a cyst-like structure forms when the neural tube does not close properly. The membrane (meninges) is pushed into openings of the vertebrae where spinal fluid builds up within the cyst. The myelomeningocele leads to severe problems as the portion of the nueral tube that is unfused allows the spinal cord to protrude through. As a result, neuronal tissue is highly exposed due to myeloschisis as well as infections and hence may lead to severe complications.

'''Spina Bifida Occulta'''

* A neural tube defect that has minimal complications in comparison to other defects. Furthermore, this defect is hidden in that a tethered spinal cord may arise as well as a thicker filum terminale and diastematomyelia (spinal cord split into two). It is also important to note that no cysts form as opposed to the other more severe spina bifida defects.

==References==

<references/>

User:Z3418981

2014-10-21T14:58:14Z

Z3418981: /* Individual Assessments */

==Lab Attendance==
Lab 1 --[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 12:45, 6 August 2014 (EST)
http://www.ncbi.nlm.nih.gov/pubmed
[http://www.ncbi.nlm.nih.gov/pubmed PubMed]
[http://www.ncbi.nlm.nih.gov/pubmed/25084016 PMID25084016]
<pubmed>25084016</pubmed>
Lab 2 --[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 12:17, 13 August 2014 (EST)
Lab 3--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 12:58, 20 August 2014 (EST)
Lab 4--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 11:48, 27 August 2014 (EST)
Lab 5--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 11:42, 3 September 2014 (EST)
Lab 6--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 11:51, 10 September 2014 (EST)
Lab 7--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 11:17, 17 September 2014 (EST)
Lab 8--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 12:30, 24 September 2014 (EST)
Lab 9--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 12:22, 8 October 2014 (EST)
Lab10--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 12:11, 15 October 2014 (EST)

==Individual Assessments==
===Lab 1 Assessment===
'''Reference''': [http://www.ncbi.nlm.nih.gov/pubmed/24726222 PMID24726222]

<pubmed>24726222</pubmed>

'''Summary of the Method'''

In this study, genomic DNA was extracted from the umbilical cord blood of a total of 185 newborn females. Patients included 60 infants conceived by intracytoplasmic sperm injection (ICSI) and 73 infants conceived by in vitro fertilization (IVF) all recruited from a number of IVF centers across Canada. In addition, 52 naturally conceived patients were recruited from hospitals across the Lower Mainland in British Columbia, Canada. A karyotype or comparative genomic hybridization (CGH) analysis of the chromosomes was performed for all newborn cases. Cases were not included if congenital and/or chromosome abnormalities were present.

The X-chromosome inactivation (XCI) assay was performed to determine the XCI skewing of different tissues in different parts of the placenta by assaying allelic ratio of methylated alleles at the androgen receptor(AR), fragile X mental retardation 1 (FMR1), and DXS6673E loci. Fisher's exact test was a statistical method used to compare the frequency of mildly skewed (≥75%) and extremely skewed (≥90%) XCI in the patients. The parental nature of the skewed allele was determined by automated fluorescence analysis which was used to measure the AR alleles of the maternal decidua of the placenta.

'''Summary of the Results'''

There was no statistically significant difference between the ICSI, IVF and NC populations in the frequency of skewing ≥75% (7.0% vs. 5.7% vs. 2.0%, respectively; P=.523) or ≥ 90% (0 vs. 1.4% vs. 2.0%, respectively; P=.747). The mean level of skewing between the ICSI, IVF, and ICSI groups also was not significantly different (63.7% vs. 61.8% vs. 60.7%, respectively). Only two samples were found to have extremely skewed cases (≥90% skewing): one IVF (89.6%) and one NC (90.6%). The parental origin of the preferentially inactivated X chromosome in these extremely skewed cases was maternal for IVF and paternal for NC case.

'''Reference:''' [http://www.ncbi.nlm.nih.gov/pubmed/24399508 PMID24399508]

<pubmed>24399508</pubmed>

'''Summary of the Method'''

All of the pregnancies conceived by in vitro fertilization in Denmark from 1995 to 2005 (n = 18 787) was included in this study using the data reported to the National In Vitro Fertilisation register (IVF register). Information about the pregnancy outcomes as well as cycle-specific information on the type and date of treatment, and the occurrence of pregnancy, abortions and deliveries was also obtained from IVF.

A study published by Virkus et al. on venous thromboembolism in pregnant and puerperal women in Denmark was used as a reference (Virkus et al., 2011). This study was used as a reference since the population used in this study (727 VTE patients among the 805 464 pregnancies recorded in the Danish National Patient Registry from 1995 to 2005) is ideal and comparable to the present study. Consequently, venous thrombosis incidence rates in pregnancies conceived by in vitro fertilization were compared with venous thrombosis incidence rates in reference pregnancies, by calculating incidence rate ratios.

'''Summary of the Results'''

The venous thrombosis incidence was significantly increased in pregnancies after in vitro fertilization. The overall ratio of venous thrombosis incidence rate during in vitro fertilization pregnancies to reference pregnancies was 3.0 (95% CI 2.1–4.3). The overall venous thrombosis incidence rate was 28.6 per 10 000 pregnancy-years (95% confidence interval (CI) 20.6–39.6) for pregnancies after in vitro fertilization compared to 10.7 per 10 000 woman-years in reference pregnancies.

Reference used in the "Summary of the Method" section:

<pubmed>21713323</pubmed>

--[[User:Z8600021|Mark Hill]] These articles are well summarised and relevant. Please do not use all capitals in sub-headings and follow the site formatting. (5/5)

===Lab 2 Assessment===
[[File:An overview of the process of fertilisation in mutant C. elegans.jpeg|300px]]

Image showing the process of fertilisation in mutant C. elegans<ref><pubmed>15086962</pubmed>|[http://www.biomedcentral.com/1471-213X/4/3 BMC Developmental Biology]</ref>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 16:19, 21 August 2014 (EST) This is all correct. The image is very large (1.15 MB), perhaps a smaller image version could have been uploaded. You can adjust the resolution and size in most image editing programs. (5/5)

<references/>

===Lab 3 Assessment===

====Abnormalities associated with neural development====
<pubmed>12454899</pubmed>
<pubmed>25007063</pubmed>
<pubmed>16530991</pubmed>
<pubmed>7504639</pubmed>
<pubmed>19651588</pubmed>
<pubmed>25135350</pubmed>
<pubmed>25128525</pubmed>
<pubmed>24397701</pubmed>

--[[User:Z8600021|Mark Hill]] These are all relevant references, and a sentence description for selection would also help. (4/5)

===Lab 4 Assessment===

'''1. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.'''

<pubmed>24104453</pubmed>

The inhibitory effect of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) on the growth of C6 glioma cells was investigated in this study. Initially C6 cells were cultured with different concentrations of hUC-MSCs in order to examine whether the hUC-MSCs inhibition of glioma cell growth was mediated by soluble factors. It was found that hUCMSCs-CM exhibited a concentration-dependent inhibitory effect on C6 cell growth which in turn suggested that soluble factors in the conditioned media from hUC-MSCs were responsible for the inhibition of C6 glioma cells. Subsequently, flow cytometric analysis was used to test the effect of the soluble factors derived from hUCMSCs-CM on the cell cycle of glioma cells. Using this method, cell cycle status of C6 cells treated with different concentrations of hUCMSCs-CM was identified. It was observed that C6 cells treated with hUCMSCs-CM showed increases in the G0/G1 phase and reductions in the S phase compared to the control group (0 % hUCMSCs). These results suggested that hUC-MSCs could potentially inhibit the growth of C6 glioma cells and stop the cell cycle at the G0/G1 phase by secreting some soluble factors.

Western blot analysis was then performed and it was observed that the expression levels of β-catenin and c-Myc in C6 cells were reduced in the conditioned media derived from hUC-MSCs. These results indicated that some soluble factors secreted from hUCMSCs-CM may play a role in the inhibition of Wnt signaling pathway in C6 cells. Further investigations demonstrated that the secretion levels of dickkopf-1 (DKK1) were positively correlated with the concentrations of hUCMSCs-CM. Subsequently, the hypothesis that stem cells secreted Wnt inhibitors, such as DKK1, which could inhibit the Wnt signaling in tumor cells, was made.

Neutralizing antibody against DKK1 was then added to the hUCMSCs-CM in order to further confirm that DKK1 is a key factor in the inhibitory effect of hUCMSCs on C6 cell proliferation. It was observed that the inhibitory effect of hUC-MSCs on C6 cells was decreased when DKK1 was neutralized by anti-DKK1 antibody. Moreover, it was found that conditioned media from hUC-MSCs transfection with siRNA targeting DKK1 mRNA altered the regulation of the Wnt signaling in C6 cells. Therefore, it was concluded that hUC-MSCs inhibited C6 glioma cell growth by secreting DKK1, an inhibitor of Wnt pathway.

'''2.There are a number of developmental vascular "shunts" present in the embryo, that are closed postnatally. Identify these shunts and their anatomical location.'''

There are three developmental vascular "shunts" present in the embryo that are closed postnatally:

Foramen ovale (Foramen Botalli)

Foramen ovale is an opening in the inter-atrial septum which allows blood from the right atrium to enter the left atrium during foetal development. Foramen ovale allows blood to bypass the non-functional foetal lungs while the foetus obtains its oxygen from the placenta. A layer of cells exist over the foramen ovale during fetal development which acts as a valve and is known as septum primum. After birth, increased pulmonary blood flow and pulmonary venous return to left heart causes the pressure in the left atrium to be higher than the pressure in the right atrium. The increased left atrial pressure results in the closure of foramen ovale after birth.

Ductus venosus

In the foetus, the ductus venosus shunts blood from the left umbilical vein directly to the inferior vena cava and therefore allows oxygenated blood from the placenta to bypass the liver. Ductus venosus plays an important role in shunting oxygenated blood to the fetal brain.The ligamentum venosum which is usually attached to the left branch of the portal vein is the fibrous remnant of the ductus venosus

Ductus arteriosus (Ductus Botalli)

Ductus arteriosus connects the pulmonary artery to the proximal descending aorta. Ductus arteriosus prevents the output of the right ventricle from entering the unexpanded, fluid-filled and non-functional foetal lung. Therefore only enough blood reaches the foetal lungs to maintain the developing lung tissue. Ductus arteriosus becomes the ligamentum arteriosum after closing at birth.

===Lab 5 Assessment===

'''Azygos Lobe'''

Azygos lobe (also known as Adam's lobe) is a congenital malformation of the lung due to an alteration in the embryonic development of the azygos vein. Azygos lobe is a common congenital anomaly with an incidence of 1 in 100-200 of anatomical samples and 0.4-0.5% of chest radiographs. In general, azygos lobe means accessory lobe or supernumerary lobe of lung. There are three main types of azygos lobes: upper azygos lobe, lower azygos lobe and the lobe of azygos vein. The upper and lower azygos lobes are of very little clinical significance compared to the lobe of azygos vein.

During normal fetal development, the right posterior cardinal vein (precursor of the thoracic segment of the azygos vein) migrates over the apex of the right upper lung to occupy a medial mediastinal position. In the case of azygos lobe, an abnormal migration of this vein occurs and it penetrates into the right upper lobe. The right posterior cardinal vein carries the parietal and visceral layers of pleura with it and forms an accessory fissure made up of a total of four pleural layers called mesoazygos. The lung parenchyma located medial to the accessory fissure is called the azygos lobe.

Subsequently in the case of azygos lobe, the abnormal azygos vein crosses the apex of lung instead of its border and forms a fissure which separates the apex of the lung into medial and lateral parts. The medial part of the ruptured apex forms the lobe of azygos vein. Therefore the azygos lobe is a variably separated portion of the right lung and not an independent segment. Moreover, some course variability of the phrenic nerve have also been observed in the presence of an azygos lobe which is of importance when performing surgery.

'''References'''

<pubmed>16333920</pubmed>
<pubmed>23705047</pubmed>

===Lab 7 Assessment===

1. Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.

<pubmed>14561778 </pubmed>

In this study, the functional characterization of ''Arx'', a gene encoding homeodomain-containing proteins that are potentially involved in endocrine pancreas development is being investigated. To study the role of this gene in pancreas development, loss-of-function mutant mice were generated by targeting the genes in mice embryonic stem cells. Arx-deficient mice developed severe and early-onset hypoglycaemia, dehydration and weakness and died only two days after birth. Immunohistochemical analysis of Arx mutant pancreas then revealed an absence of mature endocrine α cells and an increased number of β and δ cells. However, islet morphology and the total number of endocrine cells remained intact. These results suggested a requirement of Arx transcription factor for α-cell fate acquirement and a repressive action on β-and δ-cell destiny, which is exactly the opposite of the phenotype observed in Pax4-deficient mice.

Therefore, the results of this study suggest that a mutual cross-regulatory inhibition of these factors exist so that Arx promotes α-cell cycle and prevents β- and δ-cell proliferation whereas Pax4 favours β- and δ-cell fate and inhibits α-cell proliferation. It was demonstrated using multiplex reverse transcriptase PCR (RT-PCR) that Pax4 and Arx transcripts accumulate in Arx and Pax4 mutant mice, respectively. These results further suggest that the antagonistic functions of Arx and Pax4 for proper islet cell specification are based on the pancreatic levels of the respective transcripts.

2. Identify the embryonic layers and tissues that contribute to the developing teeth.

a) Neural-crest-derived mesenchymal cells that differentiate under the influence of the enamel epithelium form odontoblasts. Odontoblasts secrete predentin which calcifies to form dentin.

b) Epithelial cells give rise to ameloblasts that produce the enamel of the tooth.

c) Periodontal ligament is a special connective tissue structure that holds the tooth in place and surrounds the tooth root coating of cementum.

===Lab 8 Assessment===

1. Provide a brief time course and overview of embryonic development of either the human testis or ovary. (2-3 paragraphs)

'''Embryonic Development of Ovaries'''

The gonads are developed from mesothelium lining the posterior abdominal wall, underlying mesenchyme and primordial germ cells. The initial stages of gonadal development are the same in males and females and occur during the fifth week with the formation of the gonadal ridge, a bulge on the medial side of the mesonephros. Finger like epithelial cords then grow into the underlying mesenchyme forming the gonadal cords. In females (XX), the cortex of the indifferent gonad differentiates into an ovary, and the medulla regresses.

Primordial germ cells are the first population of cells that migrate through the primitive streak in early gastrulation. These cells then lie at the hindgut yolk sac junctional region and subsequently migrate into the gonadal ridge in early embryonic development. The primordial germ cells enter the underlying mesenchyme during week 6 and are incorporated in the gonadal cords.

The gonads of males and females are identical before week 7 and are called indifferent gonads. Germ cells migrate into the indifferent gonads. The ovaries (females, XX) or testis (males, XY) then begin to develop and the successive structure of germ cells differentiates for each of the two sexes. In females with XX, genes on X-chromosome (such as Wnt-4 and DAX-1) along with an autosomal gene are necessary for initiation of female pathway. Ovary development is a slow process in female embryos and the ovary is not histologically identifiable until week 10.

[http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00012-6--s0095&isbn=978-1-4377-2002-0&uniqId=466385578-2 Moore: The Developing Human, 9th ed. Chapter 12]

2. Include an image from the historic genital embryology section of the online notes in your description.

[[File:Bailey330.jpg|500px]]

'''Image showing a section through the ovary of a human foetus of 4 months.'''

===Lab 9 Assessment===

'''Group 1 (Respiratory System)'''

The introduction is written well and it provides sufficient background information on the anatomy and development of respiratory system. It is also well-divided into the two conducting and respiratory zones. However it lacks to provide information on what is included in the page such as current research and abnormalities. In addition, this assignment is aimed to describe the fetal development but fetal period does not seem to be the focus in this project. I understand that it is difficult to focus on fetal period, especially for the respiratory system but if that is the case, you can mention why you’re also including information on embryonic and postnatal periods in your introduction. There are also a few spelling errors within the text that should be corrected (such as ‘id’ instead of ‘is’). The images of the histological sections are relevant but there is no caption for any of the photos and it is difficult to understand what they are trying to show. There is no information provided on the summary of the image either and one of the images is missing copyright information. In addition, the text as well as the images in the introduction needs to be referenced on the page.
The table of lung development stages is simple and very well summarised. The content of this section relates to the learning objectives of embryology however there is not enough explanation considering that this section is the main part of the project. In order to aid with understanding of the development of lungs, simple diagrams could be drawn that show different developmental stages. You can then explain more on what happens in each stage.

The first paragraph of the current research and findings about the conducting system and functional unit is already discussed in the introduction and therefore there is no need to include it again in this section. Try to include more precise information on the findings of each study and also talk about the new models that have aided in understanding of the development of this system. For example you can elaborate more on the three geometrical models that are proposed in the review study in 2013(there is no information under the “current models” subheading at the moment- you can put this information there). Also it is a good idea to organise the research findings in chronological order so that new advancements are found in more recent studies (2011 must come before 2013).The two alveolar cell types under current research is irrelevant – I would put them under introduction. Also I don’t understand why the image of lung diseases is under current research (maybe put that image under abnormalities?)

The historic findings section is very informative, especially the “surfactant” section. You can also tabulate the data to make it look neater. However from my understanding, in this section we also need to provide information on the history and stages of fetal lung development. I know it is hard to find this information but maybe try looking for review articles that summarise the findings of past studies in this area. The abnormality section is well written and thorough with so many abnormalities named and described. The only suggestion is to include more images.

Overall, this web page shows a very effective team work and it is clear that work has been allocated with each person working on a different subheading. You only need to pay attention to minor issues mentioned above. Also in terms of referencing, there are many in-text references missing in different sections. It is very important to format these references correctly under one ‘references’ subheading at the end of the page (instead of having a separate reference list for each section).

'''Group 2 (Renal System)'''

Introduction is very well-written with a precise background on the renal system anatomy and function. There is also a brief introduction on the development of renal system in both embryonic and fetal period as well as the abnormalities that can be associated with the development of this system. Therefore the reader can gain an expectation of what is going to be included in the wiki-page by reading the introduction first. In-cite referencing is also used to support the information provided. I suggest including an image of the anatomy of organs in the renal system to make the introduction even more perfect.

The developmental timeline is a very good way to start the development section; however your timeline is missing some of the important features such as when the ureter and urethra develop. I would also recommend tabulating the data so that it looks neater. I also recommend placing the “current research models” section after the sections describing the development of different organs so that the timeline is located right before the section explaining the development of “kidney”. Dividing the development into different organs and the subheadings used (especially under the heading of “kidney”) are very appropriate and are evidence of significant research that has been done for this project. The information provided is very comprehensive; however it is all formatted in paragraphs. I would suggest using dot points or adding your own diagrams and figures to summarise the text and make it more interesting to the readers. For example the diagram used to illustrate the anatomical position is very helpful and effectively summarises the information to readers. You should also make sure that you remove the image used for the development of kidney since it cannot be used due to copyright. In addition, most images are missing the ‘student template’ so make sure the template is added.
There isn’t any information under the heading ‘historic findings’. I understand that this section is a bit more difficult than the rest. A suggestion I can make is to search for old articles in PubMed (by adjusting the year) which can include key historical events. Review articles that summarise historic findings related to renal development may also be helpful.

The content under “current research” is very interesting and relevant. A minor spelling error exists (“buy” instead of “by”). To further improve this section, I suggest searching for recent models that aid in better understanding of kidney development. The abnormalities section is very informative. Each disease is explained thoroughly and concisely. The images are also very helpful with the understanding of clinical manifestations. To improve this section, I suggest using dot-points and using more images. Make sure you include information for “Horseshoe Kidney” as well.

Overall, the content used in this project was very relevant and showed extensive research and understanding. The use of headings and subheadings was very appropriate which showed that the work has been well-divided among members. The use of in-cite referencing is also very good and references are all listed under one subheading; however, some references are used more than once, this can be fixed and they can be all combined under one number.

'''Group 3 (GIT)'''

Introduction is good with brief background information on the anatomy of the GIT which is an appropriate starting point for the readers. Fetal development is also described in the introduction, however I suggest including more information on embryonic period and how that leads to fetal development so that the rest of the page can focus more on the fetal stages. I also suggest including parts of each of the major subheadings in the introduction such as the common abnormalities and the recent finding. An image illustrating different organs of GIT can also help with better understanding of the anatomy. There is no referencing in the introduction to support the information provided.
Regarding the timeline section, the information needs to be tabulated in order to make it easier to compare between organs. Another alternative is to include a small timeline for each of the organs at the beginning of each section. It is very good that each stage of the timeline has been separately referenced; this shows the extensive research that has been conducted.

The recent finding section focuses on only one study in 2006 on hedge-hog signalling pathway. There are a lot of interesting and more recent studies that can be included in this section. As a starting point, you can search for recent models that help in better understanding of GIT development.
The information under each of the foregut, midgut and hindgut is very detailed and comprehensive; however the structure does not flow through the whole page with mid-gut including different subheadings and diagrams. In my opinion you should break up the foregut and hindgut sections into smaller subheadings and use diagrams like the ones used for midgut. Potential images can also be used in these sections. Additionally, the anorectal deformities under the ‘hindgut’ section can be placed under the deformities section. The “Midgut” section includes very good information and the drawings are helpful in understanding the concept however they need to be captioned.

This project does not include historic findings. I understand that this section is a bit more difficult as it is hard to find information on it. A suggestion I can make is to search for old articles in PubMed (by adjusting the year) which can include key historical events. Review articles that summarise historic findings related to GIT development may also be helpful. The abnormalities are precisely discussed and are relevant to the topic but as mentioned before, I suggest putting all the abnormalities under one subheading to make it easier for the viewers to navigate.

Overall, the main key points are addressed in this project and the content demonstrates extensive research and a good understanding of the concept. In order to facilitate learning and to make it more interesting and understandable for viewers, some of the text can be summarised in diagrams. Dot -points can also be used in some parts instead of paragraphs. The use of hand written drawings was creative and aided in understanding however I would suggest stating that the drawing is handwritten in your page. If the drawing is copied from another image, then the source of that image needs to be included as well. Also a more complete description of the image will make it easier to understand.

'''Group 4 (Genital System)'''

An introduction is recommended as it is usually a good starting point. I suggest starting by giving background information on the anatomy of male and female genital systems. You can then talk about the embryonic period and give a brief summary of how this period is different to fetal period. You can then briefly mention the significant events that occur during fetal period and the sections you are including in your project (including abnormalities and research findings).

The table in the system development is a good summary however it looks a bit messy at this stage. I suggest having two different tables for male and female, avoid using all capital letters and bold texts in the table. I also suggest starting the development section with a brief paragraph on early stages of development. The image included under ‘system development” is a very good summary but it needs to be captioned and referenced. I also recommend re-uploading the image in a smaller size to improve the quality. The use of the video is also very creative. Well done for finding this helpful video!! It would be perfect if you could reference the video and maybe include a few sentences on what it is showing. Overall, the development section is very good with the use of different methods to help in learning. To make this section perfect, you can add some details in paragraphs to explain more on different stages of development.

There is a lot of information under “current models” which shows extensive research, however I find this section hard to follow. Using paragraphs instead of dot points will result in a more coherent flow. Also the studies need to be referenced appropriately; it would be a good idea to include the name and year of the article in the text. The division into “current research” and “current models” is a smart thing to do however in both sections the amount of information provided for male is much more than female therefore more research needs to be done for female. I like how a self-drawn image is used; it would be a good idea to include a description for the image (rather than “alt text”). Also make sure that all the references are listed at the end under one reference subheading instead of having different references for each section. Also, great job for historic findings! This is the most difficult section but you have managed to include detailed information. Similar to current research section however, most of the information found is for the development of male system. Try to add to historic findings on female system if possible.

Abnormalities section includes a significant number of abnormalities with causes and treatment of each abnormality addressed precisely. I also like how you divided this section into female, male and both. Information is well referenced and helpful images are included. Make sure that your images are referenced. If self-drawn images are used, then you can briefly mention that in your text. I would also recommend adding more images for other diseases to illustrate the clinical manifestations of each disease. Overall this group has done an extensive research and the methods used (such as drawings and videos) are very creative and helpful. Well done!

'''Group 5 (Integumentary System)'''

The presentation of this page is very well with multiple images being used and text organised into tables and dot points. The introduction is short however includes necessary information regarding what is being included in the project. I recommend adding background information on anatomy of the skin (explaining on different layers) and other structures as well as a brief summary on the embryonic development of the system so that fetal development can be further expanded throughout the project.

The development overview section is done very well and is divided into different sections each explaining the development of a different structure. The use of table, images and bullet points has made the page look very interesting. The table of the timeline in the ‘Development Overview’ is done very well and the use of histological images is excellent as it helps in visualising the anatomy at each stage. There is however no proper referencing, copyright information or student template for any of the images. The table under “teeth” is also a very good summary of events during fetal period. I recommend including self-drawn diagram as well, since this is the only feature missing from your project. You can include a drawing of the different layers of skin (possibly in the introduction section). I also suggest putting all the references under one reference list at the end of the page instead of having references at the end of each section.

The “some research finding” section is presented well with a different background colour to other sections (it is similar to recent findings in mark’s wiki pages). This makes the page look very visually appealing! You have elaborated on two out of four research papers which is very good. However I recommend describing the other two papers as well and even including more papers (It would be perfect if you could provide research papers for different structures). I like how the “more research papers” can be expanded for anyone interested.

Historic findings section is very well researched considering it is difficult to find information for this section. The ‘Abnormalities’ section is also perfect and complete with all four diseases having sufficient information and appropriate references. The images are also relevant and illustrate the clinical manifestations well. Overall this page is very well-organised and only minor issues mentioned above need to be fixed.

'''Group 6 (Endocrine System)'''

The endocrine system is made up of different glands and there is so much information that could be provided regarding the the anatomy and development of each gland so very well done for working on the difficult system! I like how you have divided the page into different glands; I can imagine having the four major headings (development, historic findings, current research and abnormalities) and then subdividing it into different organs would be more confusing. Just try to follow the same structure for each organ; I recommend doing a brief introduction, anatomy, function, timeline, development, historic findings, current research and abnormalities for each organ. It is important that your page has a coherent flow by following the same structure for each subheading. An overall introduction on endocrine system might also be very useful. You can then include in the introduction how you are planning to structure your page.

The content and number of references show that extensive research has been conducted. It would be great if you could use in-text referencing and place all the references under one subheading at the end of the page. Arranging the information into tables is a great idea but you need to complete your tables for pineal gland, hypothalamus and placenta. You also need to include more images in your page (you can include at least one image for the abnormality associated with each organ). There are a few images included at the moment and they are well done and appropriately referenced. You can also try to draw your own diagrams. In my opinion, a timeline showing the development of all the systems would be a great way to compare the different stages in development of different endocrine glands. Maybe think about including this in a table after you finished all the sections; it is a good way to connect the information provided separately for each organ. Overall the content of this page is very good but it needs to be formatted so that it can have a coherent flow. Also there is no information for introduction, historic findings and development of placenta, make sure you include those.

'''Group 8 (Musculoskeletal System)'''

In this project the development section is well-researched however introduction, historical findings, current models and abnormalities still need some work. The development section is very informative with appropriate use of in-text referencing. However, to prevent having bulks of text, you can create diagrams and flow charts or use bullet points. It would also be great if you could provide a timeline under “muscle development general timeline” section. Background embryonic development section is very helpful but we do not need this much information on embryonic period for this project. You can summarise this information in introduction, so that it provides a starting point and fetal development can be further expanded through the project. The rest of the information regarding system development seems to cover the important points; however it still needs work (for e.g. “second trimester muscular development” section is clearly missing some bits).

The abnormality section only includes one abnormality (Duchenne Muscular Dystrophy). This abnormality is well described but it needs to be referenced. An image of the clinical manifestation of the disease can clearly help with understanding. There are lots of other abnormalities that you can include in this section (We learnt from the musculoskeletal development lecture that musculoskeletal conditions form 20% of all abnormalities at birth). You can also refer to “limb development lecture” to find information on musculoskeletal abnormalities.

Finding information on historic findings might be a little challenging. A suggestion I can make is to search for old articles in PubMed (by adjusting the year). These articles can include key historical events. Review articles that summarise historic findings related to musculoskeletal development may also be helpful. You also need to find information on current research.

Finally, you should add an introduction to your project. It seems like you are more focused on muscular development rather than “musculoskeletal” so you can mention that in your introduction. You can also show creativity by drawing your own diagrams, adding images, and tabulating timeline data. You should also fix the references by putting all the references under one subheading in the bottom of the page.

===Lab 10 Assessment===

'''Research article- The Involvement of Neural Retina Pax6 in Lens Fiber Differentiation'''

<pubmed>15855760</pubmed>

Specific interactions that occur between neural and ectodermal tissues as a result of regulated gene expression and controlled signalling events are necessary for proper eye formation. The homeobox gene Pax6 is proved to be essential for eye development in both vertebrates and invertebrates. Pax6 expression for the retina anlage has been revealed to be crucial in the development of different retinal cells. In this study, lab techniques such as plasmid construction, in ovo microelectroporation, in situ hybridization and section immunostaining were performed to examine the expression of several transcription factors in the lens of Pax6-negative optic vesicle eye in chick embryos. Initially, it was shown that the expression of a negative version of Pax6 isoform in developing optic vesicles of chick embryos prevents proper lens development at the lens vesicle stage as well as resulting in optic cup deformation. Following this finding, the molecular events underlying deformed lens formation were further explored.

A Pax6-EnR gene which effectively repressed endogenous Pax6 activity in neurons was used to examine the role of Pax6 in optic cup formation and lens differentiation. It was observed that overexpression of Pax6-EnR in optic vesicle results in abnormal optic cup formation. In addition, a severely deformed lens was formed in the Pax6-negative optic vesicle eye. The development of the lens was significantly delayed at stage 24 and the lens was dramatically smaller than the control lens. It was concluded from these findings that Pax6 expression plays an important role in lens development.

The remaining part of this study was focused on determining the molecular pathways underlying the previous findings. Initially, the expression of L-Maf (a transcription factor that has a crucial role in lens differentiation) was investigated. There was almost no reactivity for L-Maf in the deformed lens while the contralateral lens showed normal L-Maf expression. The expression of c-Maf was investigated afterwards. C-Maf is a transcription factor that is strongly expressed in both epithelial and fiber cells. Unlike L-Maf, C-Maf transcripts were normally expressed in both control and malformed lens. This result suggests that the function of Pax6 is not required for c-Maf expression in the lens at stage 24.

Finally, to illustrate how the Pax6-EnR effect is coupled to the down-regulation of L-Maf, the expression of fibroblast growth factor FGF8, a diffusible factor that was shown to activate L-Maf in non-lens cells was investigated. It was found that FGF8 is down-regulated in the neural tissue. This finding suggests that Pax6 in neural retina regulates FGF8 expression, which may maintain L-Maf expression in the lens to be essential for subsequent lens fiber differentiation.

[https://embryology.med.unsw.edu.au/embryology/index.php/Sensory_-_Vision_Development#Lens Sensory-Vision development Wiki page]