Embryology - User contributions [en-gb]

2014 Group Project 7

2014-10-29T10:11:19Z

Z3419587:

{{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:Z3419587

2014-10-29T01:34:59Z

Z3419587: /* Lab 11 Assessment */

{{StudentPage2014}}

==Lab Attendance==
Lab 1 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 12:45, 6 August 2014 (EST)

Lab 2 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:11, 13 August 2014 (EST)

Lab 3 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:12, 20 August 2014 (EST)

Lab 4 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:45, 27 August 2014 (EST)

Lab 5 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:02, 3 September 2014 (EST)

Lab 6 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:04, 10 September 2014 (EST)

Lab 7 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:05, 17 September 2014 (EST)

Lab 8 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:13, 24 September 2014 (EST)

Lab 9 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 10:49, 8 October 2014 (EST)

Lab 10 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:07, 15 October 2014 (EST)

Lab 11 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:23, 22 October 2014 (EST)

Lab 12 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 10:58, 29 October 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 1 Assessment==
<pubmed>25071849</pubmed>
summary:
This study was done to compare the clinical outcomes between fresh embryo transfers and frozen-thawed embryo transfers.

A total of 1891 cycle contains 1150 fresh embryo transfers and 741 frozen-thawed embryo transfers were studied. All data were transferred directly to SPSS 18 and analyzed.

A long gonadotropin releasing hormone (GnRH) agonist protocol was used in all cycles. Clinical pregnancy was defined by the observation of a gestational sac with or without a fetal heartbeat on ultrasound evaluation on the 30th day after embryo transfer. The number of sacs was taken as the number of implantations.

The results showed that there was a higher clinical pregnancy rate in fresh cleavage-stage embryo transfers than frozen-thawed cleavage-stage transfers but the clinical pregnancy rates were not different significantly.

<pubmed>25077107</pubmed>
summary:
The study was done to investigate the effect of vitamin D levels on implantation and clinical pregnancy rates in infertile women following in vitro fertilization (IVF).

173 women underwent IVF were included in the study under 3 criteria, including aged 18-41 years, follicle stimulating hormone level 12 IU/L or lower and able to provide informed consent. Vitamin D was determined by serum 25(OH)D levels and samples were collected before oocyte retrieval, while implantation was determined by the presence of a gestational sac, visible by ultrasonography.

χ2 and Student t tests or Mann-Whitney U tests were used to analyze categorical and continuous variables respectively. Multi-variable logistic regression was used to evaluate the relation between serum 25(OH)D level and implantation and clinical pregnancy after adjustment fpr parameters known to influence the IVF sucesss.

The results showed that women with sufficient levels of 25(OH)D had significantly higher rates of clinical pregnancy per IVF cycle started than that with insufficient levels. It also found that implantation rates were higher, but not statistically significant, in the sufficient 25(OH)D group. Therefore, the findings suggested that women with sufficient vitamin D levels are significantly more likely to achieve clinical pregnancy following IVF.

--[[User:Z8600021|Mark Hill]] These are both good articles and summaries (5/5)

==Lab 2 Assessment==
[[File:Development_of_nuclear_transfer_embryos.jpeg|300px]]

<ref><pubmed>23251622</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0051778]</ref>
<references/>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 15:27, 22 August 2014 (EST) I have uploaded a smaller version of this image, but you still need to adjust the size as it appears on your page to 300px and include the reference. Please use jpg format images if possible. You need to reformat the reference as shown in the class tutorial. (4/5)

==Lab 3 Assessment==
===Neural development during fetal period===
<pubmed>21042938</pubmed>
<pubmed>12060827</pubmed>
<pubmed>23727529</pubmed>
<pubmed>16905335</pubmed>
<pubmed>17848161</pubmed>
<pubmed>18760424</pubmed>
<pubmed>16971596</pubmed>
<pubmed>17032846</pubmed>

--[[User:Z8600021|Mark Hill]] These are useful references, I needed a single sentence on why you had selected these references for your section. (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>16099997</pubmed>
summary:
The paper presented the possibility of the therapeutic use of cord stem cells in Parkinson’s disease.

Human mesenchymal stem cells from Wharton’s jelly of the umbilical cord were isolated and induced to transform into dopaminergic neurons in vitro. 12.7% of the cells were successfully transformed and generated through a stepwise culturing in neuron-conditioned medium, sonic hedgehog and FGF8. The cells were transplanted into the striatum of rats previously made Parkinsonian by unilateral striatal lesioning with the dopaminergic neurotoxin 6-hydroxydopamine HCl (6-OHDA). The effects of the transplantation were examined by quantification of rotations in response to amphetamine at 1, 2, 3 and 4 months after transplantation.

It was found that the transplantation of the stem cells corrected the lesion-induces amphetamine-evoked rotation and the cells in the striatum were still viable 4 months after transplantation. These results give the possibility to human umbilical mesenchymal stem cells in treating Parkinson’s disease. However, it is suggested that the examination of the toxicity of growth factor and medium used is important, and the observation of the effects and side-effects for more than 1 year after transplantation is required before human studies

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

Ductus arteriosus: connection between the most cranial part of the pulmonary trunk and dorsal aorta

Ductus venosus: connection between the intra-abdominal umbilical vein and the inferior vena cava

Foramen ovale: located in interatrial septum, connecting left and right atria

Umbilical arteries: branch from the internal iliac arteries in the pelvis and connect to the placenta

Umbilical vein: connection between placenta and portal vein, or ductus venous

==Lab 5 Assessment==
===Congenital Laryngeal Webs===

Congenial laryngeal webs are caused by failure of recanalization of the laryngotracheal tube during the third month of gestation. Findings suggested that congenital laryngeal webs can be explained by abnormal development of the epithelial lamina, the laryngeal cecum, or the vestibulotracheal duct <ref><pubmed>16798587</pubmed></ref>. It has also been reported that there is an association between anterior webs, the most common laryngeal webs, with deletions of chromosome 22q11<ref><pubmed>10699233</pubmed></ref>.

In human embryo, congenial laryngeal webs are formed during embryogenesis of the laryngotracheal groove <ref><pubmed>20376251</pubmed></ref>. The developing laryngeal is temporarily obliterated by actively proliferating epithelium, however, the lumen is normally re-established as the vocal cords. This abnormality is resulted from incomplete resorption of the epithelial layer during the 7th and 8th week of intrauterine development.

references:

<references/>

==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. (pancreas)'''

In this study, the distribution of chromogranin A, insulin, and glucagon in 25 human fetal pancreases was studied. Immunohistochemical reactions were carried out and sections of pancreas were labelled with antibodies to chromogranin A, insulin and glucagon.

Immunopositive reaction to chromgranin A was resulted from week 8 of development onwards. During the development of pancreas, the population of endocrine cells increased and pancreatic islets are formed. The majority of cells in the pancreatic islets were found to be chromogranin A that located in the cytoplasm. Chromogranin A immunoreactive cells were also found in glandular ductal epithelium of 8-9-week fetuses, suggesting that the cells formed a population of precursors of endocrine cells without synthesizing hormones.

The express of chromogranin A, which is higher than that of insulin and glucagon, during differentiation of pancreatic endocrine cells suggested that this can be a marker for studies of the mechanisms of endocrine development of pancreas.

reference:
<pubmed>24824718</pubmed>

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

Tooth germ: aggregation of cells derived from the ectomesenchymal cells from neural crest and ectoderm of first arch. It is then organized into 3 components of the tooth germ, which are the enamel organ, dental papilla and dental follicle for the teeth development.

==Lab 8 Assessment==
'''1. Provide a brief time course and overview of embryonic development of either the human testis or ovary. (2-3 paragraphs)'''

Gonads are developed from the mesothelium of the posterior abdominal wall, the adjacent mesenchyme and the primordial germ cells. The development begins in week 5 where the mesothelium medial to the mesonephros of the developing kidneys thickens and forming the paired gonadal ridges.

The primordial germ cells are the precursors of oocytes that they migrate from the yolk sac to the mesenchyme of the gonadal ridges between weeks 3 to 5 and incorporate into the primary sex cords. The sex cords extend to the medulla of the future ovary and regress by week 8.

During week 8, gonad begins to develop into ovary due to the stimulation from germ cells. The primitive medullary cords in the ovary degenerates and the primordial germ cells differentiate under the influence of placental gonadotropins. The germ cells undergo mitotic divisions and differentiate into several million oogonia. Around week 16 to week 20, the primitive follicles organize within the fetal ovarian cortex. By 5-6 months gestation, the primitive follicles are enveloped by a layer of epithelial cells and become primordial follicles. During the development, the ovaries descend into the pelvis by the third month.

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

[[File:Bailey328.jpg|300px]]

Reference:
Bailey, F.R. and Miller, A.M. (1921). '''Text-Book of Embryology.''' New York: William Wood and Co.

==Lab 9 Assessment==
===Group 1===

The project was done well overall with lots of information and a good structure. However, I am a bit confused about the sections “respiratory” and “lung development stages”. I guess “lung development stages” is also under “respiratory”, but it seems that they are separated into two big sections.

The introduction clearly explains the development of respiratory system. It is good to divide respiratory tract into 2 main parts and explain them separately. It would be better if it includes a sentence like ‘this website will focus on fetal development of respiratory system.

Using table to explain different stages of lung development is a good idea. It would be easier to read if they are typed in point forms with some images included.

More images could be added under current research, models and findings for easier understanding. Some information should be added under current models.

The historic findings and abnormalities are good and informative.

Some images do not have the information about copyright. It would be better if there is a title for each image included.

In terms of referencing, they are missing in the sections under introduction, conducting zone and respiratory zone. In-text references are also missing in the table about the stages and features of lung development. Also, the images used have not been referenced. Reference list at the end rather than under each section should be used instead.

It is overall a good project and well-researched. More images can be included to balance with the huge amount of text.

===Group 2===

The introduction is good and describes the project well. It is good to mention the function of renal system. It would be better if it states that the website will be focused on fetal development, current research and abnormalities to give a better understanding of the content.

Information under historic findings is missing, it would be a good way to start it by looking at textbooks. Images, bullet points and table can be used for an easy understanding of this section.

Using timeline to summarise the development of kidney is a good idea, however it would be clearer if a table is used, more descriptions under each stages and some images are include. Also, some references should be included in this section.

There are a lot of details under development, current research and abnormalities. It would be easier to read if they are written in point form. It is a good idea to divide renal system into several parts (kidney, urethra…) for the explanation of development. For the abnormalities, it is well-researched but some of the details are missing. It would be better if the each type of abnormalities is discussed equally.

Regarding the images, it is good and clear to explain each of them. The only problem is that there is no copyright information under the file “kidney ascent.jpg”.

The project is informative but lacking some information under historic findings and the developmental timeline.

===Group 3===

Introduction is good as it describes and gives an overview about what is happening in the fetal period for foregut, midgut and hindgut. However, it would be better if it mentions that the project is focusing on fetal development, abnormalities, current researches, etc.

It is clear to separate the timeline of GIT development for hindgut, midgut and foregut. It is well-researched with much information in this section. However, it would be easier to follow if a table is used and images are included.

The hand-drawn images can explain the development well, however the blue colour for labelling is a bit difficult for reading. It would be better if a darker colour is used.

It is a good idea to explain the abnormalities in definition and the causes. Some more abnormalities can be included as well as images for better understanding.

There is only one reference in recent findings. More researches could be done in this section. Also, a section about historic findings could be included as well.

There are a few spelling errors, such as “esenchyme” in the hindgut section and “tot hat of” under midgut section. Some proof-readings are needed.

The referencing is overall good, but some more researches have to be done under some sections (abnormalities and recent findings). It is easy to follow as there is a reference list at the bottom of page.

It is overall a good project as the development during fetal period is well described. However, more information about recent findings and abnormalities could be included, with the use of images to illustrate the contents.

===Group 4===

The project would be easier to follow by having an introduction that give readers an idea about what is going to be covered in the website.

Under the section about system development, it contains lots of information and it is well researched. Using bullet points is good as it is easier to read, however some of them could be join together into a small paragraph which would increase the readability. It is good to see a related video about the development of reproductive system and it explains well about this topic.

It is a great way to explain abnormalities in terms of female, male, and both. Maybe try to put a table at the top to summarise the abnormalities so that it would be easier to follow. More images are needed in this section, just like the one illustrating abnormalities of uterus and vagina.

It is well-researched under historic findings, try to put more related images to make this section more interactive. Also, it would also be good to illustrate the content in this part by a timeline, followed by the explanation of each event.

In terms of referencing, in-text references are missing in the system development, current research and historic findings.

For the image file “Image.jpg”, which is about sexual differentiation, it is a good image that explains the differentiation clearly, however, it would be better to put a description or title below it to make it more relevant to the project. It is good to see some hand-drawn diagram and they match the topic and explain information well. I found it a bit hard to read the labels on the image “labelled drawing of testes.jpeg”, maybe upload the image by scanning rather than taking a photo of it would be better.

It is overall a well-researched project. The next thing to do is to include an introduction, some more in-text references and some related images.

===Group 5===

The introduction clearly states the content in the website, which is good as this can prepare the readers for understanding. However, it would be better if some information about integumentary system, such as functions, is included in this section.

The development of integument system includes a lot of information. They are presented in good structure by the use of table for skin and nail. It is a great way to put some images in the table for easy understanding of the description in the development of teeth.

The recent findings area is well-researched. I would suggest try to put the content into small paragraph or in several points as the amount of text is a bit too much. Some images should be included as well.

Abnormalities section is great with the help of the images. It would be good if some more abnormalities are included. There is a lot of details under historic findings, try to illustrate them with the help of images.

In-text references should be included in the sections under development, recent findings and historic findings.

The project is well prepared. It would be better if some more images are included and the function of integument system is stated in the introduction.

===Group 6===

Introduction is missing in the project. It would be great to include the functions of endocrine system and the contents that will be covered including system development, abnormalities, current research, etc.

There is a lot to cover in endocrine system, it is a great way to separate timeline and recent findings under each individual organ. Using table to illustrate the function of hormone is good, however, I think it would be better to have a summary of hormone in a table form at the top/the end of all individual organs. The parathyroid gland and pancreas are well-researched with the use of images. More information has to be included in other sections.

More work has to be done on abnormalities. Actually, they could be separated under each organ, just like current findings. It would also be good to see historic findings under each organ.

In terms of referencing, there is no in-text reference and the reference list at the bottom is empty at this moment. This project overall has a good structure, but more information and images are needed.

===Group 8===

Introduction is missing. Some information about the functions of the systems and topics going to be covered should be included here. The section ‘making gains’ is funny. However, more work has to be done to make it more interesting.

For the timeline, more information is needed. It would be great to include a table here and describe the changes during different stages (microfibers formation…). Table is also useful to explain the second trimester muscular development

The information under background embryonic development can be summarised and put under introduction as this project should be focused on fetal development.

It is great to have molecular and cellular regulation. However, more diagrams are needed here. It would be better if they are stated in several points rather than a big paragraph. Also, more images are needed for other sections, it would be good to draw the picture as well.

For abnormalities, in-text references are needed. Also, some more abnormalities should be included with the use of images to illustrate them.

Overall, there is a pretty good structure of the website. It could be improved by including some current and historic researches on this topic. Also, more images are needed (as there is none now) to make the webpage more interesting and informative. More contents should be included as well.

==Lab 10 Assessment==
'''Identify a recent research paper on sensory development (not hearing) and write a brief summary (several paragraphs) of the research methods and findings. Include at the end a link to the relevant wiki sensory notes page.'''

The researchers investigated the functional changes of olfactory sensory neurons (OSNs), which express mouse odorant receptor 23 (MOR23) with a known ligand (lyral), during the first postnatal month. Also, as olfactory marker protein (OMP) is recognized as a molecular marker for mature OSNs, it is hypothesized that OMP has an important role in functional maturation of OSNs.

In their research, genetically targeted MOR23-IRES (internal ribosome entry site)-tauGFP mice (with WT-MOR23 neurons) were used to record MOR23 neurons that coexpress green flurescent protein (GFP). Also homozyhous double mutant mice (with OMP -/- MOR23 neurons) were generated.

To investigate whether OSNs undergo functional changes during development, the odorant responses in individual neurons from animals at different ages (P0-P30, where P=postnatal day) were measured by perforated patch-clamp recordings on the dendritic knobs on individual OSNs. The results indicated that OSNs exhibit faster response kinetics during development. Furthermore, the effects of OMP deletion on functional properties of OSNs were also studied through the homozygous OMP -/- mice. It was found that OMP deletion results in OSNs with slow response kinetics, suggesting the OMP is necessary for the kinetic changes during the OSNs development. In addition, the selectivity of OSNs changes during the first postnatal month was tested and it was demonstrated that MOR23 neurons from P30 mice has higher selectivity to lyral. In terms of behavior test, the researchers also observed that WT but not OMP -/- mouse pups prefer the biological mother when the biological mother and another unfamiliar lactating female was given to choose.

In conclusion, the researchers showed that OMP is necessary for the maturation process in olfactory system. Also, MOR23 neurons from P30 mice have a faster response kinetics, higher sensitivity and higher selectivity when compared to the neurons from P0 mice. The results also suggested the maturation process of OSNs coincides with early development of the smell function and is critical for pups to form mother preference.

Reference: <pubmed>21414919</pubmed>

Links: [[Sensory_-_Smell_Development|Smell Development]]

==Lab 11 Assessment==

'''Identify a recent research article (using the pubmed tags to cite) on iPS cells and summarise in a few paragraphs the main findings of the paper.'''

Loss or dysfunction of trabecular meshwork (TM) cells is associated with the development of pathologically elevated intraocular pressure (IOP) that lead to gluacoma. In the research, it was demonstrated that mouse iPSCs can be induced to differentiate into trabecular meshwork (TM) like cells that are suitable for autologous transplantation.

TM-like cells (iPSC-TM) were produced by co-culture of mouse iPSCs with human TM cells for up to 21 cells. Morphological, immunohistochemical and functional tests were carried out to characterize the cells. The tests showed that the iPSC-TM cells were morphologically similar to human TM cells that they can express many markers of TM cells and also pluripotency markers includinf Nanog, Oct4, Sox2. The cells also developed the ability to phagocytose particles. In addition, the cells showed the behaviour characteristic of TM cells as there was an increase in the production and secretion and myocilin and matrix metalloproteinase-3 when the cells were exposed to dexamethasone or phorbol 12-myristate acetate respectively.

Therefore, iPSCs that resembles native TM cells can be induced. They can be transplanted into glucomatous eyes with elevated IOP as they can restore the function of TM.

<pubmed>25298418</pubmed>

User:Z3419587

2014-10-29T00:04:00Z

Z3419587: /* Group 1 */

{{StudentPage2014}}

==Lab Attendance==
Lab 1 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 12:45, 6 August 2014 (EST)

Lab 2 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:11, 13 August 2014 (EST)

Lab 3 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:12, 20 August 2014 (EST)

Lab 4 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:45, 27 August 2014 (EST)

Lab 5 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:02, 3 September 2014 (EST)

Lab 6 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:04, 10 September 2014 (EST)

Lab 7 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:05, 17 September 2014 (EST)

Lab 8 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:13, 24 September 2014 (EST)

Lab 9 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 10:49, 8 October 2014 (EST)

Lab 10 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:07, 15 October 2014 (EST)

Lab 11 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:23, 22 October 2014 (EST)

Lab 12 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 10:58, 29 October 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 1 Assessment==
<pubmed>25071849</pubmed>
summary:
This study was done to compare the clinical outcomes between fresh embryo transfers and frozen-thawed embryo transfers.

A total of 1891 cycle contains 1150 fresh embryo transfers and 741 frozen-thawed embryo transfers were studied. All data were transferred directly to SPSS 18 and analyzed.

A long gonadotropin releasing hormone (GnRH) agonist protocol was used in all cycles. Clinical pregnancy was defined by the observation of a gestational sac with or without a fetal heartbeat on ultrasound evaluation on the 30th day after embryo transfer. The number of sacs was taken as the number of implantations.

The results showed that there was a higher clinical pregnancy rate in fresh cleavage-stage embryo transfers than frozen-thawed cleavage-stage transfers but the clinical pregnancy rates were not different significantly.

<pubmed>25077107</pubmed>
summary:
The study was done to investigate the effect of vitamin D levels on implantation and clinical pregnancy rates in infertile women following in vitro fertilization (IVF).

173 women underwent IVF were included in the study under 3 criteria, including aged 18-41 years, follicle stimulating hormone level 12 IU/L or lower and able to provide informed consent. Vitamin D was determined by serum 25(OH)D levels and samples were collected before oocyte retrieval, while implantation was determined by the presence of a gestational sac, visible by ultrasonography.

χ2 and Student t tests or Mann-Whitney U tests were used to analyze categorical and continuous variables respectively. Multi-variable logistic regression was used to evaluate the relation between serum 25(OH)D level and implantation and clinical pregnancy after adjustment fpr parameters known to influence the IVF sucesss.

The results showed that women with sufficient levels of 25(OH)D had significantly higher rates of clinical pregnancy per IVF cycle started than that with insufficient levels. It also found that implantation rates were higher, but not statistically significant, in the sufficient 25(OH)D group. Therefore, the findings suggested that women with sufficient vitamin D levels are significantly more likely to achieve clinical pregnancy following IVF.

--[[User:Z8600021|Mark Hill]] These are both good articles and summaries (5/5)

==Lab 2 Assessment==
[[File:Development_of_nuclear_transfer_embryos.jpeg|300px]]

<ref><pubmed>23251622</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0051778]</ref>
<references/>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 15:27, 22 August 2014 (EST) I have uploaded a smaller version of this image, but you still need to adjust the size as it appears on your page to 300px and include the reference. Please use jpg format images if possible. You need to reformat the reference as shown in the class tutorial. (4/5)

==Lab 3 Assessment==
===Neural development during fetal period===
<pubmed>21042938</pubmed>
<pubmed>12060827</pubmed>
<pubmed>23727529</pubmed>
<pubmed>16905335</pubmed>
<pubmed>17848161</pubmed>
<pubmed>18760424</pubmed>
<pubmed>16971596</pubmed>
<pubmed>17032846</pubmed>

--[[User:Z8600021|Mark Hill]] These are useful references, I needed a single sentence on why you had selected these references for your section. (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>16099997</pubmed>
summary:
The paper presented the possibility of the therapeutic use of cord stem cells in Parkinson’s disease.

Human mesenchymal stem cells from Wharton’s jelly of the umbilical cord were isolated and induced to transform into dopaminergic neurons in vitro. 12.7% of the cells were successfully transformed and generated through a stepwise culturing in neuron-conditioned medium, sonic hedgehog and FGF8. The cells were transplanted into the striatum of rats previously made Parkinsonian by unilateral striatal lesioning with the dopaminergic neurotoxin 6-hydroxydopamine HCl (6-OHDA). The effects of the transplantation were examined by quantification of rotations in response to amphetamine at 1, 2, 3 and 4 months after transplantation.

It was found that the transplantation of the stem cells corrected the lesion-induces amphetamine-evoked rotation and the cells in the striatum were still viable 4 months after transplantation. These results give the possibility to human umbilical mesenchymal stem cells in treating Parkinson’s disease. However, it is suggested that the examination of the toxicity of growth factor and medium used is important, and the observation of the effects and side-effects for more than 1 year after transplantation is required before human studies

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

Ductus arteriosus: connection between the most cranial part of the pulmonary trunk and dorsal aorta

Ductus venosus: connection between the intra-abdominal umbilical vein and the inferior vena cava

Foramen ovale: located in interatrial septum, connecting left and right atria

Umbilical arteries: branch from the internal iliac arteries in the pelvis and connect to the placenta

Umbilical vein: connection between placenta and portal vein, or ductus venous

==Lab 5 Assessment==
===Congenital Laryngeal Webs===

Congenial laryngeal webs are caused by failure of recanalization of the laryngotracheal tube during the third month of gestation. Findings suggested that congenital laryngeal webs can be explained by abnormal development of the epithelial lamina, the laryngeal cecum, or the vestibulotracheal duct <ref><pubmed>16798587</pubmed></ref>. It has also been reported that there is an association between anterior webs, the most common laryngeal webs, with deletions of chromosome 22q11<ref><pubmed>10699233</pubmed></ref>.

In human embryo, congenial laryngeal webs are formed during embryogenesis of the laryngotracheal groove <ref><pubmed>20376251</pubmed></ref>. The developing laryngeal is temporarily obliterated by actively proliferating epithelium, however, the lumen is normally re-established as the vocal cords. This abnormality is resulted from incomplete resorption of the epithelial layer during the 7th and 8th week of intrauterine development.

references:

<references/>

==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. (pancreas)'''

In this study, the distribution of chromogranin A, insulin, and glucagon in 25 human fetal pancreases was studied. Immunohistochemical reactions were carried out and sections of pancreas were labelled with antibodies to chromogranin A, insulin and glucagon.

Immunopositive reaction to chromgranin A was resulted from week 8 of development onwards. During the development of pancreas, the population of endocrine cells increased and pancreatic islets are formed. The majority of cells in the pancreatic islets were found to be chromogranin A that located in the cytoplasm. Chromogranin A immunoreactive cells were also found in glandular ductal epithelium of 8-9-week fetuses, suggesting that the cells formed a population of precursors of endocrine cells without synthesizing hormones.

The express of chromogranin A, which is higher than that of insulin and glucagon, during differentiation of pancreatic endocrine cells suggested that this can be a marker for studies of the mechanisms of endocrine development of pancreas.

reference:
<pubmed>24824718</pubmed>

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

Tooth germ: aggregation of cells derived from the ectomesenchymal cells from neural crest and ectoderm of first arch. It is then organized into 3 components of the tooth germ, which are the enamel organ, dental papilla and dental follicle for the teeth development.

==Lab 8 Assessment==
'''1. Provide a brief time course and overview of embryonic development of either the human testis or ovary. (2-3 paragraphs)'''

Gonads are developed from the mesothelium of the posterior abdominal wall, the adjacent mesenchyme and the primordial germ cells. The development begins in week 5 where the mesothelium medial to the mesonephros of the developing kidneys thickens and forming the paired gonadal ridges.

The primordial germ cells are the precursors of oocytes that they migrate from the yolk sac to the mesenchyme of the gonadal ridges between weeks 3 to 5 and incorporate into the primary sex cords. The sex cords extend to the medulla of the future ovary and regress by week 8.

During week 8, gonad begins to develop into ovary due to the stimulation from germ cells. The primitive medullary cords in the ovary degenerates and the primordial germ cells differentiate under the influence of placental gonadotropins. The germ cells undergo mitotic divisions and differentiate into several million oogonia. Around week 16 to week 20, the primitive follicles organize within the fetal ovarian cortex. By 5-6 months gestation, the primitive follicles are enveloped by a layer of epithelial cells and become primordial follicles. During the development, the ovaries descend into the pelvis by the third month.

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

[[File:Bailey328.jpg|300px]]

Reference:
Bailey, F.R. and Miller, A.M. (1921). '''Text-Book of Embryology.''' New York: William Wood and Co.

==Lab 9 Assessment==
===Group 1===

The project was done well overall with lots of information and a good structure. However, I am a bit confused about the sections “respiratory” and “lung development stages”. I guess “lung development stages” is also under “respiratory”, but it seems that they are separated into two big sections.

The introduction clearly explains the development of respiratory system. It is good to divide respiratory tract into 2 main parts and explain them separately. It would be better if it includes a sentence like ‘this website will focus on fetal development of respiratory system.

Using table to explain different stages of lung development is a good idea. It would be easier to read if they are typed in point forms with some images included.

More images could be added under current research, models and findings for easier understanding. Some information should be added under current models.

The historic findings and abnormalities are good and informative.

Some images do not have the information about copyright. It would be better if there is a title for each image included.

In terms of referencing, they are missing in the sections under introduction, conducting zone and respiratory zone. In-text references are also missing in the table about the stages and features of lung development. Also, the images used have not been referenced. Reference list at the end rather than under each section should be used instead.

It is overall a good project and well-researched. More images can be included to balance with the huge amount of text.

===Group 2===

The introduction is good and describes the project well. It is good to mention the function of renal system. It would be better if it states that the website will be focused on fetal development, current research and abnormalities to give a better understanding of the content.

Information under historic findings is missing, it would be a good way to start it by looking at textbooks. Images, bullet points and table can be used for an easy understanding of this section.

Using timeline to summarise the development of kidney is a good idea, however it would be clearer if a table is used, more descriptions under each stages and some images are include. Also, some references should be included in this section.

There are a lot of details under development, current research and abnormalities. It would be easier to read if they are written in point form. It is a good idea to divide renal system into several parts (kidney, urethra…) for the explanation of development. For the abnormalities, it is well-researched but some of the details are missing. It would be better if the each type of abnormalities is discussed equally.

Regarding the images, it is good and clear to explain each of them. The only problem is that there is no copyright information under the file “kidney ascent.jpg”.

The project is informative but lacking some information under historic findings and the developmental timeline.

===Group 3===

Introduction is good as it describes and gives an overview about what is happening in the fetal period for foregut, midgut and hindgut. However, it would be better if it mentions that the project is focusing on fetal development, abnormalities, current researches, etc.

It is clear to separate the timeline of GIT development for hindgut, midgut and foregut. It is well-researched with much information in this section. However, it would be easier to follow if a table is used and images are included.

The hand-drawn images can explain the development well, however the blue colour for labelling is a bit difficult for reading. It would be better if a darker colour is used.

It is a good idea to explain the abnormalities in definition and the causes. Some more abnormalities can be included as well as images for better understanding.

There is only one reference in recent findings. More researches could be done in this section. Also, a section about historic findings could be included as well.

There are a few spelling errors, such as “esenchyme” in the hindgut section and “tot hat of” under midgut section. Some proof-readings are needed.

The referencing is overall good, but some more researches have to be done under some sections (abnormalities and recent findings). It is easy to follow as there is a reference list at the bottom of page.

It is overall a good project as the development during fetal period is well described. However, more information about recent findings and abnormalities could be included, with the use of images to illustrate the contents.

===Group 4===

The project would be easier to follow by having an introduction that give readers an idea about what is going to be covered in the website.

Under the section about system development, it contains lots of information and it is well researched. Using bullet points is good as it is easier to read, however some of them could be join together into a small paragraph which would increase the readability. It is good to see a related video about the development of reproductive system and it explains well about this topic.

It is a great way to explain abnormalities in terms of female, male, and both. Maybe try to put a table at the top to summarise the abnormalities so that it would be easier to follow. More images are needed in this section, just like the one illustrating abnormalities of uterus and vagina.

It is well-researched under historic findings, try to put more related images to make this section more interactive. Also, it would also be good to illustrate the content in this part by a timeline, followed by the explanation of each event.

In terms of referencing, in-text references are missing in the system development, current research and historic findings.

For the image file “Image.jpg”, which is about sexual differentiation, it is a good image that explains the differentiation clearly, however, it would be better to put a description or title below it to make it more relevant to the project. It is good to see some hand-drawn diagram and they match the topic and explain information well. I found it a bit hard to read the labels on the image “labelled drawing of testes.jpeg”, maybe upload the image by scanning rather than taking a photo of it would be better.

It is overall a well-researched project. The next thing to do is to include an introduction, some more in-text references and some related images.

===Group 5===

The introduction clearly states the content in the website, which is good as this can prepare the readers for understanding. However, it would be better if some information about integumentary system, such as functions, is included in this section.

The development of integument system includes a lot of information. They are presented in good structure by the use of table for skin and nail. It is a great way to put some images in the table for easy understanding of the description in the development of teeth.

The recent findings area is well-researched. I would suggest try to put the content into small paragraph or in several points as the amount of text is a bit too much. Some images should be included as well.

Abnormalities section is great with the help of the images. It would be good if some more abnormalities are included. There is a lot of details under historic findings, try to illustrate them with the help of images.

In-text references should be included in the sections under development, recent findings and historic findings.

The project is well prepared. It would be better if some more images are included and the function of integument system is stated in the introduction.

===Group 6===

Introduction is missing in the project. It would be great to include the functions of endocrine system and the contents that will be covered including system development, abnormalities, current research, etc.

There is a lot to cover in endocrine system, it is a great way to separate timeline and recent findings under each individual organ. Using table to illustrate the function of hormone is good, however, I think it would be better to have a summary of hormone in a table form at the top/the end of all individual organs. The parathyroid gland and pancreas are well-researched with the use of images. More information has to be included in other sections.

More work has to be done on abnormalities. Actually, they could be separated under each organ, just like current findings. It would also be good to see historic findings under each organ.

In terms of referencing, there is no in-text reference and the reference list at the bottom is empty at this moment. This project overall has a good structure, but more information and images are needed.

===Group 8===

Introduction is missing. Some information about the functions of the systems and topics going to be covered should be included here. The section ‘making gains’ is funny. However, more work has to be done to make it more interesting.

For the timeline, more information is needed. It would be great to include a table here and describe the changes during different stages (microfibers formation…). Table is also useful to explain the second trimester muscular development

The information under background embryonic development can be summarised and put under introduction as this project should be focused on fetal development.

It is great to have molecular and cellular regulation. However, more diagrams are needed here. It would be better if they are stated in several points rather than a big paragraph. Also, more images are needed for other sections, it would be good to draw the picture as well.

For abnormalities, in-text references are needed. Also, some more abnormalities should be included with the use of images to illustrate them.

Overall, there is a pretty good structure of the website. It could be improved by including some current and historic researches on this topic. Also, more images are needed (as there is none now) to make the webpage more interesting and informative. More contents should be included as well.

==Lab 10 Assessment==
'''Identify a recent research paper on sensory development (not hearing) and write a brief summary (several paragraphs) of the research methods and findings. Include at the end a link to the relevant wiki sensory notes page.'''

The researchers investigated the functional changes of olfactory sensory neurons (OSNs), which express mouse odorant receptor 23 (MOR23) with a known ligand (lyral), during the first postnatal month. Also, as olfactory marker protein (OMP) is recognized as a molecular marker for mature OSNs, it is hypothesized that OMP has an important role in functional maturation of OSNs.

In their research, genetically targeted MOR23-IRES (internal ribosome entry site)-tauGFP mice (with WT-MOR23 neurons) were used to record MOR23 neurons that coexpress green flurescent protein (GFP). Also homozyhous double mutant mice (with OMP -/- MOR23 neurons) were generated.

To investigate whether OSNs undergo functional changes during development, the odorant responses in individual neurons from animals at different ages (P0-P30, where P=postnatal day) were measured by perforated patch-clamp recordings on the dendritic knobs on individual OSNs. The results indicated that OSNs exhibit faster response kinetics during development. Furthermore, the effects of OMP deletion on functional properties of OSNs were also studied through the homozygous OMP -/- mice. It was found that OMP deletion results in OSNs with slow response kinetics, suggesting the OMP is necessary for the kinetic changes during the OSNs development. In addition, the selectivity of OSNs changes during the first postnatal month was tested and it was demonstrated that MOR23 neurons from P30 mice has higher selectivity to lyral. In terms of behavior test, the researchers also observed that WT but not OMP -/- mouse pups prefer the biological mother when the biological mother and another unfamiliar lactating female was given to choose.

In conclusion, the researchers showed that OMP is necessary for the maturation process in olfactory system. Also, MOR23 neurons from P30 mice have a faster response kinetics, higher sensitivity and higher selectivity when compared to the neurons from P0 mice. The results also suggested the maturation process of OSNs coincides with early development of the smell function and is critical for pups to form mother preference.

Reference: <pubmed>21414919</pubmed>

Links: [[Sensory_-_Smell_Development|Smell Development]]

==Lab 11 Assessment==

Identify a recent research article (using the pubmed tags to cite) on iPS cells and summarise in a few paragraphs the main findings of the paper.

Loss or dysfunction of trabecular meshwork (TM) cells is associated with the development of pathologically elevated intraocular pressure (IOP) that lead to gluacoma. In the research, it was demonstrated that mouse iPSCs can be induced to differentiate into trabecular meshwork (TM) like cells that are suitable for autologous transplantation.

TM-like cells (iPSC-TM) were produced by co-culture of mouse iPSCs with human TM cells for up to 21 cells. Morphological, immunohistochemical and functional tests were carried out to characterize the cells. The tests showed that the iPSC-TM cells were morphologically similar to human TM cells that they can express many markers of TM cells and also pluripotency markers includinf Nanog, Oct4, Sox2. The cells also developed the ability to phagocytose particles. In addition, the cells showed the behaviour characteristic of TM cells as there was an increase in the production and secretion and myocilin and matrix metalloproteinase-3 when the cells were exposed to dexamethasone or phorbol 12-myristate acetate respectively.

Therefore, iPSCs that resembles native TM cells can be induced. They can be transplanted into glucomatous eyes with elevated IOP as they can restore the function of TM.

<pubmed>25298418</pubmed>

User:Z3419587

2014-10-28T23:59:25Z

Z3419587:

{{StudentPage2014}}

==Lab Attendance==
Lab 1 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 12:45, 6 August 2014 (EST)

Lab 2 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:11, 13 August 2014 (EST)

Lab 3 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:12, 20 August 2014 (EST)

Lab 4 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:45, 27 August 2014 (EST)

Lab 5 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:02, 3 September 2014 (EST)

Lab 6 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:04, 10 September 2014 (EST)

Lab 7 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:05, 17 September 2014 (EST)

Lab 8 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:13, 24 September 2014 (EST)

Lab 9 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 10:49, 8 October 2014 (EST)

Lab 10 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:07, 15 October 2014 (EST)

Lab 11 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:23, 22 October 2014 (EST)

Lab 12 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 10:58, 29 October 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 1 Assessment==
<pubmed>25071849</pubmed>
summary:
This study was done to compare the clinical outcomes between fresh embryo transfers and frozen-thawed embryo transfers.

A total of 1891 cycle contains 1150 fresh embryo transfers and 741 frozen-thawed embryo transfers were studied. All data were transferred directly to SPSS 18 and analyzed.

A long gonadotropin releasing hormone (GnRH) agonist protocol was used in all cycles. Clinical pregnancy was defined by the observation of a gestational sac with or without a fetal heartbeat on ultrasound evaluation on the 30th day after embryo transfer. The number of sacs was taken as the number of implantations.

The results showed that there was a higher clinical pregnancy rate in fresh cleavage-stage embryo transfers than frozen-thawed cleavage-stage transfers but the clinical pregnancy rates were not different significantly.

<pubmed>25077107</pubmed>
summary:
The study was done to investigate the effect of vitamin D levels on implantation and clinical pregnancy rates in infertile women following in vitro fertilization (IVF).

173 women underwent IVF were included in the study under 3 criteria, including aged 18-41 years, follicle stimulating hormone level 12 IU/L or lower and able to provide informed consent. Vitamin D was determined by serum 25(OH)D levels and samples were collected before oocyte retrieval, while implantation was determined by the presence of a gestational sac, visible by ultrasonography.

χ2 and Student t tests or Mann-Whitney U tests were used to analyze categorical and continuous variables respectively. Multi-variable logistic regression was used to evaluate the relation between serum 25(OH)D level and implantation and clinical pregnancy after adjustment fpr parameters known to influence the IVF sucesss.

The results showed that women with sufficient levels of 25(OH)D had significantly higher rates of clinical pregnancy per IVF cycle started than that with insufficient levels. It also found that implantation rates were higher, but not statistically significant, in the sufficient 25(OH)D group. Therefore, the findings suggested that women with sufficient vitamin D levels are significantly more likely to achieve clinical pregnancy following IVF.

--[[User:Z8600021|Mark Hill]] These are both good articles and summaries (5/5)

==Lab 2 Assessment==
[[File:Development_of_nuclear_transfer_embryos.jpeg|300px]]

<ref><pubmed>23251622</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0051778]</ref>
<references/>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 15:27, 22 August 2014 (EST) I have uploaded a smaller version of this image, but you still need to adjust the size as it appears on your page to 300px and include the reference. Please use jpg format images if possible. You need to reformat the reference as shown in the class tutorial. (4/5)

==Lab 3 Assessment==
===Neural development during fetal period===
<pubmed>21042938</pubmed>
<pubmed>12060827</pubmed>
<pubmed>23727529</pubmed>
<pubmed>16905335</pubmed>
<pubmed>17848161</pubmed>
<pubmed>18760424</pubmed>
<pubmed>16971596</pubmed>
<pubmed>17032846</pubmed>

--[[User:Z8600021|Mark Hill]] These are useful references, I needed a single sentence on why you had selected these references for your section. (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>16099997</pubmed>
summary:
The paper presented the possibility of the therapeutic use of cord stem cells in Parkinson’s disease.

Human mesenchymal stem cells from Wharton’s jelly of the umbilical cord were isolated and induced to transform into dopaminergic neurons in vitro. 12.7% of the cells were successfully transformed and generated through a stepwise culturing in neuron-conditioned medium, sonic hedgehog and FGF8. The cells were transplanted into the striatum of rats previously made Parkinsonian by unilateral striatal lesioning with the dopaminergic neurotoxin 6-hydroxydopamine HCl (6-OHDA). The effects of the transplantation were examined by quantification of rotations in response to amphetamine at 1, 2, 3 and 4 months after transplantation.

It was found that the transplantation of the stem cells corrected the lesion-induces amphetamine-evoked rotation and the cells in the striatum were still viable 4 months after transplantation. These results give the possibility to human umbilical mesenchymal stem cells in treating Parkinson’s disease. However, it is suggested that the examination of the toxicity of growth factor and medium used is important, and the observation of the effects and side-effects for more than 1 year after transplantation is required before human studies

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

Ductus arteriosus: connection between the most cranial part of the pulmonary trunk and dorsal aorta

Ductus venosus: connection between the intra-abdominal umbilical vein and the inferior vena cava

Foramen ovale: located in interatrial septum, connecting left and right atria

Umbilical arteries: branch from the internal iliac arteries in the pelvis and connect to the placenta

Umbilical vein: connection between placenta and portal vein, or ductus venous

==Lab 5 Assessment==
===Congenital Laryngeal Webs===

Congenial laryngeal webs are caused by failure of recanalization of the laryngotracheal tube during the third month of gestation. Findings suggested that congenital laryngeal webs can be explained by abnormal development of the epithelial lamina, the laryngeal cecum, or the vestibulotracheal duct <ref><pubmed>16798587</pubmed></ref>. It has also been reported that there is an association between anterior webs, the most common laryngeal webs, with deletions of chromosome 22q11<ref><pubmed>10699233</pubmed></ref>.

In human embryo, congenial laryngeal webs are formed during embryogenesis of the laryngotracheal groove <ref><pubmed>20376251</pubmed></ref>. The developing laryngeal is temporarily obliterated by actively proliferating epithelium, however, the lumen is normally re-established as the vocal cords. This abnormality is resulted from incomplete resorption of the epithelial layer during the 7th and 8th week of intrauterine development.

references:

<references/>

==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. (pancreas)'''

In this study, the distribution of chromogranin A, insulin, and glucagon in 25 human fetal pancreases was studied. Immunohistochemical reactions were carried out and sections of pancreas were labelled with antibodies to chromogranin A, insulin and glucagon.

Immunopositive reaction to chromgranin A was resulted from week 8 of development onwards. During the development of pancreas, the population of endocrine cells increased and pancreatic islets are formed. The majority of cells in the pancreatic islets were found to be chromogranin A that located in the cytoplasm. Chromogranin A immunoreactive cells were also found in glandular ductal epithelium of 8-9-week fetuses, suggesting that the cells formed a population of precursors of endocrine cells without synthesizing hormones.

The express of chromogranin A, which is higher than that of insulin and glucagon, during differentiation of pancreatic endocrine cells suggested that this can be a marker for studies of the mechanisms of endocrine development of pancreas.

reference:
<pubmed>24824718</pubmed>

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

Tooth germ: aggregation of cells derived from the ectomesenchymal cells from neural crest and ectoderm of first arch. It is then organized into 3 components of the tooth germ, which are the enamel organ, dental papilla and dental follicle for the teeth development.

==Lab 8 Assessment==
'''1. Provide a brief time course and overview of embryonic development of either the human testis or ovary. (2-3 paragraphs)'''

Gonads are developed from the mesothelium of the posterior abdominal wall, the adjacent mesenchyme and the primordial germ cells. The development begins in week 5 where the mesothelium medial to the mesonephros of the developing kidneys thickens and forming the paired gonadal ridges.

The primordial germ cells are the precursors of oocytes that they migrate from the yolk sac to the mesenchyme of the gonadal ridges between weeks 3 to 5 and incorporate into the primary sex cords. The sex cords extend to the medulla of the future ovary and regress by week 8.

During week 8, gonad begins to develop into ovary due to the stimulation from germ cells. The primitive medullary cords in the ovary degenerates and the primordial germ cells differentiate under the influence of placental gonadotropins. The germ cells undergo mitotic divisions and differentiate into several million oogonia. Around week 16 to week 20, the primitive follicles organize within the fetal ovarian cortex. By 5-6 months gestation, the primitive follicles are enveloped by a layer of epithelial cells and become primordial follicles. During the development, the ovaries descend into the pelvis by the third month.

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

[[File:Bailey328.jpg|300px]]

Reference:
Bailey, F.R. and Miller, A.M. (1921). '''Text-Book of Embryology.''' New York: William Wood and Co.

==Lab 9 Assessment==
===Group 1===

The product was done well overall with lots of information and a good structure. However, I am a bit confused about the sections “respiratory” and “lung development stages”. I guess “lung development stages” is also under “respiratory”, but it seems that they are separated into two big sections.

The introduction clearly explains the development of respiratory system. It is good to divide respiratory tract into 2 main parts and explain them separately. It would be better if it includes a sentence like ‘this website will focus on fetal development of respiratory system.

Using table to explain different stages of lung development is a good idea. It would be easier to read if they are typed in point forms with some images included.

More images could be added under current research, models and findings for easier understanding. Some information should be added under current models.

The historic findings and abnormalities are good and informative.

Some images do not have the information about copyright. It would be better if there is a title for each image included.

In terms of referencing, they are missing in the sections under introduction, conducting zone and respiratory zone. In-text references are also missing in the table about the stages and features of lung development. Also, the images used have not been referenced. Reference list at the end rather than under each section should be used instead.

It is overall a good project and well-researched. More images can be included to balance with the huge amount of text.

===Group 2===

The introduction is good and describes the project well. It is good to mention the function of renal system. It would be better if it states that the website will be focused on fetal development, current research and abnormalities to give a better understanding of the content.

Information under historic findings is missing, it would be a good way to start it by looking at textbooks. Images, bullet points and table can be used for an easy understanding of this section.

Using timeline to summarise the development of kidney is a good idea, however it would be clearer if a table is used, more descriptions under each stages and some images are include. Also, some references should be included in this section.

There are a lot of details under development, current research and abnormalities. It would be easier to read if they are written in point form. It is a good idea to divide renal system into several parts (kidney, urethra…) for the explanation of development. For the abnormalities, it is well-researched but some of the details are missing. It would be better if the each type of abnormalities is discussed equally.

Regarding the images, it is good and clear to explain each of them. The only problem is that there is no copyright information under the file “kidney ascent.jpg”.

The project is informative but lacking some information under historic findings and the developmental timeline.

===Group 3===

Introduction is good as it describes and gives an overview about what is happening in the fetal period for foregut, midgut and hindgut. However, it would be better if it mentions that the project is focusing on fetal development, abnormalities, current researches, etc.

It is clear to separate the timeline of GIT development for hindgut, midgut and foregut. It is well-researched with much information in this section. However, it would be easier to follow if a table is used and images are included.

The hand-drawn images can explain the development well, however the blue colour for labelling is a bit difficult for reading. It would be better if a darker colour is used.

It is a good idea to explain the abnormalities in definition and the causes. Some more abnormalities can be included as well as images for better understanding.

There is only one reference in recent findings. More researches could be done in this section. Also, a section about historic findings could be included as well.

There are a few spelling errors, such as “esenchyme” in the hindgut section and “tot hat of” under midgut section. Some proof-readings are needed.

The referencing is overall good, but some more researches have to be done under some sections (abnormalities and recent findings). It is easy to follow as there is a reference list at the bottom of page.

It is overall a good project as the development during fetal period is well described. However, more information about recent findings and abnormalities could be included, with the use of images to illustrate the contents.

===Group 4===

The project would be easier to follow by having an introduction that give readers an idea about what is going to be covered in the website.

Under the section about system development, it contains lots of information and it is well researched. Using bullet points is good as it is easier to read, however some of them could be join together into a small paragraph which would increase the readability. It is good to see a related video about the development of reproductive system and it explains well about this topic.

It is a great way to explain abnormalities in terms of female, male, and both. Maybe try to put a table at the top to summarise the abnormalities so that it would be easier to follow. More images are needed in this section, just like the one illustrating abnormalities of uterus and vagina.

It is well-researched under historic findings, try to put more related images to make this section more interactive. Also, it would also be good to illustrate the content in this part by a timeline, followed by the explanation of each event.

In terms of referencing, in-text references are missing in the system development, current research and historic findings.

For the image file “Image.jpg”, which is about sexual differentiation, it is a good image that explains the differentiation clearly, however, it would be better to put a description or title below it to make it more relevant to the project. It is good to see some hand-drawn diagram and they match the topic and explain information well. I found it a bit hard to read the labels on the image “labelled drawing of testes.jpeg”, maybe upload the image by scanning rather than taking a photo of it would be better.

It is overall a well-researched project. The next thing to do is to include an introduction, some more in-text references and some related images.

===Group 5===

The introduction clearly states the content in the website, which is good as this can prepare the readers for understanding. However, it would be better if some information about integumentary system, such as functions, is included in this section.

The development of integument system includes a lot of information. They are presented in good structure by the use of table for skin and nail. It is a great way to put some images in the table for easy understanding of the description in the development of teeth.

The recent findings area is well-researched. I would suggest try to put the content into small paragraph or in several points as the amount of text is a bit too much. Some images should be included as well.

Abnormalities section is great with the help of the images. It would be good if some more abnormalities are included. There is a lot of details under historic findings, try to illustrate them with the help of images.

In-text references should be included in the sections under development, recent findings and historic findings.

The project is well prepared. It would be better if some more images are included and the function of integument system is stated in the introduction.

===Group 6===

Introduction is missing in the project. It would be great to include the functions of endocrine system and the contents that will be covered including system development, abnormalities, current research, etc.

There is a lot to cover in endocrine system, it is a great way to separate timeline and recent findings under each individual organ. Using table to illustrate the function of hormone is good, however, I think it would be better to have a summary of hormone in a table form at the top/the end of all individual organs. The parathyroid gland and pancreas are well-researched with the use of images. More information has to be included in other sections.

More work has to be done on abnormalities. Actually, they could be separated under each organ, just like current findings. It would also be good to see historic findings under each organ.

In terms of referencing, there is no in-text reference and the reference list at the bottom is empty at this moment. This project overall has a good structure, but more information and images are needed.

===Group 8===

Introduction is missing. Some information about the functions of the systems and topics going to be covered should be included here. The section ‘making gains’ is funny. However, more work has to be done to make it more interesting.

For the timeline, more information is needed. It would be great to include a table here and describe the changes during different stages (microfibers formation…). Table is also useful to explain the second trimester muscular development

The information under background embryonic development can be summarised and put under introduction as this project should be focused on fetal development.

It is great to have molecular and cellular regulation. However, more diagrams are needed here. It would be better if they are stated in several points rather than a big paragraph. Also, more images are needed for other sections, it would be good to draw the picture as well.

For abnormalities, in-text references are needed. Also, some more abnormalities should be included with the use of images to illustrate them.

Overall, there is a pretty good structure of the website. It could be improved by including some current and historic researches on this topic. Also, more images are needed (as there is none now) to make the webpage more interesting and informative. More contents should be included as well.

==Lab 10 Assessment==
'''Identify a recent research paper on sensory development (not hearing) and write a brief summary (several paragraphs) of the research methods and findings. Include at the end a link to the relevant wiki sensory notes page.'''

The researchers investigated the functional changes of olfactory sensory neurons (OSNs), which express mouse odorant receptor 23 (MOR23) with a known ligand (lyral), during the first postnatal month. Also, as olfactory marker protein (OMP) is recognized as a molecular marker for mature OSNs, it is hypothesized that OMP has an important role in functional maturation of OSNs.

In their research, genetically targeted MOR23-IRES (internal ribosome entry site)-tauGFP mice (with WT-MOR23 neurons) were used to record MOR23 neurons that coexpress green flurescent protein (GFP). Also homozyhous double mutant mice (with OMP -/- MOR23 neurons) were generated.

To investigate whether OSNs undergo functional changes during development, the odorant responses in individual neurons from animals at different ages (P0-P30, where P=postnatal day) were measured by perforated patch-clamp recordings on the dendritic knobs on individual OSNs. The results indicated that OSNs exhibit faster response kinetics during development. Furthermore, the effects of OMP deletion on functional properties of OSNs were also studied through the homozygous OMP -/- mice. It was found that OMP deletion results in OSNs with slow response kinetics, suggesting the OMP is necessary for the kinetic changes during the OSNs development. In addition, the selectivity of OSNs changes during the first postnatal month was tested and it was demonstrated that MOR23 neurons from P30 mice has higher selectivity to lyral. In terms of behavior test, the researchers also observed that WT but not OMP -/- mouse pups prefer the biological mother when the biological mother and another unfamiliar lactating female was given to choose.

In conclusion, the researchers showed that OMP is necessary for the maturation process in olfactory system. Also, MOR23 neurons from P30 mice have a faster response kinetics, higher sensitivity and higher selectivity when compared to the neurons from P0 mice. The results also suggested the maturation process of OSNs coincides with early development of the smell function and is critical for pups to form mother preference.

Reference: <pubmed>21414919</pubmed>

Links: [[Sensory_-_Smell_Development|Smell Development]]

==Lab 11 Assessment==

Identify a recent research article (using the pubmed tags to cite) on iPS cells and summarise in a few paragraphs the main findings of the paper.

Loss or dysfunction of trabecular meshwork (TM) cells is associated with the development of pathologically elevated intraocular pressure (IOP) that lead to gluacoma. In the research, it was demonstrated that mouse iPSCs can be induced to differentiate into trabecular meshwork (TM) like cells that are suitable for autologous transplantation.

TM-like cells (iPSC-TM) were produced by co-culture of mouse iPSCs with human TM cells for up to 21 cells. Morphological, immunohistochemical and functional tests were carried out to characterize the cells. The tests showed that the iPSC-TM cells were morphologically similar to human TM cells that they can express many markers of TM cells and also pluripotency markers includinf Nanog, Oct4, Sox2. The cells also developed the ability to phagocytose particles. In addition, the cells showed the behaviour characteristic of TM cells as there was an increase in the production and secretion and myocilin and matrix metalloproteinase-3 when the cells were exposed to dexamethasone or phorbol 12-myristate acetate respectively.

Therefore, iPSCs that resembles native TM cells can be induced. They can be transplanted into glucomatous eyes with elevated IOP as they can restore the function of TM.

<pubmed>25298418</pubmed>

User:Z3419587

2014-10-28T08:18:10Z

Z3419587:

{{StudentPage2014}}

==Lab Attendance==
Lab 1 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 12:45, 6 August 2014 (EST)

Lab 2 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:11, 13 August 2014 (EST)

Lab 3 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:12, 20 August 2014 (EST)

Lab 4 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:45, 27 August 2014 (EST)

Lab 5 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:02, 3 September 2014 (EST)

Lab 6 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:04, 10 September 2014 (EST)

Lab 7 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:05, 17 September 2014 (EST)

Lab 8 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:13, 24 September 2014 (EST)

Lab 9 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 10:49, 8 October 2014 (EST)

Lab 10 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:07, 15 October 2014 (EST)

Lab 11 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:23, 22 October 2014 (EST)

Lab 12

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 1 Assessment==
<pubmed>25071849</pubmed>
summary:
This study was done to compare the clinical outcomes between fresh embryo transfers and frozen-thawed embryo transfers.

A total of 1891 cycle contains 1150 fresh embryo transfers and 741 frozen-thawed embryo transfers were studied. All data were transferred directly to SPSS 18 and analyzed.

A long gonadotropin releasing hormone (GnRH) agonist protocol was used in all cycles. Clinical pregnancy was defined by the observation of a gestational sac with or without a fetal heartbeat on ultrasound evaluation on the 30th day after embryo transfer. The number of sacs was taken as the number of implantations.

The results showed that there was a higher clinical pregnancy rate in fresh cleavage-stage embryo transfers than frozen-thawed cleavage-stage transfers but the clinical pregnancy rates were not different significantly.

<pubmed>25077107</pubmed>
summary:
The study was done to investigate the effect of vitamin D levels on implantation and clinical pregnancy rates in infertile women following in vitro fertilization (IVF).

173 women underwent IVF were included in the study under 3 criteria, including aged 18-41 years, follicle stimulating hormone level 12 IU/L or lower and able to provide informed consent. Vitamin D was determined by serum 25(OH)D levels and samples were collected before oocyte retrieval, while implantation was determined by the presence of a gestational sac, visible by ultrasonography.

χ2 and Student t tests or Mann-Whitney U tests were used to analyze categorical and continuous variables respectively. Multi-variable logistic regression was used to evaluate the relation between serum 25(OH)D level and implantation and clinical pregnancy after adjustment fpr parameters known to influence the IVF sucesss.

The results showed that women with sufficient levels of 25(OH)D had significantly higher rates of clinical pregnancy per IVF cycle started than that with insufficient levels. It also found that implantation rates were higher, but not statistically significant, in the sufficient 25(OH)D group. Therefore, the findings suggested that women with sufficient vitamin D levels are significantly more likely to achieve clinical pregnancy following IVF.

--[[User:Z8600021|Mark Hill]] These are both good articles and summaries (5/5)

==Lab 2 Assessment==
[[File:Development_of_nuclear_transfer_embryos.jpeg|300px]]

<ref><pubmed>23251622</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0051778]</ref>
<references/>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 15:27, 22 August 2014 (EST) I have uploaded a smaller version of this image, but you still need to adjust the size as it appears on your page to 300px and include the reference. Please use jpg format images if possible. You need to reformat the reference as shown in the class tutorial. (4/5)

==Lab 3 Assessment==
===Neural development during fetal period===
<pubmed>21042938</pubmed>
<pubmed>12060827</pubmed>
<pubmed>23727529</pubmed>
<pubmed>16905335</pubmed>
<pubmed>17848161</pubmed>
<pubmed>18760424</pubmed>
<pubmed>16971596</pubmed>
<pubmed>17032846</pubmed>

--[[User:Z8600021|Mark Hill]] These are useful references, I needed a single sentence on why you had selected these references for your section. (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>16099997</pubmed>
summary:
The paper presented the possibility of the therapeutic use of cord stem cells in Parkinson’s disease.

Human mesenchymal stem cells from Wharton’s jelly of the umbilical cord were isolated and induced to transform into dopaminergic neurons in vitro. 12.7% of the cells were successfully transformed and generated through a stepwise culturing in neuron-conditioned medium, sonic hedgehog and FGF8. The cells were transplanted into the striatum of rats previously made Parkinsonian by unilateral striatal lesioning with the dopaminergic neurotoxin 6-hydroxydopamine HCl (6-OHDA). The effects of the transplantation were examined by quantification of rotations in response to amphetamine at 1, 2, 3 and 4 months after transplantation.

It was found that the transplantation of the stem cells corrected the lesion-induces amphetamine-evoked rotation and the cells in the striatum were still viable 4 months after transplantation. These results give the possibility to human umbilical mesenchymal stem cells in treating Parkinson’s disease. However, it is suggested that the examination of the toxicity of growth factor and medium used is important, and the observation of the effects and side-effects for more than 1 year after transplantation is required before human studies

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

Ductus arteriosus: connection between the most cranial part of the pulmonary trunk and dorsal aorta

Ductus venosus: connection between the intra-abdominal umbilical vein and the inferior vena cava

Foramen ovale: located in interatrial septum, connecting left and right atria

Umbilical arteries: branch from the internal iliac arteries in the pelvis and connect to the placenta

Umbilical vein: connection between placenta and portal vein, or ductus venous

==Lab 5 Assessment==
===Congenital Laryngeal Webs===

Congenial laryngeal webs are caused by failure of recanalization of the laryngotracheal tube during the third month of gestation. Findings suggested that congenital laryngeal webs can be explained by abnormal development of the epithelial lamina, the laryngeal cecum, or the vestibulotracheal duct <ref><pubmed>16798587</pubmed></ref>. It has also been reported that there is an association between anterior webs, the most common laryngeal webs, with deletions of chromosome 22q11<ref><pubmed>10699233</pubmed></ref>.

In human embryo, congenial laryngeal webs are formed during embryogenesis of the laryngotracheal groove <ref><pubmed>20376251</pubmed></ref>. The developing laryngeal is temporarily obliterated by actively proliferating epithelium, however, the lumen is normally re-established as the vocal cords. This abnormality is resulted from incomplete resorption of the epithelial layer during the 7th and 8th week of intrauterine development.

references:

<references/>

==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. (pancreas)'''

In this study, the distribution of chromogranin A, insulin, and glucagon in 25 human fetal pancreases was studied. Immunohistochemical reactions were carried out and sections of pancreas were labelled with antibodies to chromogranin A, insulin and glucagon.

Immunopositive reaction to chromgranin A was resulted from week 8 of development onwards. During the development of pancreas, the population of endocrine cells increased and pancreatic islets are formed. The majority of cells in the pancreatic islets were found to be chromogranin A that located in the cytoplasm. Chromogranin A immunoreactive cells were also found in glandular ductal epithelium of 8-9-week fetuses, suggesting that the cells formed a population of precursors of endocrine cells without synthesizing hormones.

The express of chromogranin A, which is higher than that of insulin and glucagon, during differentiation of pancreatic endocrine cells suggested that this can be a marker for studies of the mechanisms of endocrine development of pancreas.

reference:
<pubmed>24824718</pubmed>

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

Tooth germ: aggregation of cells derived from the ectomesenchymal cells from neural crest and ectoderm of first arch. It is then organized into 3 components of the tooth germ, which are the enamel organ, dental papilla and dental follicle for the teeth development.

==Lab 8 Assessment==
'''1. Provide a brief time course and overview of embryonic development of either the human testis or ovary. (2-3 paragraphs)'''

Gonads are developed from the mesothelium of the posterior abdominal wall, the adjacent mesenchyme and the primordial germ cells. The development begins in week 5 where the mesothelium medial to the mesonephros of the developing kidneys thickens and forming the paired gonadal ridges.

The primordial germ cells are the precursors of oocytes that they migrate from the yolk sac to the mesenchyme of the gonadal ridges between weeks 3 to 5 and incorporate into the primary sex cords. The sex cords extend to the medulla of the future ovary and regress by week 8.

During week 8, gonad begins to develop into ovary due to the stimulation from germ cells. The primitive medullary cords in the ovary degenerates and the primordial germ cells differentiate under the influence of placental gonadotropins. The germ cells undergo mitotic divisions and differentiate into several million oogonia. Around week 16 to week 20, the primitive follicles organize within the fetal ovarian cortex. By 5-6 months gestation, the primitive follicles are enveloped by a layer of epithelial cells and become primordial follicles. During the development, the ovaries descend into the pelvis by the third month.

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

[[File:Bailey328.jpg|300px]]

Reference:
Bailey, F.R. and Miller, A.M. (1921). '''Text-Book of Embryology.''' New York: William Wood and Co.

==Lab 9 Assessment==
===Group 1===

The product was done well overall with lots of information and a good structure. However, I am a bit confused about the sections “respiratory” and “lung development stages”. I guess “lung development stages” is also under “respiratory”, but it seems that they are separated into two big sections.

The introduction clearly explains the development of respiratory system. It is good to divide respiratory tract into 2 main parts and explain them separately. It would be better if it includes a sentence like ‘this website will focus on fetal development of respiratory system.

Using table to explain different stages of lung development is a good idea. It would be easier to read if they are typed in point forms with some images included.

More images could be added under current research, models and findings for easier understanding. Some information should be added under current models.

The historic findings and abnormalities are good and informative.

Some images do not have the information about copyright. It would be better if there is a title for each image included.

In terms of referencing, they are missing in the sections under introduction, conducting zone and respiratory zone. In-text references are also missing in the table about the stages and features of lung development. Also, the images used have not been referenced. Reference list at the end rather than under each section should be used instead.

It is overall a good project and well-researched. More images can be included to balance with the huge amount of text.

===Group 2===

The introduction is good and describes the project well. It is good to mention the function of renal system. It would be better if it states that the website will be focused on fetal development, current research and abnormalities to give a better understanding of the content.

Information under historic findings is missing, it would be a good way to start it by looking at textbooks. Images, bullet points and table can be used for an easy understanding of this section.

Using timeline to summarise the development of kidney is a good idea, however it would be clearer if a table is used, more descriptions under each stages and some images are include. Also, some references should be included in this section.

There are a lot of details under development, current research and abnormalities. It would be easier to read if they are written in point form. It is a good idea to divide renal system into several parts (kidney, urethra…) for the explanation of development. For the abnormalities, it is well-researched but some of the details are missing. It would be better if the each type of abnormalities is discussed equally.

Regarding the images, it is good and clear to explain each of them. The only problem is that there is no copyright information under the file “kidney ascent.jpg”.

The project is informative but lacking some information under historic findings and the developmental timeline.

===Group 3===

Introduction is good as it describes and gives an overview about what is happening in the fetal period for foregut, midgut and hindgut. However, it would be better if it mentions that the project is focusing on fetal development, abnormalities, current researches, etc.

It is clear to separate the timeline of GIT development for hindgut, midgut and foregut. It is well-researched with much information in this section. However, it would be easier to follow if a table is used and images are included.

The hand-drawn images can explain the development well, however the blue colour for labelling is a bit difficult for reading. It would be better if a darker colour is used.

It is a good idea to explain the abnormalities in definition and the causes. Some more abnormalities can be included as well as images for better understanding.

There is only one reference in recent findings. More researches could be done in this section. Also, a section about historic findings could be included as well.

There are a few spelling errors, such as “esenchyme” in the hindgut section and “tot hat of” under midgut section. Some proof-readings are needed.

The referencing is overall good, but some more researches have to be done under some sections (abnormalities and recent findings). It is easy to follow as there is a reference list at the bottom of page.

It is overall a good project as the development during fetal period is well described. However, more information about recent findings and abnormalities could be included, with the use of images to illustrate the contents.

===Group 4===

The project would be easier to follow by having an introduction that give readers an idea about what is going to be covered in the website.

Under the section about system development, it contains lots of information and it is well researched. Using bullet points is good as it is easier to read, however some of them could be join together into a small paragraph which would increase the readability. It is good to see a related video about the development of reproductive system and it explains well about this topic.

It is a great way to explain abnormalities in terms of female, male, and both. Maybe try to put a table at the top to summarise the abnormalities so that it would be easier to follow. More images are needed in this section, just like the one illustrating abnormalities of uterus and vagina.

It is well-researched under historic findings, try to put more related images to make this section more interactive. Also, it would also be good to illustrate the content in this part by a timeline, followed by the explanation of each event.

In terms of referencing, in-text references are missing in the system development, current research and historic findings.

For the image file “Image.jpg”, which is about sexual differentiation, it is a good image that explains the differentiation clearly, however, it would be better to put a description or title below it to make it more relevant to the project. It is good to see some hand-drawn diagram and they match the topic and explain information well. I found it a bit hard to read the labels on the image “labelled drawing of testes.jpeg”, maybe upload the image by scanning rather than taking a photo of it would be better.

It is overall a well-researched project. The next thing to do is to include an introduction, some more in-text references and some related images.

===Group 5===

The introduction clearly states the content in the website, which is good as this can prepare the readers for understanding. However, it would be better if some information about integumentary system, such as functions, is included in this section.

The development of integument system includes a lot of information. They are presented in good structure by the use of table for skin and nail. It is a great way to put some images in the table for easy understanding of the description in the development of teeth.

The recent findings area is well-researched. I would suggest try to put the content into small paragraph or in several points as the amount of text is a bit too much. Some images should be included as well.

Abnormalities section is great with the help of the images. It would be good if some more abnormalities are included. There is a lot of details under historic findings, try to illustrate them with the help of images.

In-text references should be included in the sections under development, recent findings and historic findings.

The project is well prepared. It would be better if some more images are included and the function of integument system is stated in the introduction.

===Group 6===

Introduction is missing in the project. It would be great to include the functions of endocrine system and the contents that will be covered including system development, abnormalities, current research, etc.

There is a lot to cover in endocrine system, it is a great way to separate timeline and recent findings under each individual organ. Using table to illustrate the function of hormone is good, however, I think it would be better to have a summary of hormone in a table form at the top/the end of all individual organs. The parathyroid gland and pancreas are well-researched with the use of images. More information has to be included in other sections.

More work has to be done on abnormalities. Actually, they could be separated under each organ, just like current findings. It would also be good to see historic findings under each organ.

In terms of referencing, there is no in-text reference and the reference list at the bottom is empty at this moment. This project overall has a good structure, but more information and images are needed.

===Group 8===

Introduction is missing. Some information about the functions of the systems and topics going to be covered should be included here. The section ‘making gains’ is funny. However, more work has to be done to make it more interesting.

For the timeline, more information is needed. It would be great to include a table here and describe the changes during different stages (microfibers formation…). Table is also useful to explain the second trimester muscular development

The information under background embryonic development can be summarised and put under introduction as this project should be focused on fetal development.

It is great to have molecular and cellular regulation. However, more diagrams are needed here. It would be better if they are stated in several points rather than a big paragraph. Also, more images are needed for other sections, it would be good to draw the picture as well.

For abnormalities, in-text references are needed. Also, some more abnormalities should be included with the use of images to illustrate them.

Overall, there is a pretty good structure of the website. It could be improved by including some current and historic researches on this topic. Also, more images are needed (as there is none now) to make the webpage more interesting and informative. More contents should be included as well.

==Lab 10 Assessment==
'''Identify a recent research paper on sensory development (not hearing) and write a brief summary (several paragraphs) of the research methods and findings. Include at the end a link to the relevant wiki sensory notes page.'''

The researchers investigated the functional changes of olfactory sensory neurons (OSNs), which express mouse odorant receptor 23 (MOR23) with a known ligand (lyral), during the first postnatal month. Also, as olfactory marker protein (OMP) is recognized as a molecular marker for mature OSNs, it is hypothesized that OMP has an important role in functional maturation of OSNs.

In their research, genetically targeted MOR23-IRES (internal ribosome entry site)-tauGFP mice (with WT-MOR23 neurons) were used to record MOR23 neurons that coexpress green flurescent protein (GFP). Also homozyhous double mutant mice (with OMP -/- MOR23 neurons) were generated.

To investigate whether OSNs undergo functional changes during development, the odorant responses in individual neurons from animals at different ages (P0-P30, where P=postnatal day) were measured by perforated patch-clamp recordings on the dendritic knobs on individual OSNs. The results indicated that OSNs exhibit faster response kinetics during development. Furthermore, the effects of OMP deletion on functional properties of OSNs were also studied through the homozygous OMP -/- mice. It was found that OMP deletion results in OSNs with slow response kinetics, suggesting the OMP is necessary for the kinetic changes during the OSNs development. In addition, the selectivity of OSNs changes during the first postnatal month was tested and it was demonstrated that MOR23 neurons from P30 mice has higher selectivity to lyral. In terms of behavior test, the researchers also observed that WT but not OMP -/- mouse pups prefer the biological mother when the biological mother and another unfamiliar lactating female was given to choose.

In conclusion, the researchers showed that OMP is necessary for the maturation process in olfactory system. Also, MOR23 neurons from P30 mice have a faster response kinetics, higher sensitivity and higher selectivity when compared to the neurons from P0 mice. The results also suggested the maturation process of OSNs coincides with early development of the smell function and is critical for pups to form mother preference.

Reference: <pubmed>21414919</pubmed>

Links: [[Sensory_-_Smell_Development|Smell Development]]

==Lab 11 Assessment==

Identify a recent research article (using the pubmed tags to cite) on iPS cells and summarise in a few paragraphs the main findings of the paper.

Loss or dysfunction of trabecular meshwork (TM) cells is associated with the development of pathologically elevated intraocular pressure (IOP) that lead to gluacoma. In the research, it was demonstrated that mouse iPSCs can be induced to differentiate into trabecular meshwork (TM) like cells that are suitable for autologous transplantation.

TM-like cells (iPSC-TM) were produced by co-culture of mouse iPSCs with human TM cells for up to 21 cells. Morphological, immunohistochemical and functional tests were carried out to characterize the cells. The tests showed that the iPSC-TM cells were morphologically similar to human TM cells that they can express many markers of TM cells and also pluripotency markers includinf Nanog, Oct4, Sox2. The cells also developed the ability to phagocytose particles. In addition, the cells showed the behaviour characteristic of TM cells as there was an increase in the production and secretion and myocilin and matrix metalloproteinase-3 when the cells were exposed to dexamethasone or phorbol 12-myristate acetate respectively.

Therefore, iPSCs that resembles native TM cells can be induced. They can be transplanted into glucomatous eyes with elevated IOP as they can restore the function of TM.

<pubmed>25298418</pubmed>

2014 Group Project 7

2014-10-24T03:46:27Z

Z3419587: /* 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>

* 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

2014-10-23T16:37:44Z

Z3419587: /* Development during fetal period */

2014 Group Project 7

2014-10-23T15:05:05Z

Z3419587: /* 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.

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===

==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

2014-10-23T14:28:59Z

Z3419587: /* 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==

===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===

==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

2014-10-23T13:51:57Z

Z3419587: /* 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==

===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

2014-10-23T12:50:51Z

Z3419587: /* 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==

===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. 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.

{| 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

2014-10-23T12:47:26Z

Z3419587: /* 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==

===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)'''<ref name="PMID10532616"><pubmed>10532616</pubmed></ref>

* 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. 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.

{| 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

2014-10-23T12:32:27Z

Z3419587: /* 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==

===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, 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|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'''

* 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. 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.

{| 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

2014-10-23T11:39:20Z

Z3419587: /* 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==

===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, 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|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'''

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

{| 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

2014-10-23T11:35:49Z

Z3419587: /* 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==

===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, 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|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'''

* 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'''

* 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 <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. 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.

{| 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

2014-10-23T11:12:51Z

Z3419587: /* 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==

===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|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 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, 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 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'''

* 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 <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. 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.

{| 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

2014-10-23T09:41:51Z

Z3419587: /* 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==

===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|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 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]][[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 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'''

* 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 <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==

{|
|-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.

{| 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

2014-10-23T09:34:21Z

Z3419587: /* 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 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]][[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 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'''

* 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.

{| 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

2014-10-23T09:31:39Z

Z3419587: /* 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 (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.

[[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 !! Description
|-
| 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|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 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, 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 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'''

* 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.

{| 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>
|}

{| style="width:5%; height:170px" align="left"
|-
| [[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

2014-10-23T09:20:11Z

Z3419587: /* 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 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]][[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 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'''

* 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.

{| 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>
|}

{| style="width:5%; height:170px" align="left"
|-
| [[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

2014-10-23T09:04:54Z

Z3419587: /* 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 (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 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]][[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 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'''

* 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

2014-10-22T16:03:29Z

Z3419587: /* Neural - 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

==='''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'''

[[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

- 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>

'''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

2014-10-22T15:59:48Z

Z3419587: /* 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: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'''

[[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

- 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>

'''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/>

File:Ethanol fetal neural.jpg

2014-10-22T15:49:17Z

Z3419587: /* Composite model for ethanol effects on fetal neural development */

=Composite model for ethanol effects on fetal neural development=

Ethanol causes assymetric neural stem cell (NSC) proliferation. This leads to premature depletion of NSCs in the ventricular zone (VZ) and the ultimately loss of reserve neuron generation capacity.
The appearance of radial glial-like neuronal progenitors supports expansion, increases proliferation of neuronal progenitors in the sub-ventricular zone (SVZ) and increases migration of neuronal progenitor cells out of the VZ and SVZ, leading to the formation of heterotopias or displaced neuronal aggregates.

==Reference==
<pubmed>22623924</pubmed>
Copyright: © 2012 Miranda. This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.

{{Template:Student Image}}

File:Ethanol fetal neural.jpg

2014-10-22T15:48:23Z

Z3419587: =Composite model for ethanol effects on fetal neural development= Ethanol causes assymetric neural stem cell (NSC) proliferation. This leads to premature depletion of NSCs in the ventricular zone (VZ) and the ultimately loss of reserve neuron generati...

=Composite model for ethanol effects on fetal neural development=

Ethanol causes assymetric neural stem cell (NSC) proliferation. This leads to premature depletion of NSCs in the ventricular zone (VZ) and the ultimately loss of reserve neuron generation capacity.
The appearance of radial glial-like neuronal progenitors supports expansion, increases proliferation of neuronal progenitors in the sub-ventricular zone (SVZ) and increases migration of neuronal progenitor cells out of the VZ and SVZ, leading to the formation of heterotopias or displaced neuronal aggregates.

==Reference==
<ref><pubmed>22623924</pubmed></ref>
Copyright: © 2012 Miranda. This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.

{{Template:Student Image}}

2014 Group Project 7

2014-10-22T15:26:57Z

Z3419587: /* 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'''

[[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

- 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>

'''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> ]]
|}

===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

2014-10-22T15:12:50Z

Z3419587: /* 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'''

[[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

- 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>

'''folding: sulcation and gyration'''

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> ]]
|}

===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

2014-10-22T14:58:23Z

Z3419587: /* 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'''

[[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

- 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>

'''folding: sulcation and gyration'''
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><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

2014-10-22T13:54:09Z

Z3419587: /* 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: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'''

[[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

- 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

2014-10-22T13:46:14Z

Z3419587: /* 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: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'''

[[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:Interneurons 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

- 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

2014-10-22T10:35:17Z

Z3419587: /* 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: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'''
[[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]]
|}

'''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

2014-10-22T10:26:24Z

Z3419587: /* 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: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.

{| style="width:40%; height:170px" align="center"
|-
| [[Image:Internurons migration in cerebral cortex.jpg|frame|250x250px|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/>

User:Z3419587

2014-10-22T00:23:55Z

Z3419587:

{{StudentPage2014}}

==Lab Attendance==
Lab 1 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 12:45, 6 August 2014 (EST)

Lab 2 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:11, 13 August 2014 (EST)

Lab 3 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:12, 20 August 2014 (EST)

Lab 4 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:45, 27 August 2014 (EST)

Lab 5 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:02, 3 September 2014 (EST)

Lab 6 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:04, 10 September 2014 (EST)

Lab 7 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:05, 17 September 2014 (EST)

Lab 8 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:13, 24 September 2014 (EST)

Lab 9 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 10:49, 8 October 2014 (EST)

Lab 10 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:07, 15 October 2014 (EST)

Lab 11 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:23, 22 October 2014 (EST)

Lab 12

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 1 Assessment==
<pubmed>25071849</pubmed>
summary:
This study was done to compare the clinical outcomes between fresh embryo transfers and frozen-thawed embryo transfers.

A total of 1891 cycle contains 1150 fresh embryo transfers and 741 frozen-thawed embryo transfers were studied. All data were transferred directly to SPSS 18 and analyzed.

A long gonadotropin releasing hormone (GnRH) agonist protocol was used in all cycles. Clinical pregnancy was defined by the observation of a gestational sac with or without a fetal heartbeat on ultrasound evaluation on the 30th day after embryo transfer. The number of sacs was taken as the number of implantations.

The results showed that there was a higher clinical pregnancy rate in fresh cleavage-stage embryo transfers than frozen-thawed cleavage-stage transfers but the clinical pregnancy rates were not different significantly.

<pubmed>25077107</pubmed>
summary:
The study was done to investigate the effect of vitamin D levels on implantation and clinical pregnancy rates in infertile women following in vitro fertilization (IVF).

173 women underwent IVF were included in the study under 3 criteria, including aged 18-41 years, follicle stimulating hormone level 12 IU/L or lower and able to provide informed consent. Vitamin D was determined by serum 25(OH)D levels and samples were collected before oocyte retrieval, while implantation was determined by the presence of a gestational sac, visible by ultrasonography.

χ2 and Student t tests or Mann-Whitney U tests were used to analyze categorical and continuous variables respectively. Multi-variable logistic regression was used to evaluate the relation between serum 25(OH)D level and implantation and clinical pregnancy after adjustment fpr parameters known to influence the IVF sucesss.

The results showed that women with sufficient levels of 25(OH)D had significantly higher rates of clinical pregnancy per IVF cycle started than that with insufficient levels. It also found that implantation rates were higher, but not statistically significant, in the sufficient 25(OH)D group. Therefore, the findings suggested that women with sufficient vitamin D levels are significantly more likely to achieve clinical pregnancy following IVF.

--[[User:Z8600021|Mark Hill]] These are both good articles and summaries (5/5)

==Lab 2 Assessment==
[[File:Development_of_nuclear_transfer_embryos.jpeg|300px]]

<ref><pubmed>23251622</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0051778]</ref>
<references/>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 15:27, 22 August 2014 (EST) I have uploaded a smaller version of this image, but you still need to adjust the size as it appears on your page to 300px and include the reference. Please use jpg format images if possible. You need to reformat the reference as shown in the class tutorial. (4/5)

==Lab 3 Assessment==
===Neural development during fetal period===
<pubmed>21042938</pubmed>
<pubmed>12060827</pubmed>
<pubmed>23727529</pubmed>
<pubmed>16905335</pubmed>
<pubmed>17848161</pubmed>
<pubmed>18760424</pubmed>
<pubmed>16971596</pubmed>
<pubmed>17032846</pubmed>

--[[User:Z8600021|Mark Hill]] These are useful references, I needed a single sentence on why you had selected these references for your section. (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>16099997</pubmed>
summary:
The paper presented the possibility of the therapeutic use of cord stem cells in Parkinson’s disease.

Human mesenchymal stem cells from Wharton’s jelly of the umbilical cord were isolated and induced to transform into dopaminergic neurons in vitro. 12.7% of the cells were successfully transformed and generated through a stepwise culturing in neuron-conditioned medium, sonic hedgehog and FGF8. The cells were transplanted into the striatum of rats previously made Parkinsonian by unilateral striatal lesioning with the dopaminergic neurotoxin 6-hydroxydopamine HCl (6-OHDA). The effects of the transplantation were examined by quantification of rotations in response to amphetamine at 1, 2, 3 and 4 months after transplantation.

It was found that the transplantation of the stem cells corrected the lesion-induces amphetamine-evoked rotation and the cells in the striatum were still viable 4 months after transplantation. These results give the possibility to human umbilical mesenchymal stem cells in treating Parkinson’s disease. However, it is suggested that the examination of the toxicity of growth factor and medium used is important, and the observation of the effects and side-effects for more than 1 year after transplantation is required before human studies

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

Ductus arteriosus: connection between the most cranial part of the pulmonary trunk and dorsal aorta

Ductus venosus: connection between the intra-abdominal umbilical vein and the inferior vena cava

Foramen ovale: located in interatrial septum, connecting left and right atria

Umbilical arteries: branch from the internal iliac arteries in the pelvis and connect to the placenta

Umbilical vein: connection between placenta and portal vein, or ductus venous

==Lab 5 Assessment==
===Congenital Laryngeal Webs===

Congenial laryngeal webs are caused by failure of recanalization of the laryngotracheal tube during the third month of gestation. Findings suggested that congenital laryngeal webs can be explained by abnormal development of the epithelial lamina, the laryngeal cecum, or the vestibulotracheal duct <ref><pubmed>16798587</pubmed></ref>. It has also been reported that there is an association between anterior webs, the most common laryngeal webs, with deletions of chromosome 22q11<ref><pubmed>10699233</pubmed></ref>.

In human embryo, congenial laryngeal webs are formed during embryogenesis of the laryngotracheal groove <ref><pubmed>20376251</pubmed></ref>. The developing laryngeal is temporarily obliterated by actively proliferating epithelium, however, the lumen is normally re-established as the vocal cords. This abnormality is resulted from incomplete resorption of the epithelial layer during the 7th and 8th week of intrauterine development.

references:

<references/>

==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. (pancreas)'''

In this study, the distribution of chromogranin A, insulin, and glucagon in 25 human fetal pancreases was studied. Immunohistochemical reactions were carried out and sections of pancreas were labelled with antibodies to chromogranin A, insulin and glucagon.

Immunopositive reaction to chromgranin A was resulted from week 8 of development onwards. During the development of pancreas, the population of endocrine cells increased and pancreatic islets are formed. The majority of cells in the pancreatic islets were found to be chromogranin A that located in the cytoplasm. Chromogranin A immunoreactive cells were also found in glandular ductal epithelium of 8-9-week fetuses, suggesting that the cells formed a population of precursors of endocrine cells without synthesizing hormones.

The express of chromogranin A, which is higher than that of insulin and glucagon, during differentiation of pancreatic endocrine cells suggested that this can be a marker for studies of the mechanisms of endocrine development of pancreas.

reference:
<pubmed>24824718</pubmed>

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

Tooth germ: aggregation of cells derived from the ectomesenchymal cells from neural crest and ectoderm of first arch. It is then organized into 3 components of the tooth germ, which are the enamel organ, dental papilla and dental follicle for the teeth development.

==Lab 8 Assessment==
'''1. Provide a brief time course and overview of embryonic development of either the human testis or ovary. (2-3 paragraphs)'''

Gonads are developed from the mesothelium of the posterior abdominal wall, the adjacent mesenchyme and the primordial germ cells. The development begins in week 5 where the mesothelium medial to the mesonephros of the developing kidneys thickens and forming the paired gonadal ridges.

The primordial germ cells are the precursors of oocytes that they migrate from the yolk sac to the mesenchyme of the gonadal ridges between weeks 3 to 5 and incorporate into the primary sex cords. The sex cords extend to the medulla of the future ovary and regress by week 8.

During week 8, gonad begins to develop into ovary due to the stimulation from germ cells. The primitive medullary cords in the ovary degenerates and the primordial germ cells differentiate under the influence of placental gonadotropins. The germ cells undergo mitotic divisions and differentiate into several million oogonia. Around week 16 to week 20, the primitive follicles organize within the fetal ovarian cortex. By 5-6 months gestation, the primitive follicles are enveloped by a layer of epithelial cells and become primordial follicles. During the development, the ovaries descend into the pelvis by the third month.

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

[[File:Bailey328.jpg|300px]]

Reference:
Bailey, F.R. and Miller, A.M. (1921). '''Text-Book of Embryology.''' New York: William Wood and Co.

==Lab 9 Assessment==
===Group 1===

The product was done well overall with lots of information and a good structure. However, I am a bit confused about the sections “respiratory” and “lung development stages”. I guess “lung development stages” is also under “respiratory”, but it seems that they are separated into two big sections.

The introduction clearly explains the development of respiratory system. It is good to divide respiratory tract into 2 main parts and explain them separately. It would be better if it includes a sentence like ‘this website will focus on fetal development of respiratory system.

Using table to explain different stages of lung development is a good idea. It would be easier to read if they are typed in point forms with some images included.

More images could be added under current research, models and findings for easier understanding. Some information should be added under current models.

The historic findings and abnormalities are good and informative.

Some images do not have the information about copyright. It would be better if there is a title for each image included.

In terms of referencing, they are missing in the sections under introduction, conducting zone and respiratory zone. In-text references are also missing in the table about the stages and features of lung development. Also, the images used have not been referenced. Reference list at the end rather than under each section should be used instead.

It is overall a good project and well-researched. More images can be included to balance with the huge amount of text.

===Group 2===

The introduction is good and describes the project well. It is good to mention the function of renal system. It would be better if it states that the website will be focused on fetal development, current research and abnormalities to give a better understanding of the content.

Information under historic findings is missing, it would be a good way to start it by looking at textbooks. Images, bullet points and table can be used for an easy understanding of this section.

Using timeline to summarise the development of kidney is a good idea, however it would be clearer if a table is used, more descriptions under each stages and some images are include. Also, some references should be included in this section.

There are a lot of details under development, current research and abnormalities. It would be easier to read if they are written in point form. It is a good idea to divide renal system into several parts (kidney, urethra…) for the explanation of development. For the abnormalities, it is well-researched but some of the details are missing. It would be better if the each type of abnormalities is discussed equally.

Regarding the images, it is good and clear to explain each of them. The only problem is that there is no copyright information under the file “kidney ascent.jpg”.

The project is informative but lacking some information under historic findings and the developmental timeline.

===Group 3===

Introduction is good as it describes and gives an overview about what is happening in the fetal period for foregut, midgut and hindgut. However, it would be better if it mentions that the project is focusing on fetal development, abnormalities, current researches, etc.

It is clear to separate the timeline of GIT development for hindgut, midgut and foregut. It is well-researched with much information in this section. However, it would be easier to follow if a table is used and images are included.

The hand-drawn images can explain the development well, however the blue colour for labelling is a bit difficult for reading. It would be better if a darker colour is used.

It is a good idea to explain the abnormalities in definition and the causes. Some more abnormalities can be included as well as images for better understanding.

There is only one reference in recent findings. More researches could be done in this section. Also, a section about historic findings could be included as well.

There are a few spelling errors, such as “esenchyme” in the hindgut section and “tot hat of” under midgut section. Some proof-readings are needed.

The referencing is overall good, but some more researches have to be done under some sections (abnormalities and recent findings). It is easy to follow as there is a reference list at the bottom of page.

It is overall a good project as the development during fetal period is well described. However, more information about recent findings and abnormalities could be included, with the use of images to illustrate the contents.

===Group 4===

The project would be easier to follow by having an introduction that give readers an idea about what is going to be covered in the website.

Under the section about system development, it contains lots of information and it is well researched. Using bullet points is good as it is easier to read, however some of them could be join together into a small paragraph which would increase the readability. It is good to see a related video about the development of reproductive system and it explains well about this topic.

It is a great way to explain abnormalities in terms of female, male, and both. Maybe try to put a table at the top to summarise the abnormalities so that it would be easier to follow. More images are needed in this section, just like the one illustrating abnormalities of uterus and vagina.

It is well-researched under historic findings, try to put more related images to make this section more interactive. Also, it would also be good to illustrate the content in this part by a timeline, followed by the explanation of each event.

In terms of referencing, in-text references are missing in the system development, current research and historic findings.

For the image file “Image.jpg”, which is about sexual differentiation, it is a good image that explains the differentiation clearly, however, it would be better to put a description or title below it to make it more relevant to the project. It is good to see some hand-drawn diagram and they match the topic and explain information well. I found it a bit hard to read the labels on the image “labelled drawing of testes.jpeg”, maybe upload the image by scanning rather than taking a photo of it would be better.

It is overall a well-researched project. The next thing to do is to include an introduction, some more in-text references and some related images.

===Group 5===

The introduction clearly states the content in the website, which is good as this can prepare the readers for understanding. However, it would be better if some information about integumentary system, such as functions, is included in this section.

The development of integument system includes a lot of information. They are presented in good structure by the use of table for skin and nail. It is a great way to put some images in the table for easy understanding of the description in the development of teeth.

The recent findings area is well-researched. I would suggest try to put the content into small paragraph or in several points as the amount of text is a bit too much. Some images should be included as well.

Abnormalities section is great with the help of the images. It would be good if some more abnormalities are included. There is a lot of details under historic findings, try to illustrate them with the help of images.

In-text references should be included in the sections under development, recent findings and historic findings.

The project is well prepared. It would be better if some more images are included and the function of integument system is stated in the introduction.

===Group 6===

Introduction is missing in the project. It would be great to include the functions of endocrine system and the contents that will be covered including system development, abnormalities, current research, etc.

There is a lot to cover in endocrine system, it is a great way to separate timeline and recent findings under each individual organ. Using table to illustrate the function of hormone is good, however, I think it would be better to have a summary of hormone in a table form at the top/the end of all individual organs. The parathyroid gland and pancreas are well-researched with the use of images. More information has to be included in other sections.

More work has to be done on abnormalities. Actually, they could be separated under each organ, just like current findings. It would also be good to see historic findings under each organ.

In terms of referencing, there is no in-text reference and the reference list at the bottom is empty at this moment. This project overall has a good structure, but more information and images are needed.

===Group 8===

Introduction is missing. Some information about the functions of the systems and topics going to be covered should be included here. The section ‘making gains’ is funny. However, more work has to be done to make it more interesting.

For the timeline, more information is needed. It would be great to include a table here and describe the changes during different stages (microfibers formation…). Table is also useful to explain the second trimester muscular development

The information under background embryonic development can be summarised and put under introduction as this project should be focused on fetal development.

It is great to have molecular and cellular regulation. However, more diagrams are needed here. It would be better if they are stated in several points rather than a big paragraph. Also, more images are needed for other sections, it would be good to draw the picture as well.

For abnormalities, in-text references are needed. Also, some more abnormalities should be included with the use of images to illustrate them.

Overall, there is a pretty good structure of the website. It could be improved by including some current and historic researches on this topic. Also, more images are needed (as there is none now) to make the webpage more interesting and informative. More contents should be included as well.

==Lab 10 Assessment==
'''Identify a recent research paper on sensory development (not hearing) and write a brief summary (several paragraphs) of the research methods and findings. Include at the end a link to the relevant wiki sensory notes page.'''

The researchers investigated the functional changes of olfactory sensory neurons (OSNs), which express mouse odorant receptor 23 (MOR23) with a known ligand (lyral), during the first postnatal month. Also, as olfactory marker protein (OMP) is recognized as a molecular marker for mature OSNs, it is hypothesized that OMP has an important role in functional maturation of OSNs.

In their research, genetically targeted MOR23-IRES (internal ribosome entry site)-tauGFP mice (with WT-MOR23 neurons) were used to record MOR23 neurons that coexpress green flurescent protein (GFP). Also homozyhous double mutant mice (with OMP -/- MOR23 neurons) were generated.

To investigate whether OSNs undergo functional changes during development, the odorant responses in individual neurons from animals at different ages (P0-P30, where P=postnatal day) were measured by perforated patch-clamp recordings on the dendritic knobs on individual OSNs. The results indicated that OSNs exhibit faster response kinetics during development. Furthermore, the effects of OMP deletion on functional properties of OSNs were also studied through the homozygous OMP -/- mice. It was found that OMP deletion results in OSNs with slow response kinetics, suggesting the OMP is necessary for the kinetic changes during the OSNs development. In addition, the selectivity of OSNs changes during the first postnatal month was tested and it was demonstrated that MOR23 neurons from P30 mice has higher selectivity to lyral. In terms of behavior test, the researchers also observed that WT but not OMP -/- mouse pups prefer the biological mother when the biological mother and another unfamiliar lactating female was given to choose.

In conclusion, the researchers showed that OMP is necessary for the maturation process in olfactory system. Also, MOR23 neurons from P30 mice have a faster response kinetics, higher sensitivity and higher selectivity when compared to the neurons from P0 mice. The results also suggested the maturation process of OSNs coincides with early development of the smell function and is critical for pups to form mother preference.

Reference: <pubmed>21414919</pubmed>

Links: [[Sensory_-_Smell_Development|Smell Development]]

User:Z3419587

2014-10-21T14:32:08Z

Z3419587:

{{StudentPage2014}}

==Lab Attendance==
Lab 1 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 12:45, 6 August 2014 (EST)

Lab 2 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:11, 13 August 2014 (EST)

Lab 3 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:12, 20 August 2014 (EST)

Lab 4 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:45, 27 August 2014 (EST)

Lab 5 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:02, 3 September 2014 (EST)

Lab 6 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:04, 10 September 2014 (EST)

Lab 7 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:05, 17 September 2014 (EST)

Lab 8 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:13, 24 September 2014 (EST)

Lab 9 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 10:49, 8 October 2014 (EST)

Lab 10 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:07, 15 October 2014 (EST)

Lab 11

Lab 12

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 1 Assessment==
<pubmed>25071849</pubmed>
summary:
This study was done to compare the clinical outcomes between fresh embryo transfers and frozen-thawed embryo transfers.

A total of 1891 cycle contains 1150 fresh embryo transfers and 741 frozen-thawed embryo transfers were studied. All data were transferred directly to SPSS 18 and analyzed.

A long gonadotropin releasing hormone (GnRH) agonist protocol was used in all cycles. Clinical pregnancy was defined by the observation of a gestational sac with or without a fetal heartbeat on ultrasound evaluation on the 30th day after embryo transfer. The number of sacs was taken as the number of implantations.

The results showed that there was a higher clinical pregnancy rate in fresh cleavage-stage embryo transfers than frozen-thawed cleavage-stage transfers but the clinical pregnancy rates were not different significantly.

<pubmed>25077107</pubmed>
summary:
The study was done to investigate the effect of vitamin D levels on implantation and clinical pregnancy rates in infertile women following in vitro fertilization (IVF).

173 women underwent IVF were included in the study under 3 criteria, including aged 18-41 years, follicle stimulating hormone level 12 IU/L or lower and able to provide informed consent. Vitamin D was determined by serum 25(OH)D levels and samples were collected before oocyte retrieval, while implantation was determined by the presence of a gestational sac, visible by ultrasonography.

χ2 and Student t tests or Mann-Whitney U tests were used to analyze categorical and continuous variables respectively. Multi-variable logistic regression was used to evaluate the relation between serum 25(OH)D level and implantation and clinical pregnancy after adjustment fpr parameters known to influence the IVF sucesss.

The results showed that women with sufficient levels of 25(OH)D had significantly higher rates of clinical pregnancy per IVF cycle started than that with insufficient levels. It also found that implantation rates were higher, but not statistically significant, in the sufficient 25(OH)D group. Therefore, the findings suggested that women with sufficient vitamin D levels are significantly more likely to achieve clinical pregnancy following IVF.

--[[User:Z8600021|Mark Hill]] These are both good articles and summaries (5/5)

==Lab 2 Assessment==
[[File:Development_of_nuclear_transfer_embryos.jpeg|300px]]

<ref><pubmed>23251622</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0051778]</ref>
<references/>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 15:27, 22 August 2014 (EST) I have uploaded a smaller version of this image, but you still need to adjust the size as it appears on your page to 300px and include the reference. Please use jpg format images if possible. You need to reformat the reference as shown in the class tutorial. (4/5)

==Lab 3 Assessment==
===Neural development during fetal period===
<pubmed>21042938</pubmed>
<pubmed>12060827</pubmed>
<pubmed>23727529</pubmed>
<pubmed>16905335</pubmed>
<pubmed>17848161</pubmed>
<pubmed>18760424</pubmed>
<pubmed>16971596</pubmed>
<pubmed>17032846</pubmed>

--[[User:Z8600021|Mark Hill]] These are useful references, I needed a single sentence on why you had selected these references for your section. (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>16099997</pubmed>
summary:
The paper presented the possibility of the therapeutic use of cord stem cells in Parkinson’s disease.

Human mesenchymal stem cells from Wharton’s jelly of the umbilical cord were isolated and induced to transform into dopaminergic neurons in vitro. 12.7% of the cells were successfully transformed and generated through a stepwise culturing in neuron-conditioned medium, sonic hedgehog and FGF8. The cells were transplanted into the striatum of rats previously made Parkinsonian by unilateral striatal lesioning with the dopaminergic neurotoxin 6-hydroxydopamine HCl (6-OHDA). The effects of the transplantation were examined by quantification of rotations in response to amphetamine at 1, 2, 3 and 4 months after transplantation.

It was found that the transplantation of the stem cells corrected the lesion-induces amphetamine-evoked rotation and the cells in the striatum were still viable 4 months after transplantation. These results give the possibility to human umbilical mesenchymal stem cells in treating Parkinson’s disease. However, it is suggested that the examination of the toxicity of growth factor and medium used is important, and the observation of the effects and side-effects for more than 1 year after transplantation is required before human studies

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

Ductus arteriosus: connection between the most cranial part of the pulmonary trunk and dorsal aorta

Ductus venosus: connection between the intra-abdominal umbilical vein and the inferior vena cava

Foramen ovale: located in interatrial septum, connecting left and right atria

Umbilical arteries: branch from the internal iliac arteries in the pelvis and connect to the placenta

Umbilical vein: connection between placenta and portal vein, or ductus venous

==Lab 5 Assessment==
===Congenital Laryngeal Webs===

Congenial laryngeal webs are caused by failure of recanalization of the laryngotracheal tube during the third month of gestation. Findings suggested that congenital laryngeal webs can be explained by abnormal development of the epithelial lamina, the laryngeal cecum, or the vestibulotracheal duct <ref><pubmed>16798587</pubmed></ref>. It has also been reported that there is an association between anterior webs, the most common laryngeal webs, with deletions of chromosome 22q11<ref><pubmed>10699233</pubmed></ref>.

In human embryo, congenial laryngeal webs are formed during embryogenesis of the laryngotracheal groove <ref><pubmed>20376251</pubmed></ref>. The developing laryngeal is temporarily obliterated by actively proliferating epithelium, however, the lumen is normally re-established as the vocal cords. This abnormality is resulted from incomplete resorption of the epithelial layer during the 7th and 8th week of intrauterine development.

references:

<references/>

==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. (pancreas)'''

In this study, the distribution of chromogranin A, insulin, and glucagon in 25 human fetal pancreases was studied. Immunohistochemical reactions were carried out and sections of pancreas were labelled with antibodies to chromogranin A, insulin and glucagon.

Immunopositive reaction to chromgranin A was resulted from week 8 of development onwards. During the development of pancreas, the population of endocrine cells increased and pancreatic islets are formed. The majority of cells in the pancreatic islets were found to be chromogranin A that located in the cytoplasm. Chromogranin A immunoreactive cells were also found in glandular ductal epithelium of 8-9-week fetuses, suggesting that the cells formed a population of precursors of endocrine cells without synthesizing hormones.

The express of chromogranin A, which is higher than that of insulin and glucagon, during differentiation of pancreatic endocrine cells suggested that this can be a marker for studies of the mechanisms of endocrine development of pancreas.

reference:
<pubmed>24824718</pubmed>

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

Tooth germ: aggregation of cells derived from the ectomesenchymal cells from neural crest and ectoderm of first arch. It is then organized into 3 components of the tooth germ, which are the enamel organ, dental papilla and dental follicle for the teeth development.

==Lab 8 Assessment==
'''1. Provide a brief time course and overview of embryonic development of either the human testis or ovary. (2-3 paragraphs)'''

Gonads are developed from the mesothelium of the posterior abdominal wall, the adjacent mesenchyme and the primordial germ cells. The development begins in week 5 where the mesothelium medial to the mesonephros of the developing kidneys thickens and forming the paired gonadal ridges.

The primordial germ cells are the precursors of oocytes that they migrate from the yolk sac to the mesenchyme of the gonadal ridges between weeks 3 to 5 and incorporate into the primary sex cords. The sex cords extend to the medulla of the future ovary and regress by week 8.

During week 8, gonad begins to develop into ovary due to the stimulation from germ cells. The primitive medullary cords in the ovary degenerates and the primordial germ cells differentiate under the influence of placental gonadotropins. The germ cells undergo mitotic divisions and differentiate into several million oogonia. Around week 16 to week 20, the primitive follicles organize within the fetal ovarian cortex. By 5-6 months gestation, the primitive follicles are enveloped by a layer of epithelial cells and become primordial follicles. During the development, the ovaries descend into the pelvis by the third month.

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

[[File:Bailey328.jpg|300px]]

Reference:
Bailey, F.R. and Miller, A.M. (1921). '''Text-Book of Embryology.''' New York: William Wood and Co.

==Lab 9 Assessment==
===Group 1===

The product was done well overall with lots of information and a good structure. However, I am a bit confused about the sections “respiratory” and “lung development stages”. I guess “lung development stages” is also under “respiratory”, but it seems that they are separated into two big sections.

The introduction clearly explains the development of respiratory system. It is good to divide respiratory tract into 2 main parts and explain them separately. It would be better if it includes a sentence like ‘this website will focus on fetal development of respiratory system.

Using table to explain different stages of lung development is a good idea. It would be easier to read if they are typed in point forms with some images included.

More images could be added under current research, models and findings for easier understanding. Some information should be added under current models.

The historic findings and abnormalities are good and informative.

Some images do not have the information about copyright. It would be better if there is a title for each image included.

In terms of referencing, they are missing in the sections under introduction, conducting zone and respiratory zone. In-text references are also missing in the table about the stages and features of lung development. Also, the images used have not been referenced. Reference list at the end rather than under each section should be used instead.

It is overall a good project and well-researched. More images can be included to balance with the huge amount of text.

===Group 2===

The introduction is good and describes the project well. It is good to mention the function of renal system. It would be better if it states that the website will be focused on fetal development, current research and abnormalities to give a better understanding of the content.

Information under historic findings is missing, it would be a good way to start it by looking at textbooks. Images, bullet points and table can be used for an easy understanding of this section.

Using timeline to summarise the development of kidney is a good idea, however it would be clearer if a table is used, more descriptions under each stages and some images are include. Also, some references should be included in this section.

There are a lot of details under development, current research and abnormalities. It would be easier to read if they are written in point form. It is a good idea to divide renal system into several parts (kidney, urethra…) for the explanation of development. For the abnormalities, it is well-researched but some of the details are missing. It would be better if the each type of abnormalities is discussed equally.

Regarding the images, it is good and clear to explain each of them. The only problem is that there is no copyright information under the file “kidney ascent.jpg”.

The project is informative but lacking some information under historic findings and the developmental timeline.

===Group 3===

Introduction is good as it describes and gives an overview about what is happening in the fetal period for foregut, midgut and hindgut. However, it would be better if it mentions that the project is focusing on fetal development, abnormalities, current researches, etc.

It is clear to separate the timeline of GIT development for hindgut, midgut and foregut. It is well-researched with much information in this section. However, it would be easier to follow if a table is used and images are included.

The hand-drawn images can explain the development well, however the blue colour for labelling is a bit difficult for reading. It would be better if a darker colour is used.

It is a good idea to explain the abnormalities in definition and the causes. Some more abnormalities can be included as well as images for better understanding.

There is only one reference in recent findings. More researches could be done in this section. Also, a section about historic findings could be included as well.

There are a few spelling errors, such as “esenchyme” in the hindgut section and “tot hat of” under midgut section. Some proof-readings are needed.

The referencing is overall good, but some more researches have to be done under some sections (abnormalities and recent findings). It is easy to follow as there is a reference list at the bottom of page.

It is overall a good project as the development during fetal period is well described. However, more information about recent findings and abnormalities could be included, with the use of images to illustrate the contents.

===Group 4===

The project would be easier to follow by having an introduction that give readers an idea about what is going to be covered in the website.

Under the section about system development, it contains lots of information and it is well researched. Using bullet points is good as it is easier to read, however some of them could be join together into a small paragraph which would increase the readability. It is good to see a related video about the development of reproductive system and it explains well about this topic.

It is a great way to explain abnormalities in terms of female, male, and both. Maybe try to put a table at the top to summarise the abnormalities so that it would be easier to follow. More images are needed in this section, just like the one illustrating abnormalities of uterus and vagina.

It is well-researched under historic findings, try to put more related images to make this section more interactive. Also, it would also be good to illustrate the content in this part by a timeline, followed by the explanation of each event.

In terms of referencing, in-text references are missing in the system development, current research and historic findings.

For the image file “Image.jpg”, which is about sexual differentiation, it is a good image that explains the differentiation clearly, however, it would be better to put a description or title below it to make it more relevant to the project. It is good to see some hand-drawn diagram and they match the topic and explain information well. I found it a bit hard to read the labels on the image “labelled drawing of testes.jpeg”, maybe upload the image by scanning rather than taking a photo of it would be better.

It is overall a well-researched project. The next thing to do is to include an introduction, some more in-text references and some related images.

===Group 5===

The introduction clearly states the content in the website, which is good as this can prepare the readers for understanding. However, it would be better if some information about integumentary system, such as functions, is included in this section.

The development of integument system includes a lot of information. They are presented in good structure by the use of table for skin and nail. It is a great way to put some images in the table for easy understanding of the description in the development of teeth.

The recent findings area is well-researched. I would suggest try to put the content into small paragraph or in several points as the amount of text is a bit too much. Some images should be included as well.

Abnormalities section is great with the help of the images. It would be good if some more abnormalities are included. There is a lot of details under historic findings, try to illustrate them with the help of images.

In-text references should be included in the sections under development, recent findings and historic findings.

The project is well prepared. It would be better if some more images are included and the function of integument system is stated in the introduction.

===Group 6===

Introduction is missing in the project. It would be great to include the functions of endocrine system and the contents that will be covered including system development, abnormalities, current research, etc.

There is a lot to cover in endocrine system, it is a great way to separate timeline and recent findings under each individual organ. Using table to illustrate the function of hormone is good, however, I think it would be better to have a summary of hormone in a table form at the top/the end of all individual organs. The parathyroid gland and pancreas are well-researched with the use of images. More information has to be included in other sections.

More work has to be done on abnormalities. Actually, they could be separated under each organ, just like current findings. It would also be good to see historic findings under each organ.

In terms of referencing, there is no in-text reference and the reference list at the bottom is empty at this moment. This project overall has a good structure, but more information and images are needed.

===Group 8===

Introduction is missing. Some information about the functions of the systems and topics going to be covered should be included here. The section ‘making gains’ is funny. However, more work has to be done to make it more interesting.

For the timeline, more information is needed. It would be great to include a table here and describe the changes during different stages (microfibers formation…). Table is also useful to explain the second trimester muscular development

The information under background embryonic development can be summarised and put under introduction as this project should be focused on fetal development.

It is great to have molecular and cellular regulation. However, more diagrams are needed here. It would be better if they are stated in several points rather than a big paragraph. Also, more images are needed for other sections, it would be good to draw the picture as well.

For abnormalities, in-text references are needed. Also, some more abnormalities should be included with the use of images to illustrate them.

Overall, there is a pretty good structure of the website. It could be improved by including some current and historic researches on this topic. Also, more images are needed (as there is none now) to make the webpage more interesting and informative. More contents should be included as well.

==Lab 10 Assessment==
'''Identify a recent research paper on sensory development (not hearing) and write a brief summary (several paragraphs) of the research methods and findings. Include at the end a link to the relevant wiki sensory notes page.'''

The researchers investigated the functional changes of olfactory sensory neurons (OSNs), which express mouse odorant receptor 23 (MOR23) with a known ligand (lyral), during the first postnatal month. Also, as olfactory marker protein (OMP) is recognized as a molecular marker for mature OSNs, it is hypothesized that OMP has an important role in functional maturation of OSNs.

In their research, genetically targeted MOR23-IRES (internal ribosome entry site)-tauGFP mice (with WT-MOR23 neurons) were used to record MOR23 neurons that coexpress green flurescent protein (GFP). Also homozyhous double mutant mice (with OMP -/- MOR23 neurons) were generated.

To investigate whether OSNs undergo functional changes during development, the odorant responses in individual neurons from animals at different ages (P0-P30, where P=postnatal day) were measured by perforated patch-clamp recordings on the dendritic knobs on individual OSNs. The results indicated that OSNs exhibit faster response kinetics during development. Furthermore, the effects of OMP deletion on functional properties of OSNs were also studied through the homozygous OMP -/- mice. It was found that OMP deletion results in OSNs with slow response kinetics, suggesting the OMP is necessary for the kinetic changes during the OSNs development. In addition, the selectivity of OSNs changes during the first postnatal month was tested and it was demonstrated that MOR23 neurons from P30 mice has higher selectivity to lyral. In terms of behavior test, the researchers also observed that WT but not OMP -/- mouse pups prefer the biological mother when the biological mother and another unfamiliar lactating female was given to choose.

In conclusion, the researchers showed that OMP is necessary for the maturation process in olfactory system. Also, MOR23 neurons from P30 mice have a faster response kinetics, higher sensitivity and higher selectivity when compared to the neurons from P0 mice. The results also suggested the maturation process of OSNs coincides with early development of the smell function and is critical for pups to form mother preference.

Reference: <pubmed>21414919</pubmed>

Links: [[Sensory_-_Smell_Development|Smell Development]]

2014 Group Project 7

2014-10-20T12:30:12Z

Z3419587: /* 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: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

- 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><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><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.

'''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.

'''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

'''1833''' – Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar

'''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===

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.

[[File: Occipital encephalocele associated with microcephaly.jpg|300px]]

Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia<ref><pubmed>3271622</pubmed>|[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3271622/]</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.

'''Hydrocephalus'''

* 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.

[[File: Arachnoid_cyst_with_hydrocephalus.jpg|300px]]

Magnetic Resonance image showing arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>

===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===

* 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>

===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:CNS passive.jpg

2014-10-20T12:09:56Z

Z3419587: This is a redrawn diagram illustrating the passive migration of cells after the production of neuron or glial cells in the proliferative zone in the developing CNS. The older cells are displaced outward away from the proliferative zone by the newly pr...

This is a redrawn diagram illustrating the passive migration of cells after the production of neuron or glial cells in the proliferative zone in the developing CNS.
The older cells are displaced outward away from the proliferative zone by the newly produced cells and resulting in an "outside-to-inside" spatiotemporal region.

(A) The first neurons to leave to proliferative zone are shown as triangles.
(B) The next neurons formed are shown as diamonds. They move away from the proliferative zones and displace the earlier generated ones.
(C) The final neurons are shown as stars. These cells move away from the ventricular zone and displace both earlier generated cells.

V = Ventricular surface; VZ = ventricular
zone; IZ = intermediate zone; CP = cortical plate; MZ = marginal zone; P = pial surface

Redrawn from <ref><pubmed>10532616</pubmed></ref>

===Reference===
<references/>

{{Template:Student Image}}

File:CNS active.jpg

2014-10-20T11:59:30Z

Z3419587: This is a redrawn diagram illustrating the active migration of cells after the production of neuron or glial cells in the proliferative zone in the developing CNS. The later-generated cells bypass the earlier-generated cells and result in a location fu...

This is a redrawn diagram illustrating the active migration of cells after the production of neuron or glial cells in the proliferative zone in the developing CNS. The later-generated cells bypass the
earlier-generated cells and result in a location further away from the proliferative zone, resulting in an "inside-to-outside" spatiotemporal gradient.
(A) The first neurons to leave to proliferative zone are shown as triangles and they form a corticle plate between the intermediate and the marginal zones.
(B) The next neurons formed are shown as diamonds. They leave the proliferative zones, migrate across the intermediate zone to the top of the cortical plate by passing the first neurons.
(C) The final neurons are shown as stars. The cells also migrate to the top of the cortical plate.
V = Ventricular surface; VZ = ventricular zone; SZ = subventricular
zone; IZ = intermediate zone; CP = cortical plate; MZ = marginal zone; P = pial surface

Redrawn from <ref><pubmed>10532616</pubmed></ref>

===Reference===
<references/>

{{Template:Student Image}}

2014 Group Project 7

2014-10-20T11:22:11Z

Z3419587: /* 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: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.

# 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.

[[File:Internurons migration in cerebral cortex.jpg|300px]]

Image of interneurons migration and interactions with radial glia in the developing cerebral cortex <ref><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

- 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><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><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.

'''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.

'''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

'''1833''' – Robert Remak discovers that the brain tissue is cellular. Ehrenberg discovers that it is also fibrillar

'''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===

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.

[[File: Occipital encephalocele associated with microcephaly.jpg|300px]]

Clinical photograph showing the giant occipital encephalocele associated with microcephaly and micrognathia<ref><pubmed>3271622</pubmed>|[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3271622/]</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.

'''Hydrocephalus'''

* 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.

[[File: Arachnoid_cyst_with_hydrocephalus.jpg|300px]]

Magnetic Resonance image showing arachnoid Cyst with Hydrocephalus <ref><pubmed>22069421</pubmed></ref>

===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===

* 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>

===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:Z3419587

2014-10-15T00:08:12Z

Z3419587:

{{StudentPage2014}}

==Lab Attendance==
Lab 1 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 12:45, 6 August 2014 (EST)

Lab 2 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:11, 13 August 2014 (EST)

Lab 3 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:12, 20 August 2014 (EST)

Lab 4 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:45, 27 August 2014 (EST)

Lab 5 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:02, 3 September 2014 (EST)

Lab 6 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:04, 10 September 2014 (EST)

Lab 7 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:05, 17 September 2014 (EST)

Lab 8 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:13, 24 September 2014 (EST)

Lab 9 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 10:49, 8 October 2014 (EST)

Lab 10 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:07, 15 October 2014 (EST)

Lab 11

Lab 12

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 1 Assessment==
<pubmed>25071849</pubmed>
summary:
This study was done to compare the clinical outcomes between fresh embryo transfers and frozen-thawed embryo transfers.

A total of 1891 cycle contains 1150 fresh embryo transfers and 741 frozen-thawed embryo transfers were studied. All data were transferred directly to SPSS 18 and analyzed.

A long gonadotropin releasing hormone (GnRH) agonist protocol was used in all cycles. Clinical pregnancy was defined by the observation of a gestational sac with or without a fetal heartbeat on ultrasound evaluation on the 30th day after embryo transfer. The number of sacs was taken as the number of implantations.

The results showed that there was a higher clinical pregnancy rate in fresh cleavage-stage embryo transfers than frozen-thawed cleavage-stage transfers but the clinical pregnancy rates were not different significantly.

<pubmed>25077107</pubmed>
summary:
The study was done to investigate the effect of vitamin D levels on implantation and clinical pregnancy rates in infertile women following in vitro fertilization (IVF).

173 women underwent IVF were included in the study under 3 criteria, including aged 18-41 years, follicle stimulating hormone level 12 IU/L or lower and able to provide informed consent. Vitamin D was determined by serum 25(OH)D levels and samples were collected before oocyte retrieval, while implantation was determined by the presence of a gestational sac, visible by ultrasonography.

χ2 and Student t tests or Mann-Whitney U tests were used to analyze categorical and continuous variables respectively. Multi-variable logistic regression was used to evaluate the relation between serum 25(OH)D level and implantation and clinical pregnancy after adjustment fpr parameters known to influence the IVF sucesss.

The results showed that women with sufficient levels of 25(OH)D had significantly higher rates of clinical pregnancy per IVF cycle started than that with insufficient levels. It also found that implantation rates were higher, but not statistically significant, in the sufficient 25(OH)D group. Therefore, the findings suggested that women with sufficient vitamin D levels are significantly more likely to achieve clinical pregnancy following IVF.

--[[User:Z8600021|Mark Hill]] These are both good articles and summaries (5/5)

==Lab 2 Assessment==
[[File:Development_of_nuclear_transfer_embryos.jpeg|300px]]

<ref><pubmed>23251622</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0051778]</ref>
<references/>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 15:27, 22 August 2014 (EST) I have uploaded a smaller version of this image, but you still need to adjust the size as it appears on your page to 300px and include the reference. Please use jpg format images if possible. You need to reformat the reference as shown in the class tutorial. (4/5)

==Lab 3 Assessment==
===Neural development during fetal period===
<pubmed>21042938</pubmed>
<pubmed>12060827</pubmed>
<pubmed>23727529</pubmed>
<pubmed>16905335</pubmed>
<pubmed>17848161</pubmed>
<pubmed>18760424</pubmed>
<pubmed>16971596</pubmed>
<pubmed>17032846</pubmed>

--[[User:Z8600021|Mark Hill]] These are useful references, I needed a single sentence on why you had selected these references for your section. (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>16099997</pubmed>
summary:
The paper presented the possibility of the therapeutic use of cord stem cells in Parkinson’s disease.

Human mesenchymal stem cells from Wharton’s jelly of the umbilical cord were isolated and induced to transform into dopaminergic neurons in vitro. 12.7% of the cells were successfully transformed and generated through a stepwise culturing in neuron-conditioned medium, sonic hedgehog and FGF8. The cells were transplanted into the striatum of rats previously made Parkinsonian by unilateral striatal lesioning with the dopaminergic neurotoxin 6-hydroxydopamine HCl (6-OHDA). The effects of the transplantation were examined by quantification of rotations in response to amphetamine at 1, 2, 3 and 4 months after transplantation.

It was found that the transplantation of the stem cells corrected the lesion-induces amphetamine-evoked rotation and the cells in the striatum were still viable 4 months after transplantation. These results give the possibility to human umbilical mesenchymal stem cells in treating Parkinson’s disease. However, it is suggested that the examination of the toxicity of growth factor and medium used is important, and the observation of the effects and side-effects for more than 1 year after transplantation is required before human studies

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

Ductus arteriosus: connection between the most cranial part of the pulmonary trunk and dorsal aorta

Ductus venosus: connection between the intra-abdominal umbilical vein and the inferior vena cava

Foramen ovale: located in interatrial septum, connecting left and right atria

Umbilical arteries: branch from the internal iliac arteries in the pelvis and connect to the placenta

Umbilical vein: connection between placenta and portal vein, or ductus venous

==Lab 5 Assessment==
===Congenital Laryngeal Webs===

Congenial laryngeal webs are caused by failure of recanalization of the laryngotracheal tube during the third month of gestation. Findings suggested that congenital laryngeal webs can be explained by abnormal development of the epithelial lamina, the laryngeal cecum, or the vestibulotracheal duct <ref><pubmed>16798587</pubmed></ref>. It has also been reported that there is an association between anterior webs, the most common laryngeal webs, with deletions of chromosome 22q11<ref><pubmed>10699233</pubmed></ref>.

In human embryo, congenial laryngeal webs are formed during embryogenesis of the laryngotracheal groove <ref><pubmed>20376251</pubmed></ref>. The developing laryngeal is temporarily obliterated by actively proliferating epithelium, however, the lumen is normally re-established as the vocal cords. This abnormality is resulted from incomplete resorption of the epithelial layer during the 7th and 8th week of intrauterine development.

references:

<references/>

==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. (pancreas)

In this study, the distribution of chromogranin A, insulin, and glucagon in 25 human fetal pancreases was studied. Immunohistochemical reactions were carried out and sections of pancreas were labelled with antibodies to chromogranin A, insulin and glucagon.

Immunopositive reaction to chromgranin A was resulted from week 8 of development onwards. During the development of pancreas, the population of endocrine cells increased and pancreatic islets are formed. The majority of cells in the pancreatic islets were found to be chromogranin A that located in the cytoplasm. Chromogranin A immunoreactive cells were also found in glandular ductal epithelium of 8-9-week fetuses, suggesting that the cells formed a population of precursors of endocrine cells without synthesizing hormones.

The express of chromogranin A, which is higher than that of insulin and glucagon, during differentiation of pancreatic endocrine cells suggested that this can be a marker for studies of the mechanisms of endocrine development of pancreas.

reference:
<pubmed>24824718</pubmed>

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

Tooth germ: aggregation of cells derived from the ectomesenchymal cells from neural crest and ectoderm of first arch. It is then organized into 3 components of the tooth germ, which are the enamel organ, dental papilla and dental follicle for the teeth development.

==Lab 8 Assessment==
1. Provide a brief time course and overview of embryonic development of either the human testis or ovary. (2-3 paragraphs)

Gonads are developed from the mesothelium of the posterior abdominal wall, the adjacent mesenchyme and the primordial germ cells. The development begins in week 5 where the mesothelium medial to the mesonephros of the developing kidneys thickens and forming the paired gonadal ridges.

The primordial germ cells are the precursors of oocytes that they migrate from the yolk sac to the mesenchyme of the gonadal ridges between weeks 3 to 5 and incorporate into the primary sex cords. The sex cords extend to the medulla of the future ovary and regress by week 8.

During week 8, gonad begins to develop into ovary due to the stimulation from germ cells. The primitive medullary cords in the ovary degenerates and the primordial germ cells differentiate under the influence of placental gonadotropins. The germ cells undergo mitotic divisions and differentiate into several million oogonia. Around week 16 to week 20, the primitive follicles organize within the fetal ovarian cortex. By 5-6 months gestation, the primitive follicles are enveloped by a layer of epithelial cells and become primordial follicles. During the development, the ovaries descend into the pelvis by the third month.

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

[[File:Bailey328.jpg|300px]]

Reference:
Bailey, F.R. and Miller, A.M. (1921). '''Text-Book of Embryology.''' New York: William Wood and Co.

==Lab 9 Assessment==
===Group 1===

The product was done well overall with lots of information and a good structure. However, I am a bit confused about the sections “respiratory” and “lung development stages”. I guess “lung development stages” is also under “respiratory”, but it seems that they are separated into two big sections.

The introduction clearly explains the development of respiratory system. It is good to divide respiratory tract into 2 main parts and explain them separately. It would be better if it includes a sentence like ‘this website will focus on fetal development of respiratory system.

Using table to explain different stages of lung development is a good idea. It would be easier to read if they are typed in point forms with some images included.

More images could be added under current research, models and findings for easier understanding. Some information should be added under current models.

The historic findings and abnormalities are good and informative.

Some images do not have the information about copyright. It would be better if there is a title for each image included.

In terms of referencing, they are missing in the sections under introduction, conducting zone and respiratory zone. In-text references are also missing in the table about the stages and features of lung development. Also, the images used have not been referenced. Reference list at the end rather than under each section should be used instead.

It is overall a good project and well-researched. More images can be included to balance with the huge amount of text.

===Group 2===

The introduction is good and describes the project well. It is good to mention the function of renal system. It would be better if it states that the website will be focused on fetal development, current research and abnormalities to give a better understanding of the content.

Information under historic findings is missing, it would be a good way to start it by looking at textbooks. Images, bullet points and table can be used for an easy understanding of this section.

Using timeline to summarise the development of kidney is a good idea, however it would be clearer if a table is used, more descriptions under each stages and some images are include. Also, some references should be included in this section.

There are a lot of details under development, current research and abnormalities. It would be easier to read if they are written in point form. It is a good idea to divide renal system into several parts (kidney, urethra…) for the explanation of development. For the abnormalities, it is well-researched but some of the details are missing. It would be better if the each type of abnormalities is discussed equally.

Regarding the images, it is good and clear to explain each of them. The only problem is that there is no copyright information under the file “kidney ascent.jpg”.

The project is informative but lacking some information under historic findings and the developmental timeline.

===Group 3===

Introduction is good as it describes and gives an overview about what is happening in the fetal period for foregut, midgut and hindgut. However, it would be better if it mentions that the project is focusing on fetal development, abnormalities, current researches, etc.

It is clear to separate the timeline of GIT development for hindgut, midgut and foregut. It is well-researched with much information in this section. However, it would be easier to follow if a table is used and images are included.

The hand-drawn images can explain the development well, however the blue colour for labelling is a bit difficult for reading. It would be better if a darker colour is used.

It is a good idea to explain the abnormalities in definition and the causes. Some more abnormalities can be included as well as images for better understanding.

There is only one reference in recent findings. More researches could be done in this section. Also, a section about historic findings could be included as well.

There are a few spelling errors, such as “esenchyme” in the hindgut section and “tot hat of” under midgut section. Some proof-readings are needed.

The referencing is overall good, but some more researches have to be done under some sections (abnormalities and recent findings). It is easy to follow as there is a reference list at the bottom of page.

It is overall a good project as the development during fetal period is well described. However, more information about recent findings and abnormalities could be included, with the use of images to illustrate the contents.

===Group 4===

The project would be easier to follow by having an introduction that give readers an idea about what is going to be covered in the website.

Under the section about system development, it contains lots of information and it is well researched. Using bullet points is good as it is easier to read, however some of them could be join together into a small paragraph which would increase the readability. It is good to see a related video about the development of reproductive system and it explains well about this topic.

It is a great way to explain abnormalities in terms of female, male, and both. Maybe try to put a table at the top to summarise the abnormalities so that it would be easier to follow. More images are needed in this section, just like the one illustrating abnormalities of uterus and vagina.

It is well-researched under historic findings, try to put more related images to make this section more interactive. Also, it would also be good to illustrate the content in this part by a timeline, followed by the explanation of each event.

In terms of referencing, in-text references are missing in the system development, current research and historic findings.

For the image file “Image.jpg”, which is about sexual differentiation, it is a good image that explains the differentiation clearly, however, it would be better to put a description or title below it to make it more relevant to the project. It is good to see some hand-drawn diagram and they match the topic and explain information well. I found it a bit hard to read the labels on the image “labelled drawing of testes.jpeg”, maybe upload the image by scanning rather than taking a photo of it would be better.

It is overall a well-researched project. The next thing to do is to include an introduction, some more in-text references and some related images.

===Group 5===

The introduction clearly states the content in the website, which is good as this can prepare the readers for understanding. However, it would be better if some information about integumentary system, such as functions, is included in this section.

The development of integument system includes a lot of information. They are presented in good structure by the use of table for skin and nail. It is a great way to put some images in the table for easy understanding of the description in the development of teeth.

The recent findings area is well-researched. I would suggest try to put the content into small paragraph or in several points as the amount of text is a bit too much. Some images should be included as well.

Abnormalities section is great with the help of the images. It would be good if some more abnormalities are included. There is a lot of details under historic findings, try to illustrate them with the help of images.

In-text references should be included in the sections under development, recent findings and historic findings.

The project is well prepared. It would be better if some more images are included and the function of integument system is stated in the introduction.

===Group 6===

Introduction is missing in the project. It would be great to include the functions of endocrine system and the contents that will be covered including system development, abnormalities, current research, etc.

There is a lot to cover in endocrine system, it is a great way to separate timeline and recent findings under each individual organ. Using table to illustrate the function of hormone is good, however, I think it would be better to have a summary of hormone in a table form at the top/the end of all individual organs. The parathyroid gland and pancreas are well-researched with the use of images. More information has to be included in other sections.

More work has to be done on abnormalities. Actually, they could be separated under each organ, just like current findings. It would also be good to see historic findings under each organ.

In terms of referencing, there is no in-text reference and the reference list at the bottom is empty at this moment. This project overall has a good structure, but more information and images are needed.

===Group 8===

Introduction is missing. Some information about the functions of the systems and topics going to be covered should be included here. The section ‘making gains’ is funny. However, more work has to be done to make it more interesting.

For the timeline, more information is needed. It would be great to include a table here and describe the changes during different stages (microfibers formation…). Table is also useful to explain the second trimester muscular development

The information under background embryonic development can be summarised and put under introduction as this project should be focused on fetal development.

It is great to have molecular and cellular regulation. However, more diagrams are needed here. It would be better if they are stated in several points rather than a big paragraph. Also, more images are needed for other sections, it would be good to draw the picture as well.

For abnormalities, in-text references are needed. Also, some more abnormalities should be included with the use of images to illustrate them.

Overall, there is a pretty good structure of the website. It could be improved by including some current and historic researches on this topic. Also, more images are needed (as there is none now) to make the webpage more interesting and informative. More contents should be included as well.

User:Z3419587

2014-10-14T23:31:01Z

Z3419587:

{{StudentPage2014}}

==Lab Attendance==
Lab 1 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 12:45, 6 August 2014 (EST)

Lab 2 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:11, 13 August 2014 (EST)

Lab 3 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:12, 20 August 2014 (EST)

Lab 4 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:45, 27 August 2014 (EST)

Lab 5 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:02, 3 September 2014 (EST)

Lab 6 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:04, 10 September 2014 (EST)

Lab 7 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:05, 17 September 2014 (EST)

Lab 8 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 11:13, 24 September 2014 (EST)

Lab 9 --[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 10:49, 8 October 2014 (EST)

Lab 10

Lab 11

Lab 12

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 1 Assessment==
<pubmed>25071849</pubmed>
summary:
This study was done to compare the clinical outcomes between fresh embryo transfers and frozen-thawed embryo transfers.

A total of 1891 cycle contains 1150 fresh embryo transfers and 741 frozen-thawed embryo transfers were studied. All data were transferred directly to SPSS 18 and analyzed.

A long gonadotropin releasing hormone (GnRH) agonist protocol was used in all cycles. Clinical pregnancy was defined by the observation of a gestational sac with or without a fetal heartbeat on ultrasound evaluation on the 30th day after embryo transfer. The number of sacs was taken as the number of implantations.

The results showed that there was a higher clinical pregnancy rate in fresh cleavage-stage embryo transfers than frozen-thawed cleavage-stage transfers but the clinical pregnancy rates were not different significantly.

<pubmed>25077107</pubmed>
summary:
The study was done to investigate the effect of vitamin D levels on implantation and clinical pregnancy rates in infertile women following in vitro fertilization (IVF).

173 women underwent IVF were included in the study under 3 criteria, including aged 18-41 years, follicle stimulating hormone level 12 IU/L or lower and able to provide informed consent. Vitamin D was determined by serum 25(OH)D levels and samples were collected before oocyte retrieval, while implantation was determined by the presence of a gestational sac, visible by ultrasonography.

χ2 and Student t tests or Mann-Whitney U tests were used to analyze categorical and continuous variables respectively. Multi-variable logistic regression was used to evaluate the relation between serum 25(OH)D level and implantation and clinical pregnancy after adjustment fpr parameters known to influence the IVF sucesss.

The results showed that women with sufficient levels of 25(OH)D had significantly higher rates of clinical pregnancy per IVF cycle started than that with insufficient levels. It also found that implantation rates were higher, but not statistically significant, in the sufficient 25(OH)D group. Therefore, the findings suggested that women with sufficient vitamin D levels are significantly more likely to achieve clinical pregnancy following IVF.

--[[User:Z8600021|Mark Hill]] These are both good articles and summaries (5/5)

==Lab 2 Assessment==
[[File:Development_of_nuclear_transfer_embryos.jpeg|300px]]

<ref><pubmed>23251622</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0051778]</ref>
<references/>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 15:27, 22 August 2014 (EST) I have uploaded a smaller version of this image, but you still need to adjust the size as it appears on your page to 300px and include the reference. Please use jpg format images if possible. You need to reformat the reference as shown in the class tutorial. (4/5)

==Lab 3 Assessment==
===Neural development during fetal period===
<pubmed>21042938</pubmed>
<pubmed>12060827</pubmed>
<pubmed>23727529</pubmed>
<pubmed>16905335</pubmed>
<pubmed>17848161</pubmed>
<pubmed>18760424</pubmed>
<pubmed>16971596</pubmed>
<pubmed>17032846</pubmed>

--[[User:Z8600021|Mark Hill]] These are useful references, I needed a single sentence on why you had selected these references for your section. (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>16099997</pubmed>
summary:
The paper presented the possibility of the therapeutic use of cord stem cells in Parkinson’s disease.

Human mesenchymal stem cells from Wharton’s jelly of the umbilical cord were isolated and induced to transform into dopaminergic neurons in vitro. 12.7% of the cells were successfully transformed and generated through a stepwise culturing in neuron-conditioned medium, sonic hedgehog and FGF8. The cells were transplanted into the striatum of rats previously made Parkinsonian by unilateral striatal lesioning with the dopaminergic neurotoxin 6-hydroxydopamine HCl (6-OHDA). The effects of the transplantation were examined by quantification of rotations in response to amphetamine at 1, 2, 3 and 4 months after transplantation.

It was found that the transplantation of the stem cells corrected the lesion-induces amphetamine-evoked rotation and the cells in the striatum were still viable 4 months after transplantation. These results give the possibility to human umbilical mesenchymal stem cells in treating Parkinson’s disease. However, it is suggested that the examination of the toxicity of growth factor and medium used is important, and the observation of the effects and side-effects for more than 1 year after transplantation is required before human studies

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

Ductus arteriosus: connection between the most cranial part of the pulmonary trunk and dorsal aorta

Ductus venosus: connection between the intra-abdominal umbilical vein and the inferior vena cava

Foramen ovale: located in interatrial septum, connecting left and right atria

Umbilical arteries: branch from the internal iliac arteries in the pelvis and connect to the placenta

Umbilical vein: connection between placenta and portal vein, or ductus venous

==Lab 5 Assessment==
===Congenital Laryngeal Webs===

Congenial laryngeal webs are caused by failure of recanalization of the laryngotracheal tube during the third month of gestation. Findings suggested that congenital laryngeal webs can be explained by abnormal development of the epithelial lamina, the laryngeal cecum, or the vestibulotracheal duct <ref><pubmed>16798587</pubmed></ref>. It has also been reported that there is an association between anterior webs, the most common laryngeal webs, with deletions of chromosome 22q11<ref><pubmed>10699233</pubmed></ref>.

In human embryo, congenial laryngeal webs are formed during embryogenesis of the laryngotracheal groove <ref><pubmed>20376251</pubmed></ref>. The developing laryngeal is temporarily obliterated by actively proliferating epithelium, however, the lumen is normally re-established as the vocal cords. This abnormality is resulted from incomplete resorption of the epithelial layer during the 7th and 8th week of intrauterine development.

references:

<references/>

==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. (pancreas)

In this study, the distribution of chromogranin A, insulin, and glucagon in 25 human fetal pancreases was studied. Immunohistochemical reactions were carried out and sections of pancreas were labelled with antibodies to chromogranin A, insulin and glucagon.

Immunopositive reaction to chromgranin A was resulted from week 8 of development onwards. During the development of pancreas, the population of endocrine cells increased and pancreatic islets are formed. The majority of cells in the pancreatic islets were found to be chromogranin A that located in the cytoplasm. Chromogranin A immunoreactive cells were also found in glandular ductal epithelium of 8-9-week fetuses, suggesting that the cells formed a population of precursors of endocrine cells without synthesizing hormones.

The express of chromogranin A, which is higher than that of insulin and glucagon, during differentiation of pancreatic endocrine cells suggested that this can be a marker for studies of the mechanisms of endocrine development of pancreas.

reference:
<pubmed>24824718</pubmed>

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

Tooth germ: aggregation of cells derived from the ectomesenchymal cells from neural crest and ectoderm of first arch. It is then organized into 3 components of the tooth germ, which are the enamel organ, dental papilla and dental follicle for the teeth development.

==Lab 8 Assessment==
1. Provide a brief time course and overview of embryonic development of either the human testis or ovary. (2-3 paragraphs)

Gonads are developed from the mesothelium of the posterior abdominal wall, the adjacent mesenchyme and the primordial germ cells. The development begins in week 5 where the mesothelium medial to the mesonephros of the developing kidneys thickens and forming the paired gonadal ridges.

The primordial germ cells are the precursors of oocytes that they migrate from the yolk sac to the mesenchyme of the gonadal ridges between weeks 3 to 5 and incorporate into the primary sex cords. The sex cords extend to the medulla of the future ovary and regress by week 8.

During week 8, gonad begins to develop into ovary due to the stimulation from germ cells. The primitive medullary cords in the ovary degenerates and the primordial germ cells differentiate under the influence of placental gonadotropins. The germ cells undergo mitotic divisions and differentiate into several million oogonia. Around week 16 to week 20, the primitive follicles organize within the fetal ovarian cortex. By 5-6 months gestation, the primitive follicles are enveloped by a layer of epithelial cells and become primordial follicles. During the development, the ovaries descend into the pelvis by the third month.

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

[[File:Bailey328.jpg|300px]]

Reference:
Bailey, F.R. and Miller, A.M. (1921). '''Text-Book of Embryology.''' New York: William Wood and Co.

==Lab 10 Assessment==
===Group 1===

The product was done well overall with lots of information and a good structure. However, I am a bit confused about the sections “respiratory” and “lung development stages”. I guess “lung development stages” is also under “respiratory”, but it seems that they are separated into two big sections.

The introduction clearly explains the development of respiratory system. It is good to divide respiratory tract into 2 main parts and explain them separately. It would be better if it includes a sentence like ‘this website will focus on fetal development of respiratory system.

Using table to explain different stages of lung development is a good idea. It would be easier to read if they are typed in point forms with some images included.

More images could be added under current research, models and findings for easier understanding. Some information should be added under current models.

The historic findings and abnormalities are good and informative.

Some images do not have the information about copyright. It would be better if there is a title for each image included.

In terms of referencing, they are missing in the sections under introduction, conducting zone and respiratory zone. In-text references are also missing in the table about the stages and features of lung development. Also, the images used have not been referenced. Reference list at the end rather than under each section should be used instead.

It is overall a good project and well-researched. More images can be included to balance with the huge amount of text.

===Group 2===

The introduction is good and describes the project well. It is good to mention the function of renal system. It would be better if it states that the website will be focused on fetal development, current research and abnormalities to give a better understanding of the content.

Information under historic findings is missing, it would be a good way to start it by looking at textbooks. Images, bullet points and table can be used for an easy understanding of this section.

Using timeline to summarise the development of kidney is a good idea, however it would be clearer if a table is used, more descriptions under each stages and some images are include. Also, some references should be included in this section.

There are a lot of details under development, current research and abnormalities. It would be easier to read if they are written in point form. It is a good idea to divide renal system into several parts (kidney, urethra…) for the explanation of development. For the abnormalities, it is well-researched but some of the details are missing. It would be better if the each type of abnormalities is discussed equally.

Regarding the images, it is good and clear to explain each of them. The only problem is that there is no copyright information under the file “kidney ascent.jpg”.

The project is informative but lacking some information under historic findings and the developmental timeline.

===Group 3===

Introduction is good as it describes and gives an overview about what is happening in the fetal period for foregut, midgut and hindgut. However, it would be better if it mentions that the project is focusing on fetal development, abnormalities, current researches, etc.

It is clear to separate the timeline of GIT development for hindgut, midgut and foregut. It is well-researched with much information in this section. However, it would be easier to follow if a table is used and images are included.

The hand-drawn images can explain the development well, however the blue colour for labelling is a bit difficult for reading. It would be better if a darker colour is used.

It is a good idea to explain the abnormalities in definition and the causes. Some more abnormalities can be included as well as images for better understanding.

There is only one reference in recent findings. More researches could be done in this section. Also, a section about historic findings could be included as well.

There are a few spelling errors, such as “esenchyme” in the hindgut section and “tot hat of” under midgut section. Some proof-readings are needed.

The referencing is overall good, but some more researches have to be done under some sections (abnormalities and recent findings). It is easy to follow as there is a reference list at the bottom of page.

It is overall a good project as the development during fetal period is well described. However, more information about recent findings and abnormalities could be included, with the use of images to illustrate the contents.

===Group 4===

The project would be easier to follow by having an introduction that give readers an idea about what is going to be covered in the website.

Under the section about system development, it contains lots of information and it is well researched. Using bullet points is good as it is easier to read, however some of them could be join together into a small paragraph which would increase the readability. It is good to see a related video about the development of reproductive system and it explains well about this topic.

It is a great way to explain abnormalities in terms of female, male, and both. Maybe try to put a table at the top to summarise the abnormalities so that it would be easier to follow. More images are needed in this section, just like the one illustrating abnormalities of uterus and vagina.

It is well-researched under historic findings, try to put more related images to make this section more interactive. Also, it would also be good to illustrate the content in this part by a timeline, followed by the explanation of each event.

In terms of referencing, in-text references are missing in the system development, current research and historic findings.

For the image file “Image.jpg”, which is about sexual differentiation, it is a good image that explains the differentiation clearly, however, it would be better to put a description or title below it to make it more relevant to the project. It is good to see some hand-drawn diagram and they match the topic and explain information well. I found it a bit hard to read the labels on the image “labelled drawing of testes.jpeg”, maybe upload the image by scanning rather than taking a photo of it would be better.

It is overall a well-researched project. The next thing to do is to include an introduction, some more in-text references and some related images.

===Group 5===

The introduction clearly states the content in the website, which is good as this can prepare the readers for understanding. However, it would be better if some information about integumentary system, such as functions, is included in this section.

The development of integument system includes a lot of information. They are presented in good structure by the use of table for skin and nail. It is a great way to put some images in the table for easy understanding of the description in the development of teeth.

The recent findings area is well-researched. I would suggest try to put the content into small paragraph or in several points as the amount of text is a bit too much. Some images should be included as well.

Abnormalities section is great with the help of the images. It would be good if some more abnormalities are included. There is a lot of details under historic findings, try to illustrate them with the help of images.

In-text references should be included in the sections under development, recent findings and historic findings.

The project is well prepared. It would be better if some more images are included and the function of integument system is stated in the introduction.

===Group 6===

Introduction is missing in the project. It would be great to include the functions of endocrine system and the contents that will be covered including system development, abnormalities, current research, etc.

There is a lot to cover in endocrine system, it is a great way to separate timeline and recent findings under each individual organ. Using table to illustrate the function of hormone is good, however, I think it would be better to have a summary of hormone in a table form at the top/the end of all individual organs. The parathyroid gland and pancreas are well-researched with the use of images. More information has to be included in other sections.

More work has to be done on abnormalities. Actually, they could be separated under each organ, just like current findings. It would also be good to see historic findings under each organ.

In terms of referencing, there is no in-text reference and the reference list at the bottom is empty at this moment. This project overall has a good structure, but more information and images are needed.

===Group 8===

Introduction is missing. Some information about the functions of the systems and topics going to be covered should be included here. The section ‘making gains’ is funny. However, more work has to be done to make it more interesting.

For the timeline, more information is needed. It would be great to include a table here and describe the changes during different stages (microfibers formation…). Table is also useful to explain the second trimester muscular development

The information under background embryonic development can be summarised and put under introduction as this project should be focused on fetal development.

It is great to have molecular and cellular regulation. However, more diagrams are needed here. It would be better if they are stated in several points rather than a big paragraph. Also, more images are needed for other sections, it would be good to draw the picture as well.

For abnormalities, in-text references are needed. Also, some more abnormalities should be included with the use of images to illustrate them.

Overall, there is a pretty good structure of the website. It could be improved by including some current and historic researches on this topic. Also, more images are needed (as there is none now) to make the webpage more interesting and informative. More contents should be included as well.

Talk:2014 Group Project 8

2014-10-14T23:25:52Z

Z3419587: /* Peer Reviews */

{{ANAT2341Project2014discussionheader}}
==Peer Reviews==
===1===
Let me start by saying that the “Muscle Gains” section is funny but obviously very irrelevant to the project. Looking at the contents of this page, there seem to be a lot of focus on the development and very little on the other sections. The development section is well-researched and great job on the in-text citations! Some parts look a bit bulky though so maybe try to break some of them down into bulletpoints if possible. A timeline of development is also very helpful in this project.

On abnormalities, very concise and detailed. Try to write about 3-4 abnormalities and find information on how they’re treated or managed presently. As for historic findings, there is a section on the Wikipage that has old books on embryology. It’s under the “Explore” tab and you’ll see “Historic embryo”. Those books have a lot of information regarding that section. Don’t forget to write about current findings as well. Another thing, try to use images since these really help with understanding the content of the page. Overall, a lot of work has to be done before the due date. I do understand why because there are only two people in this group. Goodluck and I wish you the best in finishing this project!

===2===

The key points of musculoskeletal development appear as headings however there is still much that needs to be clearly discussed beneath each of these points. The main headings are good and specific but some are way too specific and should be under much larger headings, for example, 1.2-1.9 could be subheadings that come under the heading ‘System Development’. ‘Background embryonic development’ is useful to understand but perhaps it is better to not have so much detail, or summarise it in a table. The ‘Abnormalities’ heading is done well, with one disease listed (Duchenne Muscular Dystrophy). It might be better to have more than one abnormality listed and clearly described as well. I particularly like the use of statistics and genetic references. It seems most of the key points relating to system development have been clearly described, but some tidying up in terms of editing needs to be done.

Also, more work needs to be done on historic findings, current research, models and findings. Once all the research parts are completed, the timeline can be correctly constructed. Also like the idea of putting a timeline and the heading shows that this is intended. More subheadings could be used to make the page look more organised and pleasing to the eye.

There are also no graphs or tables as well as pictures. A table could be used to make the timeline or highlight the differences between the second, third trimesters and neonatal periods of fetal muscular development. Maybe the initial heading of the page should be changed to ‘Muscular Fetal Development’ to indicate that muscular development is actually being covered instead of both muscular and skeletal. There also isn’t much information regarding limb fetal development, so maybe it would be good to go through that on a deeper level.

It could also help to have images loaded onto the page or to draw flow diagrams to assist in the description of how the muscles develop in the fetal period. For example, upload an image showing the difference between slow twitch and fast twitch muscle fibres or draw a flow chart to show better understanding of the molecular and cellular regulation of fetal myogenesis.

References need to be in one larger section at the end under the heading ‘References’, not two and scattered throughout as is seen. The major section of references appears to be referenced correctly and in-cite references are done very well. There are also many references which are good and show that this group has thoroughly researched their topic.

Overall, this group has done very well and just needs to add more information for certain headings, as well as organise the page a bit better in neater headings and subheadings. Pictures should be added, as well as graphs, tables and own student-drawn images.

===3===

There is no introduction that allows the audience an insight to your project page. This is something that needs to be worked on and maybe add some images also. I’m not sure what I think about the “making gains” section, it’s funny however needs a bit of work. However I do see what you are trying to do here, trying to make it more inviting, interesting and alluring the audience and I appreciate that.
The Muscle development timeline needs some work and progress. I don’t see a timeline, or dot points, maybe work on format here even if it’s in a table format for this section.

Most of the following sections have great amount of detail with a number of in text citations and this is great to see. However I do notice that there is no images what so ever, not sure if you are having trouble finding, or if you have left this until the last thing, try and draw images, or look at a youtube video that sums one section or maybe the entire system. This could help balance the amount of text you have, making the page more interesting, not overwhelming. Also work on making things more concise and simplifying paragraphs.

Third trimester, neonatal and mechanisms are all sections that need more content in there whether it be images or information there is not much attention given to these areas.

Overall this project page has room for improvement by giving certain sections of the page the attention they deserve. Images are imperative in allowing a balance between text and the image itself. It can sometimes be refreshing, and less overwhelming to see an image among paragraphs of content. Also try and look for a youtube video that can help summaries the content on your page. Try and work on time management, or set a group deadline that everyone has to meet so that all the information can be well up before the due date so your group can have time to edit and add images and play around with the page comfortably.
Goodluck!

===4===

Overall the Group project page seems to be set out quite well with its headings and sub headings. Just needs a bit more info for some of the sub headings particularly from ‘second trimester muscular development’ onwards and a few formatting adjustments. The use of timelines, tables and dot points might help in those sections. The content provided is written well and in a detailed manner, which is still understood. There is a significant amount of research presented and this is seen through the in text citations and then further identified in the reference list. A good use of referencing is seen supporting the content info provided. The content uses examples of past and current research to help develop and establish ideas that are presented well. The abnormalities section on ‘Duchenne muscular dystrophy’ is described really well, maybe other abnormalities could also be added later.

To improve the page some suggestions include the use of diagrams and images, would help to add a bit more vibrancy to the page. Images and drawings are a great way to help in understanding the content. They are also a great way to make the content clearer especially if there are a number of processes involved in the development. Some of the longer paragraphs of content may also be formatted into dot points just to avoid lengthy paragraphs of info. It might also be useful to include some of the headings mentioned on the assessment page (identify current research models and findings, historic findings etc.).
Finally, the page so far is done well however it will need a little bit more work to be completely finished. Try to just gather as much info as you can to ensure you have enough content and then add images and any other visual aids later. Keep up the good work and good luck :).

===5===
Firstly, I thought the “Making Gains” bit was great- and I can guess who came up with that. I know you’ll take it our prior to submission though haha. The structure of your project is quite good, and the subheadings would make it much easier to read- the only thing is you need to add more content! I think because your system encompasses quite a lot, it would be a better idea for you to put as much information as you can into tables and include diagrams- I saw that musculoskeletal development has quite a few visual resources so it you should use them!
There are some areas where the content is really sparse, yet others where it is extremely heavy. In these areas, you may benefit from putting your information into bullet points so as to alleviate any confusion that may arise and overall enhance the clarity of your work. The references you have done are quite good, but there appears to be some missing.

Overall, I think your project would greatly benefit from the incorporation of images and diagrams. Because you are describing so much, a visual aid will help you immensely and also assist in retaining the attention of the reader throughout the entirety of the piece. Also, I see that you have deviated from the recommended headings. This may be a good idea to individualise your project- but make sure all topics are covered. I think it’s a good start considering you only have two team members, and I’m sure you will be able to pull it all together by the time it is due.

===6===
Musculoskeletal
There is no introduction that has been added - you should really add one because its great to introduce the readers to what will be in the wiki page. I hope the person incharge of the first two sections of your group will / does have some work to add soon. Hardly any information has been added to the majority of the assignment, and to be honest, this wiki project has had the least amount of work done on it. You need pictures, diagrams, graphs and a LOT more information. You guys are doing a “musculoskeletal” topic, and I can’t find anything on “skeletal” on your page yet. Mark has posted that your page will only be focusing on fetal muscle development - why not change the name of the page from musculoskeletal to muscular only? That will prepare the reader in regards to the topic being addressed.
As for abnormalities, all the other pages have on average 5 abnormalities being introduced, whereas this page only has 1. Although it is really well worded and introduced, I think you should try to find at least another 2 abnormalities to put into your group project.
Sections for historic findings, current research, models and findings will need to be added.
Your page seems to focus only on how the actual muscle fibres develop, but perhaps, you could write about skeletal muscle development contributing to limb development or something to widen your topics?
Overall, your page needs a lot more work! Hope you can get a lot of work done until the project is due, make sure to add pictures!

===7===

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.

===8===
I think this page needs a lot of work in improving the overall layout. First, I think the page would benefit from a more formal introduction that introduces the content of the page in a way that is helpful to your audience. The age could also be improved by breaking it up into ‘Development’, ‘Historic Findings’, ‘Current Research Models and Findings’ as well as the Abnormalities section already included to make it flow better.

The text in under the ‘Molecular and Cellular Reputation of Fetal Myogenesis’ is really good but it is appears as a large slab of information that would be better presented with dot points to break it up and images to make it more interesting. The Abnormalities section is well written but is very brief. This section could be improved by including more abnormalities and the appropriate images.

Overall there is a lot of work to be carried out for this page but I understand that this is a smaller group. Perhaps breaking the work up into those smaller headings mentioned will help you split the work evenly. When all the text is uploaded, make sure that there is an effort to include in text citations to support all your information and images to make the page interesting. Try to avoid writing big slabs of information – tabulate or use dot points to break up large portions of text.

===9===

I think the group has found some useful and relevant sources of information however there still needs to be work done in writing up content under some headings. The structure of the wiki page has been laid out and I think the idea of splitting up the developmental process into three trimesters is a good idea to avoid lengthy paragraphs or an overly lengthy timeline that may be difficult to absorb. I would suggest using a table to write up the timeline with a brief description of what exactly the process occurring involves. There are some references that are missing in the tendon development section.
I think the ‘Molecular and Cellular regulation of fetal myogenesis’ section was the most well written section with a thorough description of the process involved. Try to find relevant pictures and diagrams to accompany this text, they will make the explanation much more beneficial and easier to understand. Overall a good structure has been laid out for the wiki page but more content still needs to be added.

===10===

I understand that you only have two people in your group so you have made a good start considering this. It does seem a bit unorganized at the moment though. Be aware that mark has set out guidelines that include that include making sure you have an introduction, historic findings and models. These can be found when you click on the student projects at the top of the page.

The information you do have is good but your page isn’t visually entertaining as there are no images. Adding images makes it more interesting and I particularly recommend student images to make it more student-like and in my opinion these will attract attention from the viewer. Obviously the making gains part, while blatantly funny it is quite irrelevant.

Referencing appears to be a bit of an issue at the moment as some parts have been done well with in text citations but you need to make sure all of the text has in text citations. Also it would be a good idea to put all your references down the bottom of the page to make it look more tidy and aesthetically pleasing.

I like how you have split your page into different parts, it would be a good idea if you were to finish off the general timeline at the start as well. Think about tabulating it as this has been done by other projects and it looks really good. I think the fact that you have only two people you have got just about all the information you need there as it is difficult to do as much as the other groups when there is only two of you. So even the abnormalities part it’s good that you have even one to the effort to have it there.

Overall, a very good start from both of you. I think it’s important to make sure that everything mark has mentioned is put into your page at the start even if there isn’t as much information in each as other pages have. Also make sure you include some sort of images because it’s a bit monotonous at the moment. The referencing needs a bit of tweaking as well. Best of luck with the rest of the assignment.

===11===
The Making Gains section is quite funny but as you said, this is not Broscience and I’m sure it will be removed for the final submission. Once that is removed, begin the project with an introduction and the developmental general timeline. The main idea of the timeline is present, however when constructing one, use specific weeks within the foetal period and what developmental changes occur in those weeks. The information found under Background Embryonic development may be used to form the introduction, but if you are going to do that do not make the introduction as detailed as this section is, particularly in terms of the transcription factors and signalling molecules, they can be moved and added into the other sections that look at the various musculoskeletal developments individually.

It is evident that there is great understanding of this topic and that it is only a case of further research and addition of those information to complete the sections. Certain sections lack information all together, such as the Third Trimester Muscular development and Recent findings, whereas other sections only contain the research articles and no summaries of them such as Abnormalities. However I understand this is a draft and that all those areas will be addressed adequately, contributing to the final copy.

Only the Background Embryonic development and Molecular and Cellular regulation of foetal myogenesis have in text citations, whereas the other sections that do contain information are not cited. It might become difficult to later find the correct article from which you obtained the information so it is advised to cite the text while adding it. In terms of the citations present, there is no need for a comma between the superscripts and you have also allocated two sections to references, one subsequent to Abnormalities and another at the bottom of the page, it is best to collate all the references in one list at the end of the page. This is also the case for Abnormalities as there are two subheadings for it, merge them into one.

No images, tables, or timelines are added. The information you have now is well written and divided into small paragraphs, which is a good way of presenting the information, however other forms such as images and tables should be used. A timeline should be added under the Muscle development General Timeline subheading, this may be done as a table or a drawing and uploaded as it simplifies the information and breaks the page from continuous writing.

Overall this group project page is great, containing all the headings and articles present. It is only a matter of summarising those articles and adding the information. All the information present thus far is appropriate and emphasises great research skills.

===12===

The project is split up into different sections well but you need to include an introduction to your project. Really good information and references but use bullet points and diagrams to break up the text so that it is easier to read. There is good information on DMD but you could possibly write about another abnormality linked to muscle development.

===13===
Introduction is missing. Some information about the functions of the systems and topics going to be covered should be included here. The section ‘making gains’ is funny. However, more work has to be done to make it more interesting.

For the timeline, more information is needed. It would be great to include a table here and describe the changes during different stages (microfibers formation…). Table is also useful to explain the second trimester muscular development

The information under background embryonic development can be summarised and put under introduction as this project should be focused on fetal development.

It is great to have molecular and cellular regulation. However, more diagrams are needed here. It would be better if they are stated in several points rather than a big paragraph. Also, more images are needed for other sections, it would be good to draw the picture as well.

For abnormalities, in-text references are needed. Also, some more abnormalities should be included with the use of images to illustrate them.

Overall, there is a pretty good structure of the website. It could be improved by including some current and historic researches on this topic. Also, more images are needed (as there is none now) to make the webpage more interesting and informative. More contents should be included as well.

==4==
This page needs a lot of work; there are sections with little to no information, while others have just slabs of text, some of which have no references. Of those that have info presented, the topic is well covered with the large amount of content. You should use some dot points for some areas where you have a lot of info. You also need to use some images!! They will help to alleviate the slabs of content you have and add some colour to the page. Make sure you caption and reference them correctly, and add the correct copyright info.

Overall, there isn’t much I can say except add content, reference is correctly both in text and at the bottom of the page, and images and use some dot points and/or tables; don’t write everything in large slabs of text. Also, maybe get rid of that 'Muscle Gains' section, unless you actually plan to write something relevant in there haha. Otherwise, Good luck!

==5==
Let me start by saying, for only having two people in the group, well done. The page should have an introduction though, and this is missing. Just by simply summarizing all the information that will be covered in the page and adding it to the introduction, will improve the overall presentation significantly, you may wish to leave this to last, or edit as you go along.

The section “Making gains” is amusing, but inappropriate and should be omitted from the final submission. The timeline for the page I believe should be put into a table to save time and add to the presentation of the page, it can be easily done if you follow the steps outlined in the ‘editing basics’ page

The background information is comprehensive, however, the page is in desperate need of some images as there are just slabs of text. Images will really help break up the contents of the page and make it visually appealing.

The abnormalities section also seems to be coming along quite well. Keep up the good work.

==6==

This is great work so far from a group consisting of only 2 people. Keep up the good work and continue to work hard in finishing this page. Very admirable.

Overall, I would suggest reformatting and adding pictures to enhance the presentation of this page. Consider the use of lists and tables, throughout this wiki.

Instead of the rather hilarious (but rather inappropriate) ‘Making gains’ subheading, I believe an introduction should be added. Remember to clearly indicate the outcomes that the page hopes to achieve.

I also believe that the development/timeline section of this page is informative, with a very good use of headings and sub-headings. There is excellent evidence of significant scientific research and is correctly referenced and cited. However, this section could be further summarised or improved through the use of a table I believe- just a suggestion however. Adding pictures would also add to the overall understanding of this section.

This page has no information for the “recent findings” or “historic findings” section. Remember to include relevant information/pictures and references to these sections.

The abnormalities section is also looking very promising. Include more varying abnormalities. The abnormality included, DMD, is well written and informative. It needs to be correctly referenced however.

==7==
In this review I hope to highlight the merits of your project and suggest some areas for improvement in line with the marking criteria.

I see that you have conducted a great amount of research on the fetal development of the musculoskeletal system. The content clearly goes beyond the material covered in the lectures. It was interesting to read about the different transcriptions factors involved in induction and regulation of myoblast differentiation. I think it will be good to see a summary of all this information in a timeline format. I suggest simply highlighting the main developments at each stage.

You have made a good start on abnormalities. I suggest that you begin by selecting one abnormality include Description; Epidemiology; Cause and Treatment. You can add more later.

The page needs a little more structure. Make sure you include appropriate sub-heading and organise the information before you submit the project. Remember we were asked specifically to address the topics of current research and historic findings.

Finally it would be good see some images to support the text. Perhaps diagrams on tendon development would help summarise the process.

Great work so far!! Hope this feed back helps.

==8==

Overall, the project has some very detailed sections and some sections where content is scarce. It would be helpful to start off with an introduction of the musculoskeletal system so the reader is aware of its components and what the page intends to cover. The timeline of muscle development has good potential, I understand it is still being planned at this stage and with further research, it could definitely be effective. A table format would be useful to present this information. The following sections on background embryonic development and fetal myogenesis are well-researched and have a lot of content, however I would consider breaking it down into dot points to improve readability. The sections are cited correctly in-text though, which is good to see.

There is much more improvement in the tendon and second trimester development sections, as the chunks of text have been reduced to provide a succinct summary, however these need to have citations also. The use of some images here, either hand-drawn or from online would be beneficial, to have a balance between text and pictures and make the page more visually appealing. Other than the abnormalities section which provides a good, concise summary of Duchenne Muscular Dystrophy, the following sections seem to be only references at this stage. As long as these are used to compose some relevant paragraphs/dot points, this is fine considering there is still time to improve the page.

Overall, this page has good potential as the groundwork has been completed; it is now more a matter of writing up more information, adding images and possibly a relevant video. The part on ‘making gains’ would need to be removed for the final, but otherwise, it is definitely a decent amount of work so far, especially considering the few group members involved.

==9==

“Making Gains” is pretty funny but offcourse irrelevant to this project.
Your timeline needs a lot of work done as it is missing copious amounts of information.
Background embryonic development section is well detailed though it lacks images to aid the information. Also molecular and cellular regulation of fetal myogenesis section is the same; it is well informed but lacks images.
Much more is needed on tendon development, second and third trimester muscular development, neonatal, mechanisms/structure of muscle fibres and abnormalities.
Over all very good in text citations for the development (top) section. References from the background section should be at the bottom of the page with other references. The page mostly looks like a bulk of writing so include images where possible. A LOT more work is needed but I understand your situation as your group only has 2 members now so do as much as you can and GOOD LUCK!

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==10==

The project doesn’t have an introduction yet; however information such as what the Musculoskeletal system is about, the features of the system as well as the difference between the embryonic and fetal stages of development should be mentioned. Not to mention a brief summary of each key subheading such as abnormalities under introduction e.g. any deformations in the fetal stages of musculoskeletal development can result in to such and such abnormalities which will be addressed. This will help the viewer’s understand what the project will be going through. I like the ‘making gains’ subheading as it adds humour to the page and engages the viewers. The general timeline needs information including what events take place at certain phases of fetal development. This could be present in a table to make the information more clear. It’s good that the project has information on the embryonic development so that the viewers can understand how the fetus arises to that point in development (fetal period).

All of the content seems to relate to the key topic and is appropriately paragraphed. However much of the content is still missing such as in ‘recent findings’ and ‘introduction’. More information could be added under the associated ‘trimesters’ and ‘abnormalities’. There are no historic findings which is great to have on your page for viewer’s fascination into the group project. Members could search on pubmed about the musculoskeletal system and view dates on the side that may contain key findings for historical events. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections.

There are no images on this page and definitely needs to be added with the appropriate information such as the description, referencing, copyright issues and ‘student template’. If images are not readily available, it is best to draw them. Also captions should be added on the page to state what the images are showing. As for referencing, there are some sections which shows incite referencing such as in the content under ‘Molecular and Cellular regulation of fetal myogenesis’ and some that don’t have any like in ‘tendon development’. There needs to be references in all sections. There is a huge list of references under ‘abnormalities’ which need to be placed all under one ‘references subheading’; similarly to any other reference list on the page. Number 15 of the reference list has an error in it and needs to be fixed right away. Overall, this is a working progress and if the group makes edits based on the peer-reviews received, this could enhance their project.

Week 5

--[[User:Z3418989|Z3418989]] ([[User talk:Z3418989|talk]]) 22:34, 26 August 2014 (EST)
Hi guys
After discussing in lab last week we tried to divide the categories and work as following;
* skeletal and cartilaginous development - Joel
* muscular development - Gowtem
* overall skeletal and muscular arrangement macroscopically - Danny
What do you guys think about addressing these topics as well
* Historical findings
* Abnormalities
* New findings

--[[User:Z3418779|Z3418779]] ([[User talk:Z3418779|talk]]) 12:44, 27 August 2014 (EST)
Great idea m8 Danny can probably also do abnormalities, remember to post any articles of particular relevance to New/historical findings. To complete after main content assembled

--[[User:Z3418779|Z3418779]] ([[User talk:Z3418779|talk]]) 01:02, 28 August 2014 (EST)
I would suggest that we narrow down the topic to focusing on the appendicular musculoskeletal system, so that;
*To make work load more managable
*To avoid the multiple highly specialised and irregular muscles/bones of the head
*The muscles I would suggest to include in are all muscles which have attachments to the appendicular skeleton including axioappendicular muscles (petoralis major, pectoralis minor, subclavious, serratus anterior, Latissimus Dorsi, Traps, levator scap, rhomboid major and minor.
*Joints and tendons are included in the musculoskeletal system, we should about wether we want to have a section for them.

--[[User:Z3418779|Z3418779]] ([[User talk:Z3418779|talk]]) 09:05, 31 August 2014 (EST)

Hi guys just posted the topics of abnormalities of muscle and skeletal system im gonna talk bout and references of relevant articles to the topics. Sorry for being late btw

--[[User:Z3418779|Z3418779]] ([[User talk:Z3418779|talk]]) 14:57, 9 September 2014 (EST)
Disregard the rest of the stuff I said in earlier discussions, I believe that to make it significantly easier we just do muscular system. I will Reformat everything to make it make sense.

--[[User:Z3418989|Z3418989]] ([[User talk:Z3418989|talk]]) 01:51, 10 September 2014 (EST)
Yeah completely agree, I think focusing on the muscular system would be much easier than doing both. Appendicular muscles sounds good - so muscles of limbs. Could divide it into upper and lower limbs. May have to talk about bone/cartilage a bit to describe how the muscle forms around it. Maybe how developing of muscles in embryonic development is important and eventually affects origin and insertions and actions of muscles when fully developed.

--[[User:Z3418779|Z3418779]] ([[User talk:Z3418779|talk]]) 12:56, 17 September 2014 (EST) This link shows a very good description of myogenesis; http://books.google.com.au/books?id=1ZRCMRXbbwoC&pg=PA38&lpg=PA38&dq=primary+secondary+myofibers&source=bl&ots=RSRcVVe5xr&sig=eDJBF_3qkYzA8WSin1tnbzT2xYY&hl=en&sa=X&ei=OegYVL_UHpOB8gWMxoDYAw&ved=0CCoQ6AEwAw#v=onepage&q&f=false

--[[User:Z3418989|Z3418989]] ([[User talk:Z3418989|talk]]) 12:27, 20 September 2014 (EST)
Ill add a bit more on embryonic muscle development guys

--[[User:Z3418779|Z3418779]] ([[User talk:Z3418779|talk]]) 22:30, 6 October 2014 (EST)
Here are some article which would probably be helpful
Nrk2b-mediated NAD+ production regulates cell adhesion and is required for muscle morphogenesis in vivo: Nrk2b and NAD+ in muscle morphogenesis
Coexpression of two distinct muscle acetylcholine receptor a-subunits during development

At the moment I have a general structure for tendon development and abnormalities will add to wiki tommorrow.

the good indepth morphogenesis studies focus on gluteus maxximus, extrenal urethra spincter, tensor veli palatini very little are done of the other muscles, so will try to apply the conclusions from these studies to related skeltal muscles

Talk:2014 Group Project 6

2014-10-14T23:01:58Z

Z3419587: /* Peer Reviews */

{{ANAT2341Project2014discussionheader}}
==Peer Reviews==
Introduction is missing in the project. It would be great to include the functions of endocrine system and the contents that will be covered including system development, abnormalities, current research, etc.

There is a lot to cover in endocrine system, it is a great way to separate timeline and recent findings under each individual organ. Using table to illustrate the function of hormone is good, however, I think it would be better to have a summary of hormone in a table form at the top/the end of all individual organs. The parathyroid gland and pancreas are well-researched with the use of images. More information has to be included in other sections.

More work has to be done on abnormalities. Actually, they could be separated under each organ, just like current findings. It would also be good to see historic findings under each organ.

In terms of referencing, there is no in-text reference and the reference list at the bottom is empty at this moment. This project overall has a good structure, but more information and images are needed.
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An introduction has not yet been added, however when doing so aim to mention the gist of the project and the manner in which is has been divided so that the reader/marker can effectively understand what is in this project. The wikipage is separated into the numerous endocrine organs, which is great as a future student can easily navigate to the organ of interest.

As it is only a draft copy it is assumed that improvement and adding of information will take place leading to the submission of the final as there are subheadings such as “Recent findings” that have been left blank. With what is currently present, each organ contains well researched information. In the beginning two organs, the pineal gland and hypothalamus, there is a subheading for abnormalities, however there is also a section towards the end of the wikipage solely for abnormalities, so refrain from doubling up on the information and either place all the abnormalities in one section or separate the malformations in terms of their respective structure. References are also seen at the end of each section or subsection and no in-text citation has been used yet, so it might be easier to cite the dot points or information as you go so you can remember where you got that from instead of trying to find that piece in the numerous research articles you have. Once that has been done, it will be best to relocate all the references at the end of the page, where you have already made the heading.

The structure is consistent throughout the page with each organ having a timeline and most containing an image and a table. This makes the project appealing and easy to read and understand. All the images uploaded contain comprehensive information and thus I am able to decipher the image and as a result enriches the learning aims of this assignment. The creation of a timeline for each organ is clever as each exhibits its own developmental process. The separation into many smaller timelines allows for specific events to be included that would otherwise overload a collective timeline. The setup of a table under the organisation of hormone, cells and function further simplifies an extremely complicated developmental system. As a student learning about the endocrine system I would be relieved to discover tables and content of this standard and structure.
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The introduction section is blank so I suggest you start on it as soon as possible.
I like how you have organised the sections in terms of each gland.
Pineal gland section requires in text citations and more information with the aid of an image. Spelling error for abnormalities.
Hypothalamus section needs more information and images. Good idea to use a table but it is incomplete. In text citations are needed throughout.
Pituitary gland section only has the timeline and references. It needs much more information and images with in text citations.
Thyroid section is a bit better but still is missing little information.
Parathyroid gland has a very good image and the information is well presented. Once again in text citations are needed.
Thymus section only has little information so work more on this.
Pancreas by far is a much better section compared to others as it consists of an image, table and a timeline. In text citation are missing.
Adrenal gland section is missing a little information and an image that’s all. Also in text citation is missing.
Gonad development section is well presented just add images to it.
Placenta section just has references. You need to start researching information on this.
Associated abnormalities section just has an incomplete table.
The page could use a bit more uniformity. Throughout the page, two different spellings are used for fetal (fetal and foetal). Try keeping the context consistent.
Overall I suggest you start researching more for your project as A LOT of work may be needed to be done. In text citation is crucial as you have noticed by my constant repetition for it. Recent findings and historic sections are missing. I suggest researching on pubmed under “(gland name) historic/research findings”. All the references will look better and more professional if it was in the end of the page in a bulk. There are some really good information and images on your page. If possible try adding hand drawn images too. You may only have 1-2 weeks to complete this project but I believe you can do it so good luck!

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This project would greatly benefit from an introduction, to present the contents of the project. The content is broken up into individual organs, of all the systems endocrine definitely one of the most varied in location so this approach does have some merit for initial data gathering. It does present the problem for viewers in navigation and resulting in continual repletion of timelines. Each organ is subdivided into timeline, introduction, structure, function, development and abnormalities. The content presented is solid and obviously well referenced. Placenta section should be added, because of its significant endocrine organ during fetal development. The references are mostly placed at the bottom of each organs section, these should be moved to bottom of the whole project in combination with in text citation. This will make the body of the project less cluttered and more fluid.

The table for hypothalamus hormones and associated abnormalities are mostly incomplete with “Example” filling many of the boxes. I would advise completion of hypothalamus hormone table and removal of associated abnormalities. In total there were only 3 images, addition of 2+ more images would help readers visualize the developmental organs. With at least one image per organ and preferably an additional image for an abnormality. Sufficient content is presented in this project though significant formatting changes are needed to create a completed project, additional images would be preferable.

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Overall, this is quite a good project considering the complexity of the system. I think that generally, this project would benefit from some restructuring, so as to improve the cohesiveness of your work. I think that an introduction is a good idea to organize your ideas and give the reader a good background when trying to understand some of the more difficult concepts. I think that the choice of sub headings should be advised. It is interesting that you have chosen to deviate from the given subheadings, and I understand for your system that that may be necessary- however I think that some structure or regular subheadings for each part may be a bit easier to control. Also I think an overall timeline is always a great idea as it provides a visual representation and puts things into perspective.
I also think that some areas could use a bit more research, for example a large part of the pineal gland and hypothalamus appears to be missing and there are kind of “insert text here” sections- which I’m sure you’ll work on by the submission date.
I also think its important to remember that your referencing needs to be carefully done and consistent. Currently it seems quite poorly organized, and I think overall could use with a few more resources for every section. I think because you are already deviating from the normal structure of things, it would be a good idea to leave your references until last, just so your work isn’t broken up even further. The abnormalities section is severely lacking- the table is a good idea, but make sure you fill it!
Overall a good start, some places need some serious content others just need a tidy up.

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Great job on doing the endocrine system! There are lots of content for each organ of this system, which is good. I can see that this system was broken down into organs and allocated to different members. The only problem I see with this format is that presentation could be incoherent. I suggest try to follow the outline Dr. Hill gave us like development, current findings, etc. and just break each section into sub-sections for each organ. If that’s too much, then maybe just a single timeline of the development of the whole system. Also try to have a uniform layout for the tables about the hormones secreted by each gland.

There aren’t many images used in the page so maybe try to add more images. They really help with getting the readers to understand the information. In terms of referencing and citations, good job on choosing the research articles. All of them seem to be relevant to the the project. Don’t forget to use in-text citations. Not only is it important but it will make the page look a lot cleaner. Also, try to get all the references into one bulk at the bottom of the page. Overall, there aren’t a lot of problems in terms of the content but mainly about organising the page, making it coherent, and cleaning it up. I think the thyroid, parathyroid, pancreas, and adrenal sections were remarkable. Well done!

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Group Project 6 – Endocrine Development

An introduction could be very useful to summarise what the page is going to discuss. Sections 1.2-1.11 could all be subheadings under the main heading ‘System Development’, and then each of these subheading could be further divided into smaller subheadings with timeline, introduction detailing structure/ function of the endocrine organ. It is however very well done how the headings of each organ are then further subdivided into ‘abnormalities’, ‘research findings’ and ‘timeline’. However, the fact that each section has its own references and is subdivided as such, shows that even though the page may appear more ordered, there appears to be little communication between group members at this stage. So perhaps a goal could be to make the page look like one flowing work piece as opposed to sections that each person has done.

I think the content is very well researched and I like the way each organ of the endocrine system is discussed, as all are important in fetal development. The use of images is appropriate and very well done as they are referenced correctly and when you click on an image it takes you to a new page showing the student image template, copyright information as well as extra information regarding the image. There are no student-drawn images however, so perhaps it could be possible to draw a flow chart perhaps of gonadal fetal development. The use of tables is also done very well and is frequent throughout the page, with some being used to illustrate the anatomical development of certain organs, for example, the adrenal gland and pancreas. The graphs are also useful in portraying information from research findings.

The project page is missing information regarding historic findings, and I think that if this page is going to have a main heading for Abnormalities, then the group should put all their information regarding abnormalities under this section. Although it is not an endocrine organ that grows within the developing foetus, but is an important part of the mother, there is not much information on the page regarding the placenta. This section needs to be completed as the placenta is an important source of hormones and acts as an endocrine organ during the pregnancy, sustaining the foetus.

It is good that there are many references, indicating thorough research into the endocrine system with each organ heading have its own sources, however I think these references need to be ordered better. The actual referencing is done correctly, however in-text referencing is absent, so it may be best to fix this. Most images are referenced correctly as well.

Overall, keep up the good work, but just edit the page to make it look neater and finish the sections you need to.

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At first glance, a lot of sections seem to be incomplete. On second glance, I’ve noticed that you have added all the headings used by other groups (timeline, current findings, abnormalities) as subheadings for your own project, which I think it a really smart idea. Because you have so many glands that need to be covered, writing these sections separately can be confusing with the information quickly becoming muddled up. Doing it this way eliminates that confusion.

Make sure the use of tables is appropriate, using a table for one row of info is kind of pointless (pineal gland). The timelines used should also start with the week number, otherwise it can be quite confusing trying to work out the time (e.g. try not to say times such as ‘by the second trimester’). The information presented was concise and to the point, no long-winded explanations or slabs of text which was good. The images used were relevant and captioned.

Concerning the work completed, overall it was done well. A lot more work still needs to be completed however. References should also be made in text. If you are unsure how to do this, just go into edit mode in another group’s project and see how they have done it, instead of listing all the references at the bottom of the corresponding section. Make sure all the references are also presented at the bottom of the page, not separated into sections. It would also be nice if more images are used, if not one image for every gland then at least one for every second gland mentioned (it just needs more images).

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There seems to be no introduction on the page, don’t forget to add content to this section before the final submission. The overall page looks disjointed by the choice of sub-headings. I think an overall timeline is needed to know which glands/organs develop when and originate from where. It would look much neater and would be easier to follow.

The parathyroid gland and pancreas seems to be the only sections that are properly completed. Both sections have good use of images and the tables provide easy readability. The images are all properly cited, good job.

The overall referencing of the page is all over the place and lacks in-text citations. I suggest you go through the contents and add these where necessary. If you are unsure how to do this, just look at the handout Mark gave out in week 2 for further reference. Or, alternatively you could look at some of the other project pages in edit mode. I would also suggest you leave all the references to the end of the page by simply putting </references> at the bottom of the page, as it looks neater to have them all in one place, rather than at the bottom of each sub-heading.

The abnormalities section is lacking content and there is only 2 diseases listed, with no description.

Overall, the page has good content, just needs to be edited to put in-text referencing. Some sections need contents such as the placenta and adding images to the page will also improve its presentation.

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So far you have made a good start. The introduction is a really important part of the project so it’s important that you get that down. The pineal gland part has made a good start but it would be good if some more hormones could be added. I think it would be good maybe if you all combined all of your times line and put them at the top of the page. You could maybe do this in a table form, but it’s certainly something that would make the project more succinct. Also instead of having references spread all over the page it would be a good idea to put the all of them at the page to make the page look more neat and tidy.

The hypothalamus part also needs to add extra information on the hormone part and add their illustration. I think it may be a good idea to add a student image because this makes the page more interesting and people looking at the page will be instantly attracted to this. Something that is really important and goes for the whole page is that you need to do in text referencing, as having the references at the end of the writing is tough because we don’t know which parts came from where.

Its good that there is recent findings in the hypothalamus part but I think this probably highlights the biggest issue with your project, being that It probably doesn’t link with all parts that well. I think it would be good if you could link all parts of the endocrine system together to make it easier to understand. For example, if you put the recent findings as a whole new part then everyone puts their recent findings in there it will make it easier to understand and look more collaborative. Also there is an imbalance in written information to pictures which tips in favor of the information. While it’s great to have a lot of information it becomes a bit boring just reading all the time so I think adding more images, particularly student drawn images would be something that would definitely improve the page.

Overall it has been a good start but the main points that need to be focused on are to finish off the information, make sure you correctly reference with in text citations and putting the references at the end of the page, and adding more images to make it more interesting. Good luck with the rest of the project.

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There is no introduction! You should definitely add one!
The graph in the pineal gland only has one rows; I suppose you are planning on adding more rows and hormones secreted by the pineal gland? If not, maybe just scrap the graph in general cause there’s really not much point. The graph in the hypothalamus section doesn’t have any examples yet, I presume that you’ll be adding stuff soon?
The overall project having been divided according to the each endocrine organs is really nice.
Hardly any work has been done yet on the pituitary gland yet, you might want to get started.
Beautiful work on the thyroid, parathyroid and pancreas; easy to understand the paragraphs, and they are visually aided with pictures. For the development of the adrenal glands, and the testis and ovaries, I think you should find a picture.
Historic findings, placental development and abnormalities are basically non-existent, which are vital components to this project.
Overall, the project is very very informative and very well done! The page has good content, just add the in-text referencing, and maybe try to improve the aesthetics to make it more appealing to your readers. Good luck group 6!

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The page is set out really well especially since the endocrine development covers so many organs. It’s a nice clear and concise way of structuring the page. Each particular organ is addressed really well. There is good consistency with each one on the page that is great. The page contains a sufficient about of content and detail in the info for each section of an organ addressed. It is good to see the use of tables and some dot point formatting which always helps to keep the content clear. There are parts in each section that are missing info these include the abnormalities and tables. The use of images with captions containing well detailed descriptions are also constant under each section. Some suggestions to consider include adding more info to the abnormalities would be great. Focusing on discussing what each abnormality is, how it’s contracted, statistics and then treatment. Throughout the whole page in text citations have not been used at all which should be included, especially when research studies are mentioned. A way to assist with this is to use the following format; for pubmed <ref name=PMIDnumber><pubmed>pubmedIDnumber</pubmed></ref> and then for other references <ref>insert source</ref> . Then after those are inserted, add an additional referencing heading and under it write <references/> .

Overall the page does not need too many changes, just a few adjustments mostly with formatting and references. Then some sections need a little bit more info to be completed. An introduction would also be a great way to provide an overview of the content that will be covered since there is a lot discussed. So far it can be seen that a great deal of research has been conducted. It’s also understandable that not all sections are completed just yet as this is a pretty lengthy system. Try to also incorporate some graphs, drawings and even video’s, they are a great visual aids. Keep up the good and the page will be really great, good luck ☺.

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Just must say, this must be one of the hardest topics to cover! Excellent work overall and continue to work hard in completing and finalising this page. But please don’t forget to add an introduction which clearly lists the outcomes that the page will hope to address

I really believe that this page would greatly benefit by re-structuring the entire layout by the headings suggested to us- ie. Development timeline, recent findings, current research and abnormalities. Seems a bit disjointed and is hard to follow.

Due to the manner in which you guys have subdivided the sections via organs, it is hard to comment and critique via the headings suggested. Some organs have been excellently covered (pancreas, thyroid, parathyroid), however, some organs do need a bit more development (eg. Pineal gland). Also, due to the way you guys have decided to approach this page, the writing styles and presentation of information does have notable differences amongst the oragans.

Overall, there is an excellent choice of headings and subheadings though. There is also excellent and correct citing in most of the sections. However, this page could be greatly benefited by re-structuring the entire page to follow the suggested headings. I really believe that the information and research included in this (hard) topic is excellent and demonstrates significant scientific research, however, the overall structure makes it hard to follow and understand! I believe re-structuring will address a lot of the issues mentioned. But again, excellent work so far in this very hard topic!

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In this review I intend to highlight the merits of your project and suggest some areas for improvement in light of the marking criterial provided.

I believe that an organ-by-organ approach to this section is great. This really helps organise the information. This layout also makes the page easy to navigate allowing students to directly refer to the section that they want to learn about. However by doing so I think you may have neglected some of the areas.

Each endocrine organ has a great introduction describing the structural features and nature of the organ. I suggest including an image or a hand-drawn diagram of each gland and location, as this would really aid understanding The time line is a great way to summaries the major stages in development, I feel that this section has been completed with sufficient research and detail.

The section on abnormalities needs to be completed, even if only one abnormality is addressed make sure you include information on the following areas. Epidemiology; Description; Cause and Treatment. Furthermore ensure that the section on current research and historical findings is researched and addressed addressed.

I feel that your project is incredibly cohesive and attempts to provide a through summary of all the main endocrine organs. However a number of sections are yet to be completed. You have a great template right now. If all these areas are completed the project will be a success. In addition; I suggest placing all the references at the end of your project page, under one heading. Good Luck!

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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.

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The breaking down of this system into organs is a real strong point of this page and there is plenty of information under each of these subheadings. The page could benefit from a ‘Current Findings’ section or perhaps by including relevant articles under each organ.

The text in this page is great but it could really benefit from the inclusion of some more images to support the information. I can see that your group did plenty of research but in text citations need to be included with your text with a ‘References’ section at the bottom of the page to stop the reference lists scattered along the page from interrupting the flow of your page.

Overall the page is definitely well resourced and has plenty of detailed text. Along with the inclusion of images and some minor improvements with the organisation of your text, this page will become a very good finished product.

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I noticed that there is no introduction, however the page does have introduction heading, I’m assuming you didn’t get the chance to upload information there or you haven’t had the time. This is something you need to work on so that the audience has some note of what this page is about, instead of just going straight into the pineal gland. It would make your page more appealing and professional if you followed through with an introduction.
There is great amount of reference at the end of each section however there is no in- text referencing. Having in-text referencing will allow the audience to know exactly where the information was read from and for the interest of the audience can read that specific paper in detail.
There is a great amount of information in almost every section with great detail however, consider subheadings to make the section easier to read and allows the audience to navigate the page effortlessly. Also consider some images in each section, to make it more inviting and not overwhelming with just content.
I do appreciate that each section is subdivided into “development, timeline”, maybe consider adding in the current research, historic research and abnormalities to ensure that you can get all the marks possible by addressing all the key concepts.

Overall this page is coming along nicely, I can appreciate the difficulty of this system in trying to make the page more coherent. However if you work on the subheading within each section and add some images as well as some in text referencing I think that should make a significant difference by making this page more inviting, easier to navigate and also appear greatly organised.
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You have covered the main topics by listing the endocrine organs. However the sections are lacking some key information which I assume you will add later. The introduction is empty and it would be very helpful it outlined what the page was about and what the page was focusing in terms of endocrine development. Also historic findings and current research models and findings haven’t been addressed yet. It is present to a small extent in some endocrine organ descriptions. By identifying these topics the page could be greatly contributed too. The page has good use of timeline for all the organ descriptions. However the timelines need to be expanded on with more detail.

Maybe a better use of headings is possible, where subheadings under each sections can be made. For example under hypothalamus the following subheadings can be added and used; historic findings, recent models and findings, hypothalamus development during fetal period, abnormalities occurring during fetal period. These topics are covered in some sections, but if subsection headings were made, it would be much more easy to read and navigate through. As there is a lot of organs to cover this may be useful.

Diagrams and tables could really help fill the page up and help in giving a more comprehensive coverage of the topic. Some tables aren’t fully filled up, for example the table under ‘hypothalamus’ and ‘Associated Abnormalities’. The filled up tables which are in the pancreas and adrenal gland really help these sections and if added and fully filled up for other sections could really add to the page. There is a helpful use of dot points within the page which helps make the material readable and structured, particularly in thymus, pancreas and gonad development.

Some sections don’t have adequate information on fetal development for example the Hypothalamus and Pituitary sections. There seems to be a teaching level of knowledge being displayed. Deeper research could be done to further enhance the project and fulfil project aims. Also more tools for helping peers understand the topic could be used, for example diagrams and hand drawn diagrams, video links etc.
References are done and there is a lot of in text citations. Some sections like the ‘Pineal Gland’ and ‘Hypothalamus’ section has no in text citations, which need to be added. The official references section is empty. If all the references from each of the sections could be added to the main reference section it would be great for the page. This can easily be done by referring to the how to reference page on the website; https://embryology.med.unsw.edu.au/embryology/index.php/Help:Reference_Tutorial.
Overall good job guys ! Good luck

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== Group Project Topic - Endocrine ==

--[[User:Z3414648|Z3414648]] ([[User talk:Z3414648|talk]]) 11:17, 20 August 2014 (EST) We have chosen our group project to be on the endocrine system.

--[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 13:07, 20 August 2014 (EST) We have decided to allocate 2 topics (endocrine organs) to each group member. We will go and research each and look for research articles and then figure out the best way to structure the content.

--[[User:Z3414648|Z3414648]] ([[User talk:Z3414648|talk]]) 12:19, 26 August 2014 (EST) This is a draft allocation for research topics for our project.
Janaki - Pineal, Hypothalamus.
Ali (z3414648)- Pituitary, thyroid.
Samrah (z3418837) - parathyroid, thymus, pancreas.
Ruth - Adrenal, gonad, placenta.
Samrah and Ruth if there is heaps to do on those three parts that i've allocated just let Janaki and I know and we can also help out. If anyones topics are sparse on info also let us know and we can reshuffle the allocations

--[[User:Z3418698|Z3418698]] ([[User talk:Z3418698|talk]]) 22:02, 26 August 2014 (EST) Hey guys, I was thinking we should maybe have a heading 'Recent findings' for maybe a few of the topics and have a short, brief summary of any new developments. I think it would be really interesting!

--[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 00:00, 27 August 2014 (EST) That's a good idea, should we put a separate section on recent findings, or just some information on recent findings under each section? Also we need historical findings

--[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 00:44, 27 August 2014 (EST)Hey guys, it's better to post student numbers to the parts allocated to each group member so it's easier for the tutor to mark. I would do this but i'm not sure about who is who :P Also I like the idea of recent findings. I think it's also better to post articles related to the recent findings and abnormalities as we go along as this will make it easier instead of leaving it to the end. For now, I think we should just post up as many articles related to each topic as possible and then figure out how to structure the content.

--[[User:Z3414648|Z3414648]] ([[User talk:Z3414648|talk]]) 21:22, 2 September 2014 (EST) Hey guys, I've done some research on the prenatal development of the thyroid gland so I'll add that to my section. We can always change it up later.

I also found this review article that goes into a lot of detail about the pituitary gland. It explains the cellular differentiation involved to create the cells responsible for manufacturing hormones like ACTH. There is a lot of complex gene involvement but I was thinking we could condense a lot of the information into a table. I suggest you guys do that for your organs too rather than having a lot of jargon on our page that only an advanced biochemist will understand.

<pubmed>22872762</pubmed>

--[[User:Z3414648|Z3414648]] ([[User talk:Z3414648|talk]]) 10:09, 9 September 2014 (EST) Hey i found a great article on normal and abnormal thyroid development and it's given me a lot of great information for the timeline part.
<pubmed>10.1016/j.beem.2013.08.005</pubmed>

--[[User:Z3418698|Z3418698]] ([[User talk:Z3418698|talk]]) 12:44, 10 September 2014 (EST)We are going to incorporate the Timeline and Abnormalities under each individual sub heading rather than at the end of the page. We are also going to find image links and post them in the discussion page before uploading them. We are also going to tabulate the hormones released by the glands under the subheadings. This will summarise the function of the glands in the embryo and how they contribute to fetal development.

--[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 00:46, 17 September 2014 (EST) Hi guys, I've added some info about adrenal development through gestation, at this stage some simple dot points which will probably be expanded upon later. There is a lot of content about the cell morphology at different weeks but I'm not sure as yet whether it's necessary to include that level of detail?

--[[User:Z3414648|Z3414648]] ([[User talk:Z3414648|talk]]) 12:59, 17 September 2014 (EST) Hey guys, i found this link for an image that i'm thinking of using on the project. It's from PLOSone which is good because it's free to use those images. This is the link for it: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0016752

--[[User:Z3418698|Z3418698]] ([[User talk:Z3418698|talk]]) 13:06, 17 September 2014 (EST) Hey guys, I found this image I wanted to use for hypothalamus development in a rodent, it basically illustrates the different nuclei in the hypothalamus once it it fully developed but I will be focusing on those that are present during development and the role of hormones each of them releases.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2082685/figure/fig1/

--[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 23:50, 23 September 2014 (EST)--[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 23:50, 23 September 2014 (EST) Hi guys, I think I might use this image (figure 3), it's from the PLoS too so totally fine to re-use and shows the fetal adrenal gland using 3 different techniques, like MRI, gross imaging and histological stain. I like it because it shows the gland from different perspectives. I'll upload it soon but here's the link:
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0075511

--[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 03:29, 24 September 2014 (EST) I might use this image for the pancreas section http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0007739 . It basicallys shows the development of the islet of langerhans and the ratio of alpha & beta cells at different phases of fetal development. Also Z3418698, I don't think that image can be used as it has copyright restrictions. Try looking in Plos One =]

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*Firstly, props on choosing the endocrine system. It seems like one of the harder ones to take on
*I don't understand why you chose to divide tasks based on endocrine organs as that has seemed to cause your research to become really disjointed. I guess now work harder to collaborate your separate findings particularly for things like having 1 united timeline overview
*Ensure uniformity throughout the page with little things like is it "fetal" or "foetal"? Choose one then go with it
*Maybe have labels for tables more distinguished as being separate to the main text
*Include the references throughout discussion, rather than a collection at the end of each section. Then have the entire reference list at the bottom like all the other pages have. You can look at the "edit" of other pages to copy and paste the codes
*Your timeline isn't really a timeline if there are no times mentioned in the "pineal gland" section. Try using a week-by-week format and separating information that way for all of your findings altogether. Then format that into a table
*Proofread for typos "Abnormalities" in "pineal gland" section
*Need more images for earlier sections
*Great formatting of images and tables for the adrenal gland, parathyroid and pancreas sections

Talk:2014 Group Project 5

2014-10-14T21:54:41Z

Z3419587: /* Peer Reviews */

{{ANAT2341Project2014discussionheader}}
==Peer Reviews==

The introduction clearly states the content in the website, which is good as this can prepare the readers for understanding. However, it would be better if some information about integumentary system, such as functions, is included in this section.

The development of integument system includes a lot of information. They are presented in good structure by the use of table for skin and nail. It is a great way to put some images in the table for easy understanding of the description in the development of teeth.

The recent findings area is well-researched. I would suggest try to put the content into small paragraph or in several points as the amount of text is a bit too much. Some images should be included as well.

Abnormalities section is great with the help of the images. It would be good if some more abnormalities are included. There is a lot of details under historic findings, try to illustrate them with the help of images.

In-text references should be included in the sections under development, recent findings and historic findings.

The project is well prepared. It would be better if some more images are included and the function of integument system is stated in the introduction.
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This group has made an outstanding effort in their efforts. I particularly liked the fact that they summarized the actual purpose of the page and what it would contain within the introduction itself, something the other groups have not really done. They have structured and organized the page extremely well and it is consistent and flows between each of the headings. I would suggest to tabulate the three types of cells in skin and have a column describing their origin and then their function to make it easier to read. The table for development of dermal layers and the table for teeth development should also ideally have a title and table numbers. In general the content is very well written and informative, supported with relevant images and diagrams that illustrate the actual development process. The recent findings heading is also well written however there are a few formatting issues with the text box sizes that need to be fixed up. I think it would be a good idea to list the sources of historic findings and then elaborate on what contribution they may have made to our current understanding. The referencing just seems to be inconsistent in this section. Additionally it would be a good idea to move all the references for the other sections to the end of the page under the actual references heading rather than having them scattered over the wiki page. The abnormalities section is highly commendable and written extremely well. Great job on the excellent and informative wiki page you have produced.
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The introduction is a great summary of what the project page will discuss making sure to highlight every aspect. However, the introduction should also mention more about the integumentary system listing all the organs involved, their function, anatomical position and the difference between the embryonic and fetal stages of integumentary development. The content presented on the page is fantastic. All information under the subheadings looks complete and has key information related to the topic. I like how the timeline is divided into each organ making it easy to understand and navigate. The use of the table to format the information is a brilliant idea and has been presented beautifully with images in each textbox. Also the content under current research is relating to the topic and shows extensive research. The use of the purple background is appealing to the viewer highlighting its significance. I do however believe that the information under ‘historic findings’ should be formatted into a table to make it easier to navigate. The content under ‘abnormalities’ has the right amount of information and clearly relates to the key topic of the project.

In terms of images, I believe a satisfactory amount of images have been used which clearly describes the content. However, some images are missing the all the copyright information needed as well as the description, references and student template such as those in the ‘development overview’ table. This should be added right away to ensure these images do not get deleted. The use of captions on these pictures is important to highlight what the image is referring to and this is present in the page. Although, images could be added under current research as this section looks like it could use more images. Great job on the images under abnormalities, they accurately relate to the content mentioned.

There are some incite references missing such as in the development overview. I’m not sure if the references listed below are supposed to the references for it, however all references should be placed under one ‘references’ subheading. The same references have been combined into one number showing that the group knows how to make the references set out. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections. Overall, this is a great project and if the group makes edits based on the peer-reviews received, this could enhance their project.

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Much more information on introduction is needed maybe. Also in text citations is needed.
EXCELLENT job on the overview development section. The table and the images are great especially. Great use to information and the corresponding images. One suggestion though, put in text citations.
Try to avoid repetitions as in the overview “this page” is repeated and in the table “a study” is repeated. Try being specific to which study you are referring to.
Well balance of text and images in the development overview section. In text citations are needed and all the references would look better in the end of the page in a bulk.
For your first research findings maybe obtain an image/s to aid the information.
Historic findings section is just a bulk of text. No images can be seen so if possible I suggest you add images to this section. Although it is VERY WELL researched.
VERY WELL DONE with the abnormalities section as each abnormality is well explained and has an image to accompany it.
Try not to use a lot of pictures and references from the Embryology website.
Over all this page is good but a lot of in text citation needs to be done and the references need to be in the end of the page in a bulk.

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Group Project 5 – Integumentary Development

This page looks very neat and well organised, with an introduction that explains exactly what is going to appear and be discussed on the page. The Development Overview section is very well done, with the appropriate use of subheadings and content. The use of dot points is very effective, making the page look neater. Perhaps it would be good to draw a histological diagram of the skin layers, and uploading it to the skin development section. Specialised cells or important names throughout the page could be highlighted in bold or underlined as well, to highlight important terms and make it easier to learn and remember from. The title ‘Some Recent Findings’ accurately portrays what we as students can only do, which is identify SOME of the recent findings. This section could have more than 2 recent findings however and could be further subdivided by subheadings into the different components of the integumentary system – perhaps have 2-3 research articles for each component of the system. Historic findings are well researched but some more information would be good. The ‘Abnormalities’ section is so far the best looking section as it seems it is almost completed. Perhaps a few more abnormalities would be even better.

The table of the timeline in the ‘Development Overview’ section is superbly done and the use of histological images is fantastic as it provides the anatomical information visually. When I clicked on an image however, there was no proper referencing of the image and the copyright information and student image information was not present. The images are described very well.
One image has a problem and is present in red writing, so might need to remove this as something is wrong with the file and it could not be uploaded. There are no student-drawn images and I think if this group did this, it would really benefit their project and emphasise their understanding.

The ‘Some Recent Findings’ section has a purple background, which makes the page look more aesthetically pleasing and less monochrome. I like the ‘More recent papers’ box that can be expanded to reveal any more research papers related to the integumentary fetal development, in case anyone wants to have a further read- very clever.

Journal articles are correctly referenced but website references need to be improved upon- to find how to do this go to the ‘How to reference’ page. References are all over the place and need to be compiled under each heading or one main heading titled ‘References’ at the bottom of the page.

Overall, this page is looking fantastic at this point in time so keep up the great work!

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Introduction is short though luckily few words can go a long way, with all sections of the wiki page being properly addressed. Development overview content is good; the use of table integrated with pictures allows viewers to visually grasp the progression in skin and teeth development. The changing between dot-points and paragraph format should be standardized or use paragraphs with dot-point only for list based information. References need to be properly integrated into the page, instead of at the bottom of each section.

In the recent findings section 2 out of the 4 studies presented have any content. To improve cutting some of excess information for the 2 studies already addressed and creating summaries for the other 2 will create better scope of recent findings. The formatting of recent findings is unusual, proper placement of the “Hematoxylin/eosin” image”, removal of dot-point and removal of purple highlighting, will make the section easier for viewers to understand. Historical findings okay, more detail could be added to “skin”, “glands”, “nails”. Use of capital letters like “DEVELOPMENT” show be replaced with subheadings, the image “File:Screen Shot 2014-10-08 at 10.38.04 am.png” has not appeared properly, should be easy to fix.

Straight up the abnormalities section is amazing, no improvement needed. All 4 diseases have in-depth relevant information, sufficient referencing and images to allow viewers to visualise clinical manifestation. To improve use of dot-points or paragraphs should be standard throughout the project, referencing in beginning sections needs to compiled at ending of each Main heading or bottom of page, recent findings need 1-2 more studies, and recent findings need significant reformatting.

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Overall I was very impressed with this project page. I loved your use of pictures and diagrams as it provided a great understanding of what was happening- and also, a lot of the images were quite interesting- which is a great thing for a project! I also enjoyed the use of bullet points- it was very to the point and it retained my attention throughout the piece. I did find, however, that the introduction was a bit short. Whilst it did cover most of what was required, I don’t think it hurts to be a bit more exhaustive in what you’re saying, because the introduction sets the mindset of the reader for the rest of the project- and if they have a clear understanding from the start, it makes it much easier when you are explaining more complex things such as the abnormalities later on.

Overall, I thought that the developmental timeline was extremely well done, and a highlight of your project. The rest of the developmental overview was quite well done, however I think in areas it was a bit sloppy, and it would be of great benefit to clear this up so as to improve the clarity of your work. Further, I enjoyed the succinctness of your paragraphs, it made it easy to read and wasn’t too much to take in at once. I think that currently, your use of colour is a bit random in the recent findings. I think that this could really boost your project if you applied it to more areas of the page. As far as the content goes, I think that the recent findings is just too wordy and I began to lose my concentration a bit. I think maybe by forming more succinct dot points- you will be able to convey your message more clearly.

I think the historic findings could do with a bit more beefing up, but what you have so far is well done. The abnormalities is also very well done, and I think that your use of images really grab the readers attention.

I think that overall this project is shaping up to be a great one. I think you need to be careful and consistent with your referencing though as I noticed some sections lacked in-text citations.

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This page seems to be done extremely well. It looks very visually appealing as multiple images are used, information is presented in tables, bullet points and very few slabs of text. The introduction is short and to the point. You could possibly add to this area a tiny bit of info concerning the embryonic development of this system, where it first started, then mention how you will expand on the fetal development. Otherwise it just seems way too short.

Explanation of the organs in this system is well done and concise. In the glands section, I would suggest not using dot points for the function of the vernix caseosa as it looks as though the dot points continue from those of the glands, therefore can be confusing when first looked at. Other than that, I would suggest that you make sure your referencing is correct and is used within the text.

The recent findings area is nicely done, but I still can’t help but feel the amount of text is just too much, even though the section is made better looking by making it purple (keep the colour, it looks awesome). The slab of text is just too much, so you should try and simplify it a bit. Historic findings are few but there is at least one for every organ which is good (more would be better). The abnormalities covered are done well, going into detail and providing a good image to describe what it looks like. I would suggest having at least 5 abnormalities, one for each organ discussed.

Overall, this page is very well done, with lots of images and colour used. The main thing I would suggest would be to make sure correct referencing is used. There were some paragraphs were no references were used at all. Also, all references should be at the bottom of the page, not within individual sections.

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This page has great overall structure and presentation. The introduction gives good insight of the overall contents of the page, however it is very brief and should be expanded upon.

The table included in the developmental overview serving, as a timeline is excellent, really well done. It’s easy to follow and looks very neat. I like how there is an image for each of the weeks mentioned, just don’t forget to add in-text citations for its contents. The glands sub-section is very brief and would benefit if there were more contents added. Great job on the images though. The nail section is the same, more contents needs to be added and image would look really good.

The developmental overview and historic findings sections also seems to lack in-text citations. There is also has an image with a broken link. The subsection hair seems to be well researched, however I would also suggest either bolding or underlining the words you want to emphasize such as “structure” for a neater look.

The recent findings section looks superb I love the purple background colour. Its very well researched and the link to more research papers are very helpful for readers. I would suggest you put the image at the bottom of the mentioned content though, just to avoid the big gap on the page, or even if you can manage to wrap the text around the image, it would look much better in terms of presentation.

Although disturbing, the abnormalities section I could not fault. Very well done. It is evident that it has been research well and the images allow for great visualization of the diseases mentioned.

Overall, excellent page just needs a very formatting edits and some expanded contents mentioned above. Good luck!

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Integumentary
The introduction seems really over formal and non friendly. Maybe try rewording some parts to make it more reader-friendly and welcoming.
The developmental time line is absolutely BEAUTIFUL! It shows the week of development, a brief explanation of each, and a picture to visually explain what is happening! I think it’s the best developmental timeline of all the wiki pages! Awesome job :)
The references should be put together at the end of the wiki page before final submission.
Hair and nail sections are very well done, teeth section are in dot points; this should be converted into paragraphs to match the wiki page format.
The section on recent findings seem to be copy pasted? Or not yet converted into the students’ own words. The formatting is very different to the whole of the wiki page as well which should be changed. On the section on historic findings, you should try to find a picture to supplement the information you have.
The abnormalities section is very well done, pictures visually supplementing each of the abnormalities. The picture of the infant with harlequin ichthyosis especially helps the reader understand the degree of extremity of the abnormality.
Overall, very informative and well done!

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This is a really well done project. You have made sure that that you have ticked all the boxes as well that Mark has asked for. The abnormalities section is really good. You have done well with most of your images as when you click on them there is a good description and they are well referenced. The development overview table is exceptional and makes the project easy to understand. For the week 22 maybe include the study in which you got your information from.

Apart from the abnormalities section it appears as though the referencing is a bit all over the place. Need to follow the abnormalities section and put references into the specific parts of the information you are using it for. Because otherwise it becomes difficult to know exactly where you got your information from. The historic findings are really good and well done however there is probably a space for more information to be included as I feel as though some of the findings are a bit hard to follow at times. It may have just been my computer I couldn’t see the picture of ‘fetal hair development’.

I think it would give a nice touch to the project if you were to add some student images because it would give the page a more ‘student’ and also make it easier to understand. Don’t mind the purple background on the ‘some recent findings’ part but it just looks a bit out of the blue. It’s certainly unique and attracts the eye but it puts a lot of emphasis on this section which I’m not entirely sure you want.

Overall though a really good project with excellent information. There needs to be a bit more focus on referencing technique, some minor edits which I have mentioned and maybe introduce some student pictures to make the project more student-like. Great work though and good luck in finishing it off.

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The introduction of this page was good as it provided a great overview and insight into what the project would later go on to discuss. Perhaps a little information on defining the integumentary system itself would be valuable though, to let the reader know the constituents.

The sub-sectioning of the page’s content into ‘introduction, ‘development overview’, ‘recent findings’, ‘historic findings’ and ‘abnormalities’ was clever, as the development section then went on to describe each component such as skin, nails etc. This effectively segmented the information into smaller chunks that could easily be navigated to. I especially liked the use of the table in the ‘skin’ section, showing the week of development, description and image corresponding alongside it, as it provided a holistic approach to that section. However, there were no in-text citations in the ‘skin’, ‘hair’, ‘nail’ or ‘teeth’ sections, hence the source of the information is unclear. To do this correctly, Dr Hill’s Wiki help page should be consulted.

The use of various images with labelled captions was a strength of this project, as the pictures were effective in balancing the text components to make the page more visually appealing. Most of the sections under ‘development overview’ have a decent amount of content, however the ‘nails’ part is a bit lacking and also needs to be correctly cited. The use of the table of images alongside the description of developmental stage in the ‘teeth’ section was very good to include, however the image is captioned ‘The stages of embryonic teeth development’. This may be irrelevant as the project’s focus is on fetal development. Further research into this area may uncover more relevant information.

Although the section on ‘recent findings’ contains a lot of information, the use of chunky paragraphs detracts from the readability of the page and the purple boxes could be summarised into dot points to help the reader understand the content more quickly. The section on historic findings seems concise and relevant, however the image included says it has been removed/deleted, so this requires editing. Lastly, the ‘abnormalities’ section was very well-structured and written, as each example had a captioned image accompanying it to help the reader visualise. This section was also well-done in terms of in-text citations, with an extensive reference list provided at the end. Perhaps consider adding some student-drawn images and possibly a relevant video, but otherwise it is very good as it is. Overall, the project has a good layout and a decent amount of content; with some editing and formatting it can be improved further.

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Overall this is an impressive and well researched wiki page incorporating lots of pictures and tables to keep the reader engaged and interested. However there are a few areas that have the potential to be tweaked. Firstly there are references scattered throughout the page. A more attractive way of presenting the references is as a long list at the end of the page. The introduction is clear, concise and short. All the organ development section is well presented and has the right amount of information. It is well structured in the sense that the student introduces the organ, it’s embryonic origin, the fetal growth stage and then goes into slightly more depth in a bullet point form. Along with complementary pictures, this is a very effective way of presenting their topic. This page could be improved by adding student-drawn schematic diagrams to summarise the layers of the skin in particular since histological images can be confusing and unclear to a non-expert embryology student.

The skin development section appears to dwell on the content that was covered in lectures. Considering there appears to be only three references associated with the entire integumentary organ development section, the depth of the information is limited. By doing some more research you might be able to find interesting additional information that can be added. The recent findings section is interesting and the images are great. However the dense block of information and slightly odd formatting make it hard to follow. Perhaps using diagrams to explain the differing gene expression and breaking down the information into bullet points would make it more readable.

The historic findings and abnormalities section is particularly well done. The images complement the minimal yet important points made. I was left wanting to read more into it so that suggests there’s room for further development and a deeper explanation of skin abnormalities.

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*Great overview given in the introduction. Maybe look to replacing the words "this page" to something else to avoid repetition
*I'm really liking how everything has been simplified into dot points and tables where relevant. Don't forget to include relevant references all throughout though, to justify all that you've included in each section
*I can't express how much I love your first table. Great work!
*Proofread so that you don't repeat the same things in your table though. You mention "in a study" numerous times but there's no indication to which studies they are
*I'm sure Mark would be thinking this same thing, but look to getting different references outside of this Embryology website, maybe from textbooks or otherwise for preliminary information on development
*The "recent findings" section looks nicely formatted but just a bit wordy. Maybe think of dividing the text up with bullet points or images
*Really liking your "historic findings" section! Great research
*Maybe think of re-creating some of the simpler pictures by drawing them yourselves. That way you're not using too many pictures from this Embryology website, Mark warned our group about this point
*Great choices for the "abnormalities" section. Traumatising at first, but very well-researched and presented

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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.

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The introduction to this page offers a brief insight into the information presented in this wiki and is a good way to start your page. In the ‘Developmental Overview, the use of dot points to break up the text is a great way of presenting the information in conjunction with the table. The table is a really good piece of work and the images make it really interesting addition to the page.

The ‘Recent Findings’ section contains a good selection of articles but I think it could benefit from a brief description of each paper to reveal the relevance of the studies. The ‘Historic Findings’ section is well written but could also be improved by including some historic images to make it more interesting.

Overall this page is really well written with plenty of detailed text. The strong point of this page is the ‘Abnormalities’ section - it has great information and really good images to support it. It could be made even better if some more abnormalities were included. This page also benefits from its neat presentation and plenty of references.

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==Week 5==
Hey guys!! I found some research material that we can use to construct our time line!

Historic information is hard to find! I might go look at some text books in the library
--[[User:Z3418340|Z3418340]] ([[User talk:Z3418340|talk]]) 12:50, 27 August 2014 (EST)
How is everyone else going?

--[[User:Z3417843|Z3417843]] ([[User talk:Z3417843|talk]]) 12:52, 27 August 2014 (EST) Hey!! That's great! I also found some material for abnormalities. There seem to be a lot about septal defects. I'm gonna try to look up for more defects.

--[[User:Z3417843|Z3417843]] ([[User talk:Z3417843|talk]]) 22:53, 30 August 2014 (EST)Woo!! Nice to see more links in the page! Rehmina and I also thought that it would be easier for marking if one of the two people in current research do timeline instead because that would make marking easier and less confusing. But that's not final, it's only a suggestion. Also, Dr. Hill gave us some tips on what to focus/include in our research such as:
*Remodelling during the fetal period
*Changes during ossification - haematopoietic elocution from liver to bone marrow
*Early development of WBCs — hot topic right now!!

Hey everyone, yeah that sounds good with me.. :) so rather each person focuses on 1 of the 4 topics right? --[[User:Z3417796|Z3417796]] ([[User talk:Z3417796|talk]]) 12:35, 31 August 2014 (EST)

--[[User:Z3417843|Z3417843]] ([[User talk:Z3417843|talk]]) 18:36, 1 September 2014 (EST)Yep, exactly! I'm really glad that's alright with you but we can still talk about more in the lab.

--[[User:Z3417843|Z3417843]] ([[User talk:Z3417843|talk]]) 12:14, 2 September 2014 (EST)Hey everyone! I just asked Dr. Hill about using review articles. He said it's alright to use review articles as long as you say that the information came from a review article when citing. We can also use images from review articles and there is no need to say that it came from a review article.

==Week 6==
--[[User:Z3418488|Z3418488]] ([[User talk:Z3418488|talk]]) 20:19, 3 September 2014 (EST)Hey guys, I had a good talk with Mark today after the lab. Since we're doing the Cardiovascular system, it incorporates the (i) development of the heart, (ii) development of the blood vessels and (iii) the formation of red blood cells/white blood cells. But Mark said that as a group, we would be able to create and produce this web-site in a manner that we thought was appropriate. We could focus on one of the specific areas or more broadly on each area, if we chose to. But, MOST IMPORTANTLY, our project should be cohesive. What we talk about should be introduced well at the start and should be cohesive through out all of the subsections that we're working on. He really stressed the importance of us having a single, unified vision of our end product and that it should be succinct throughout it all. Im proposing that we actually decide what to focus on very soon.

: --[[User:Z3418488|Z3418488]] ([[User talk:Z3418488|talk]]) 20:19, 3 September 2014 (EST) I'd particularly like to just focus on the development of the heart? Maybe incorporate the formation of blood cells if the research in the other areas is interesting and notable?

--[[User:Z3418488|Z3418488]] ([[User talk:Z3418488|talk]]) 20:24, 3 September 2014 (EST)In regards to the use of the textbook, we are allowed to use the information from it if we cite it properly, but he really want us to be using articles (and even Review articles) to discuss our information.

I agree, the heart should remain our focus, but of course other aspects such as blood vessel formation/ blood cells would naturally fall into it as well- maybe just a brief mention wherever appropriate? --[[User:Z3417796|Z3417796]] ([[User talk:Z3417796|talk]]) 21:22, 3 September 2014 (EST)

==Week 7==
--[[User:Z3417843|Z3417843]] ([[User talk:Z3417843|talk]]) 21:05, 8 September 2014 (EST) Hmm. I agree. Let's try and focus on the heart for now and see how we go? And if time permits, maybe we will be able to include the development of blood vessels and blood cells. Sorry I didn't reply so soon, kinda busy week for me haha!
: --[[User:Z3418488|Z3418488]] ([[User talk:Z3418488|talk]]) 00:24, 10 September 2014 (EST)Ok that sounds really good and reasonable! I'd be happy to follow that plan. And yeah, same! Very busy week for me as well! But yeah, I think lets just focus and refine our research to just the development of the heart at the moment

--[[User:Z3418488|Z3418488]] ([[User talk:Z3418488|talk]]) 00:40, 10 September 2014 (EST)Hey guys, Im having difficulty knowing whether the use of an article is fine or not?! If it says "Full-free-text" does that mean we're allowed to incoporate it? Because a lot of the copyright information, is very brief. Thanks heaps, if you guys know an answer haha
: --[[User:Z3418488|Z3418488]] ([[User talk:Z3418488|talk]]) 00:55, 10 September 2014 (EST)Ok, never mind.. I find out the answer haha. If it says "Open-Access" or "Full-free-text" it is only free to read online and may/may not be allowed for re-use. You'; have to read carefully or apply for permission lol. I guess i'll just be sticking to mainly the Public Library of Science (PLoS), Biomed central (BMC) and Springer Open... which we are pretty much able to use, with the right referencing and acknowledgement. I read this on the 'Copy rights' page on this wiki. http://php.med.unsw.edu.au/embryology/index.php?title=Help:Copyright_Tutorial. Can someone verify or correct me if i'm wrong haha?

--[[User:Z3417843|Z3417843]] ([[User talk:Z3417843|talk]]) 11:56, 10 September 2014 (EST) I thought copyright only applied on images and not on content. It would be really difficult to write a report when the most papers have copyright. We can ask Dr. Hill in the lab just to confirm.

==Week 8==
--[[User:Z3417796|Z3417796]] ([[User talk:Z3417796|talk]]) 12:56, 17 September 2014 (EST) Hey guys, so Carl and I had a talk with Dr. Hill and he has agreed to allow us to change topics from Cardio to Integumentary. To finalise the change all members have to personally email him saying we all agree to the topic change. Carl and I have started thinking about our approach to the topic and we think we should have a main focus on skin and smaller sub-topics on hair, nails, glands and teeth. Each members role just remains the same and any problems we will all still help eachother :)

==Week 9==
--[[User:Z3417796|Z3417796]] ([[User talk:Z3417796|talk]]) 12:46, 22 September 2014 (EST)Hey guys, I've added some headings for our new page just to get a start, we've got alot to catch up on, I guess we still have to talk about it as a group for the overall layout, we should all start adding some content soon.

--[[User:Z3417843|Z3417843]] ([[User talk:Z3417843|talk]]) 12:41, 23 September 2014 (EST) Thank you for fixing it! Yeah, we have a lot to do but that's okay. Midsem break is next week and hopefully we can get most of the bulk done before week 10.

==Midsem Break==
--[[User:Z3417843|Z3417843]] ([[User talk:Z3417843|talk]]) 23:24, 29 September 2014 (EST) Just wanted to let you guys know that Dr. Hill gave us some tips on what to look at a few weeks back. He mentioned "vernix caseosa and fetal hair." Here's a wikipedia link to vernix caseosa (http://en.wikipedia.org/wiki/Vernix_caseosa) just to give you guys an idea on what it is. I'm aiming to finish before the end of the week so that I could help anyone with their parts. Anyway, I hope everyone's having a good break!

Talk:2014 Group Project 4

2014-10-14T21:27:46Z

Z3419587: /* Peer Reviews */

{{ANAT2341Project2014discussionheader}}
==Peer Reviews==

There is definitely plenty of useful information and your group has clearly put in a lot of effort to do extensive research on the topic. However there are some inconsistencies with formatting and references, which you can easily iron out once you have time for a final edit. There’s a lot of content on the page and understandably its difficult to organize it in a way that’s meaningful and easy to read. I think there are a few too many subheadings and it becomes a little confusing to follow, for example under the current research, models and findings heading, the female subheading was hard to follow so I think that just needs a brush up. I think it would be a good idea to avoid presenting all the information under this heading just as bullet points. Try to have at least 2-3 current research articles and under them elaborate on what the findings were and what they may imply. I think it would be much more interesting if it was presented that way rather than spread over so many bullet points. I particularly liked the use of original hand-drawn diagrams with colour helps to make the page more visually appealing and interesting to read. I see there is still work to be done under the current findings section. It would be a good idea to summarise the findings and state their implications on current knowledge under each article. The historical findings section is definitely extremely elaborate but I feel it may be a little too much. I think it’s important to keep in mind the purpose of the assignment and focus more on the actual fetal development and keep information succinct and relevant rather than overloading with information. The Abnormalities section was done extremely well and had a lot of useful information on many different diseases. Overall a great effort by the group, definitely can see how much effort you have all put in.

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Great progression on the table in text citation for it is missing. Also in the table for week 5 you have bullet points and for weeks 1-7 you have a different type of bullet point. Try keeping it consistent.
The diagram used to illustrate the genital development of different genders is very good and effective.
Current research and models section needs more pictures to help aid with the information. Under current models section, the hand drawn image is very good and effective in portraying the overview. Also in the current research and model section, try using more than one reference.
Current findings section is currently empty but that’s ok as you still might have 1-2 weeks to finish the project.
Historic findings needs more images as it seems like a big bulk of text. However it is very well researched.
Abnormalities needs more pictures as it seems like a bulk of text. I suggest obtaining a picture for each abnormality you talk about if possible. This aids the readers’ understanding of that specific abnormality. Also ‘pictures say a thousand words’ so it would be great if you can include pictures.
All hand drawn images are great and clear to read and understand.
Your references from other sections need to be in the end of the page in a bulk.

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The project doesn’t have an introduction yet; however information such as what the genital system is about, the features of the system as well as the difference between the embryonic and fetal stages of development should be mentioned. Not to mention a brief summary of each key subheading such as abnormalities under introduction e.g. any deformations in the fetal stages of genital development can result in to such and such abnormalities which will be addressed. As for system development, I can see how there is dot-point description above the table which summarises the same thing. This structure is a bit confusing for me. I believe if the information was summarised into paragraphs and then tabulated it would make more sense. It’s best to format all that information into that table. The use of a table is a great way for the viewers to differentiate between the two sexes and understand the information more easily. I hope to see the table filled out completely soon. A glossary subheading should also be placed on the project page and have keywords defined to make viewers completely understand the content.

As for current findings, the information again is in dot points which should be paragraphed instead. However, the current findings are indeed interesting and the right amount of information is used to describe them in both sexes. The content under historic findings such as the ‘female genital development’ doesn’t show any historical events. There are no dates which show when something related was discovered. The ‘male genital development’ however shows dates and discoveries. In my opinion, if this information were tabulated rather than paragraphed, it’d be easier for viewers to navigate and understand. There is a good amount of detail under the abnormalities which relates to the key topic and is easy to understand. Overall, the content is relatable to the genital development of the fetus and underlines all the keys points. However, if this information were paragraphed in some areas and mentioned above, it would make the content easier to navigate and comprehend.

In terms of images, there are many places where images are missing such as introduction, system development and current models. I believe there needs to be more images on this page that relate to the content to make it more appealing and understandable to the viewers. The image called ‘File:Flow Diagram of Fetal Development of External Genitalia.pptx’ isn’t permissible and needs to be removed. The use of a hand drawn image on the testes is great, however there is information missing on referencing, student template and copyright laws. On the other hand, there are some images which correctly follow the uploading picture procedures such as the image on the ‘abnormalities of the vagina’; group members should follow this procedure. Captions should be added to each image to address what the images are showing.

There are sections where incite referencing are used, however some sections are void of them such as the ‘introduction’ and ‘system development’. The use of a ‘references’ subheading is good, the same references have been combined into one number showing that the group knows how to make the references set out. However reference 20 and 21 are the same, please fix this. Also there are references under each subheading which should be placed all under one ‘references’ subheading. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

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The Introduction, Current Models and Current Research section all in dot-point form, which obviously allowed you to more easily, put information on the page. These need to be converted into paragraph form to give the content greater readability and flow.

Presuming the system development is supposed to be the introduction, there should be inclusion of current research, historical research and abnormalities. Without these the reader will not know all the sections of the page after reading the introductory section, which is the intros purpose. The use of bold and capital letters is unneeded. The existence of a table is good though has a bunch of formatting and text problems (capitals, bold, captions, lack of lines). “(around week 4-6) that sexual differentiation occurs in the fetus ” this statement is incorrect since it is an embryo during the week4-6, it becomes a later around week 10. “450px” has not been inserted properly, the sexual differentiation image requires caption and references.

Current Research and Models has in-depth content for undifferentiated and male, though limited information on current female genital research. The headings are repetitive also many without any content, similar content needs to be merged under single headings. In Historic findings the content and wording is good but same trend continues significantly more text on Male development compared to female.

Abnormalities section is great with even attention given to female, male and both. Information is appropriately in-depth and referenced, addressing causes, process and treatment. Addition of 1-2 images in the “both” section is advised, to allow readers to identify clinical features of the diseases. Like the use of drawings especially “Abnormalities of the Uterus and Vagina” and “Anat of Testes”, you should change the caption of the testes drawing from “alt text”.

For improvement; covert of dot-points into paragraphs, expand on female sections of “current research” and “historical research”, fix a few image problems and remove unnecessary bold/capitals/captions.

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A great start on tabulating the information about the development of this system. There are references but I don’t see any in-text citations. The image used in this section is really good and relevant. It clearly shows the major processes in the development of the genital system. However, it is a bit pixelated so maybe try resizing the image to a smaller size. Maybe try uploading the image again with a different filename, change it to something more appropriate rather than “Image.jpg”. And also, if possible, try to include it in the table. Good job on embedding a video! I think this is the only group so far that has included a video. It’s a good video about the development, I just wish it had a voice-over explaining what is happening but that’s not really the group’s fault. Nonetheless, great job on the development section.

With the current research section, great use of dot points but a bit excessive. Maybe try to make paragraphs where it is appropriate. It is well-researched, very detailed and very informative. It’s good to see student drawings. Great job on that. I see that an image was not properly uploaded into the page, so just fix that. Good job on referencing. All research articles seem to be relevant to this section but try to incorporate some of the in-text citations of the remaining articles, not just the first three. Overall, really great job on the content of this section. It is evident that the person responsible for this section put a lot of effort in research.

As for historic findings, great job! I know this is probably the hardest of all the four sections in terms of finding information and this section is well-researched, very detailed, and very informative much like the current research section. Maybe try to use some dot points to lessen the bulk of this section. Great drawing included in this section. Try to add more, especially for the males since that is the bulk of this section.

Lastly, for abnormalities, great job on finding lots of abnormalities! Lots of references and each area of this section seems to be well-cited. The content of this section is very concise. All the important information about the disease is included, from the cause to the treatment. Good work! Try to find more images for the other abnormalities. It may be tedious but it will help in visualising the clinical manifestations of each disease. Overall, this group has done their research and did it well. Great job on the table for development and images. Their page is very clean and very organised, particularly the references. Don’t forget to write an introduction for your project’s page.

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Just looking at the contents, if feels a little intimidating both in that it is so long as well as the use of caps. You should try and limit both; the use of all caps can be quite annoying in text and the extensive contents list can make people dread reading through your page if it looks like it’s quite long.

An introduction is recommended as it is usually a good starting point to provide the reader as sense of everything the page will cover. The system development is a little messy, but I will heed your note and pay attention to only the table. The table itself is a great idea to lay out all the events happening in the corresponding weeks, making it look neat and concise. However, the use of all caps, bold text, and two different fonts still makes this section look messy. Having both male and female events on the same table makes it look as if there is a chunk of info missing for the female side as well. I would suggest having them in separate tables next to each other, which would eliminate the empty rows in both areas. Both the image and the video (congrats on finding a video! Really good addition to the page) should be captioned.

The current research, models and findings seems well researched as there are a lot of points made. However, it is all presented in bullet points which can be visually unappealing. Some sections look incomplete as well, so an effort needs to be made to finish these areas as well as present them in an appealing manner e.g. in paragraph form with a picture next to it to both describe the text visually and offset the amount of text. The drawing of the testes should be captioned appropriately instead of the ‘alt text’ provided. It should also be enlarged, as its current size isn’t large enough to view any of the labels properly.

Historic findings looks well researched on first glance, but then I saw that only 4 sources were used to reference the section. It looks really bad when only one source is used to reference a large slab of text, which you have done twice. I suggest finding articles that state similar information and using them as references as well, to back up your current information found. Other than that, I suggest possibly formatting your section in a more appealing way; either summarize some areas in dot points, and add a picture.

The abnormalities section is nice and concise, without going into too much detail which is good. Just make sure you explain what it is, how it is formed/how you get it, some statistics and possibly an image to show what it looks like, and that’s all I believe you really need for this section.

Overall, your page is well researched with lots of info. Just make sure it looks visually appealing, is consistent in terms of font and presentation, images are used and captioned correctly, and all references are placed at the bottom of the page.

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Firstly, great job on all the contents you guys managed to present, it’s quite detailed. There seems to be no introduction though, and the page jumps straight into explaining genital development. I think if an introduction were added, it would give the whole page better structure and formatting so the reader knows what to expect when they decide if they want to read on. The dot points used for the developmental section allows for easy readability of the contents, however, the use of caps lock and arrows takes away from the overall presentation of the page. I would suggest any text you want to emphasize to make bold or underline the word. I also noticed that there was a note stating the attempt to put all the developmental information into a table, but had issues. I suggest you look at the editing basic page you can search for in the top right hand corner as it outlines a step-by-step guide into making tables etc.

In regards to referencing, there are no in-text citations for the first two subheadings. The sections were they do have citations also have a list of references at the bottom of each section. I would recommend just adding a final list of references at the bottom of the page, as it looks much neater.

I’m impressed with the level of hand-drawn diagrams uploaded. I would also recommend adding captions to the image. For example:
[[File: Flow Diagram of Fetal Development of External Genitalia.pptx|1000px|thumb|right|alt text]]. The “alt text” should be edited to describe the caption of the drawing. This particular image seems to have a broken link though; the “alt text” also appeared in the labeled diagram of the testes. Otherwise, good job on the other images.

The current findings section seems to be untouched, with the exception of some pubmed journal article links, I’m assuming you are still in the process of adding content. The historic findings, however, is extensive and well researched. Good job.

The abnormalities section is done well. There is more than enough abnormalities listed, and they are researched well, I would just suggest adding a few more images for better visualization. Overall, great page, just needs better formatting for the mentioned sections.

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This project would benefit from having an introduction to prepare the reader for what is to come and summarise everything briefly. The system development part is interesting and clearly there has been a lot of research put into finding the information. I suggest adding pictures or student-drawn diagrams, particularly of the chromosome and the SRY gene location to make it more comprehendible. If you’re not a geneticist, it can be difficult to picture that much detail at an embryonic level.

It is clear you have considered inserting images so it would be important to follow through with that before the final stages of marking. I’m not really sure why you’ve inserted a table here as well since a lot of the information was already covered previously. Maybe use less information in the table. The references at the end of this section should appear at the very end of the wiki page. A lot of other groups have already done that so if you need to copy the formatting, it’s definitely possible. The use of a video on your page is commendable and sets this project above others in that sense. It’s a great idea to have a youtube clip. However, it is 9 minutes long which is a bit long for a student page that is designed to inform students on the genital system on a wholistic scale rather than tackling complicated ideas. Maybe try editing the youtube video so you only use a 30 second or 1minute clip.

The male and female genital development section is clearly presented and the use of bullet points make it easy to follow. However reading the information, it appears that a lot of it I recognised from the lectures. This doesn’t suggest the student explored external embryology sources. On another note, perhaps the lecture on the genital system was very indepth and this student did do research but found all the relevant information had already been covered. None the less, I think it would be advantageous to add a subheading in the section that looks at recent findings. This would broaden the understanding an embryology student can achieve by reading this wiki-page. Also there has been an error uploading an image so that should be fixed.

Although the information is presented well, the bulk of references should be included at the very end of the page. This project is very good but there is still some further research needed, particularly under the current findings subheading. The information presented under the historical findings subheading is quite dense and would benefit from being broken up into a table or simple bullet points. The abnormalities part is excellent and there has clearly been broad research into different embryological resources.

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Overall, it is evident that a lot of work has been completed on this project as each section has a decent amount of information and there are images throughout the page. However, the addition of an ‘introduction’ section would help to orient the reader and help students gain an overall understanding of the topic.

The section on ‘system development’ seems to be well-researched, however the formatting of the content in short, one-sentence dot points makes it difficult to read and incongruent, so writing this out in small paragraphs would improve the readability. The capitalization of some words is unnecessary in both the dot points and the table, creating inconsistencies in the formatting. Also, some words are unnecessarily bolded which detracts from the aesthetic appeal of the page. However, the inclusion of a table to summarise the timeline information is an effective tool, although there is much more information provided for the male system than female system. It is really good to see the use of an image as it is relevant and clearly compares the male and female system development side-by side. I also think the video inclusion is fantastic as it would be an effective way to learn for a reader with no previous knowledge, making the page more interactive.

The section on ‘current research, models and findings’ contains lots of relevant information, however this is not referenced in-text and it is thus unclear where the information has been derived from. There also seems to be some unevenness between the depth of information between male and female systems, which some more research can easily remedy. In terms of current findings, the listing of the information in dot points makes it easier to read, however there are some parts italicised and capitalized that are not needed. It is great to see some hand-drawn images as these are simplistic, colourful and effective ways to accompany the text, adding to the page’s appeal. Take care to properly include images, as one of them appears as ‘alt text’ and the link does not show the image itself. Although some references appear under a ‘references’ title in this section others appear as a website links; formatting of these could improve neatness.

The following section on ‘historic findings’ contains evidence of extensive research as it is very detailed and well-written. However, I would consider breaking this part up into smaller sections using dot points as large paragraphs seem tedious to read. The hand-drawn image is a good inclusion, but labelling of it would be effective and adding a couple more would break up the long section visually. Also, there seem to only be in-text citations after long chunks of information; perhaps more sources should be used/consulted.

Lastly, the abnormalities section was comprehensive and detailed and enough information was given on some examples. This was just the right amount of content, as any more would seem excessive. Adding some more images with appropriate captioning is advised also. I liked that the references were listed altogether at the end of the page, making it neat and tidy. Overall, a solid project which just needs some formatting to improve further.

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Don’t forget to add an introduction which clearly lists the outcomes that the page hopes to achieve!

The table in the development section is excellent and very clear and informative. I believe you could summarise the text above and add it to table to improve the presentation. There is a very good choice of categories and headings/subheadings. The information presented is excellent. Remember to just correctly cite the information and improve the overall format of this section.

There is an excellent choice of headings and subheadings in the current research section. It is very informative and demonstrates significant scientific research. I do believe that this section could be summarised or the presentation improved? It is a bit wordy- try to summarise more or present the information in paragraphs/a table? (only a suggestion though). The addition of hand-drawn diagrams was excellent and very admirable

The historic findings section was excellent. There was a very good choice of headings/subheadings. The information provided was very informative and demonstrated significant scientific research. However, it is a bit wordy and would be benefited with summarising the content further. Though the content has been referenced correctly, I believe it could be further enhanced with more references to verify the possible points. The addition of pictures would also benefit. Excellent work nevertheless. Very informative section

The abnormalities section was excellent. A very good choice of headings/subheadings and a good variation of abnormalities included. It was referenced and cited correctly. Demonstrated strong scientific research. Maybe improve this section with the addition of more images? Nevertheless, an excellent, clear and informative section.

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The project would be easier to follow by having an introduction that give readers an idea about what is going to be covered in the website.

Under the section about system development, it contains lots of information and it is well researched. Using bullet points is good as it is easier to read, however some of them could be join together into a small paragraph which would increase the readability. It is good to see a related video about the development of reproductive system and it explains well about this topic.

It is a great way to explain abnormalities in terms of female, male, and both. Maybe try to put a table at the top to summarise the abnormalities so that it would be easier to follow. More images are needed in this section, just like the one illustrating abnormalities of uterus and vagina.

It is well-researched under historic findings, try to put more related images to make this section more interactive. Also, it would also be good to illustrate the content in this part by a timeline, followed by the explanation of each event.

In terms of referencing, in-text references are missing in the system development, current research and historic findings.

For the image file “Image.jpg”, which is about sexual differentiation, it is a good image that explains the differentiation clearly, however, it would be better to put a description or title below it to make it more relevant to the project. It is good to see some hand-drawn diagram and they match the topic and explain information well. I found it a bit hard to read the labels on the image “labelled drawing of testes.jpeg”, maybe upload the image by scanning rather than taking a photo of it would be better.

It is overall a well-researched project. The next thing to do is to include an introduction, some more in-text references and some related images.

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Genital

There is a lot of information with hardly any pictures or diagrams to support the information. It is currently very not appealing visually.
System developments, Current research, and models and findings are all written in dot point form which should be converted in paragraph format before final submission to match the wiki format. I think that you should add an introductory section to tell the readers what the genital system is about, and what its function is in the adult. Also you should definitely put the references together before the final submission date.

The historic finding section is very detailed and well explained; it’s very well done. The abnormalities section was very well done and easy to understand with no punctuation errors etc; the drawing of the uterus/vaginal abnormalities were very easy to understand and self explanatory. I found it really nice that the abnormalities section was further divided up into female / male and those which both genders can have.

As for points to improvement, flow of information and it’s formatting can be improved by moving subheadings to more appropriate places, and also by labelling the pictures and diagrams.The contents at the start of the page is very well sectioned. I love the video; your group wiki page is the only one with a video, and it’s really informative and helpful, especially for visual learners like myself.
Overall: VERY well researched and detailed!!

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In this review I will attempt to highlight the merits of your project and provide some constructive criticisms in light of the marking criteria.

Great work on system development, a lot of research has been done and the page seems well organised. I suggest using the information you have collected to write up succinct paragraphs, with forget in-text referencing. Furthermore, I find that that the table is a really effective means of summarising everything, you’ve made good progress so far. I also feel that the diagrams and video really support the text and have been appropriately selected.
The current research section is a looking good, it’s great that you are exploring the molecular signals driving genital development, with references to FGFs, SHH and BMPs. I think this area needs to be addressed in further depthg. I also suggest including relevant studies, methods and findings. Finally don’t forget to include references!

I see that a significant amount of research has been conducted on the historical understanding of genital system development. Your project provides a particularly interesting insight into the debate on mechanisms of testicular decent. To make this section more interactive and engaging I would suggest the inclusion of historic illustrations and diagrams. There are many images available on both the UNSW embryology database and the UNSW library database. I also suggest that further research of the female genital system. Finally use in text referencing to support your data.

The section final section of your project investigates a number of male and female genital abnormalities. The diagram on abnormalities of the vagina and uterus is particularly interesting and certainly assists my understanding of these abnormalities. I simply suggest that you provide a little more depth on each abnormality. Ensure that you address the following areas are addressed: Cause; Description; Treatments.
The page is well structured and incredibly cohesive. The references are well organised. Finally I’m really impressed by the drawing and diagrams. Great work so far! Just make sure you include that introduction in the end and add all the diagrams and images you plan to.

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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!

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The definite strengths of this page are the ‘Historic Findings’, ‘Current Models and Findings’ and ‘Abnormalities’ sections. They have plenty of detail and are well referenced but could benefit further with the addition of more images (some historic images would really make the ‘Historic Findings’ section even better). The ‘Historic Findings’ section would also be easier to follow if it were broken up (perhaps by using dot points or tables). Some of the uploaded images need captions to help explain them to the audience.

The attempt to tabulate the information in the ‘Development’ section of this page is a good way of presenting the text and makes it easier to understand. It needs to be completed and supported by more images. The inclusion of the video is also a great addition to this page but it does suffer from a lack of explanation. A brief explanation of the video or some time links in your table would make it easier for the audience to understand.

Overall your page has some great detail and it is apparent that a lot of research has been carried out to give plenty of citations to your text. An introduction to your page would be a great asset as it would introduce your page to the audience and give a general overview of what this page is presenting.

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==Group Topic==

--[[User:Z3417458|Z3417458]] ([[User talk:Z3417458|talk]]) 14:08, 18 August 2014 (EST)
Hi everyone :),
We all need to decide on a system for our group asap, does anyone have any suggestions ? I was thinking we could do the Genital or Musculoskeletal ?

--[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 17:45, 19 August 2014 (EST)
Hello, I was thinking of covering the genital system development as well.

--[[User:Z3417753|Z3417753]] ([[User talk:Z3417753|talk]]) 20:39, 19 August 2014 (EST)
Genital it is :)

--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:07, 20 August 2014 (EST)
Great can't wait! there seems to be a lot of info about genital embryogenesis

--[[User:Z3417458|Z3417458]] ([[User talk:Z3417458|talk]]) 21:07, 26 August 2014 (EST) Hey everyone, just wanted to make a note of what each of us was going to research. So as we all discussed last week, I am happy to do part 5. Abnormalities :)

--[[User:Z3417753|Z3417753]] ([[User talk:Z3417753|talk]]) 23:18, 26 August 2014 (EST) Hey ! Yes im doing current research models and findings :)

--[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 01:05, 27 August 2014 (EST) Thank you all for referencing your articles. I am having some difficulty with referencing 1 of my 3 articles mainly because they are not from Pubmed. I will consult with Mark tomorrow and have my part completely uploaded during the lab. Thanks for your understanding.

--[[User:Z3417458|Z3417458]] ([[User talk:Z3417458|talk]]) 14:57, 1 September 2014 (EST) Hey All, just wanted to let you know that there are some really good pictures showing the differentiation between the male and female genital development in the textbooks. So maybe this week we could decide which ones we like and then I can try to draw them. :)

--[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 17:27, 2 September 2014 (EST) That sounds really good. If we are not given some time tomorrow during the lab to meet with our group and if you all don't mind we can stay back for 10 minutes or so to have a look at the images you found and if anyone has found any interesting material. See you all tomorrow in the lab.

--[[User:Z3417458|Z3417458]] ([[User talk:Z3417458|talk]]) 18:06, 9 September 2014 (EST) Hi, I know we can only use one image from wikipedia so maybe we could use this one ? Or has anyone found any others ? Heres the link -- > http://en.wikipedia.org/wiki/Sexual_differentiation#mediaviewer/File:2915_Sexual_Differentation-02.jpg

--[[User:Z3417458|Z3417458]] ([[User talk:Z3417458|talk]]) 18:14, 16 September 2014 (EST) Hi everyone, I am going to post 2 images on here tonight, please let me know which you prefer :)

1. [[File:Image.jpg|350px]]

--[[User:Z3417458|Z3417458]] ([[User talk:Z3417458|talk]]) 21:04, 16 September 2014 (EST) Or this one ->

2. [[File:Sexual Differentiation.jpg|350px]]

--[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 14:42, 21 September 2014 (EST) Since my part is historical findings, I have found a few old articles around 50-100+ years old. Below I'm going to past a paragraph about the female genital system development I have composed from information of two articles, one is from the 1950s and the other is 1890s. My only concern is what I have written doubles up with the system development part of this assignment so I have not uploaded onto the page but if you guys think it's fine for historical finding then I will, if not we can add that into system development and the timeline. I am still searching for historical teachings and images that can be used in this assignment.

The mullerian (paramesonephric) ducts, found laterally to the wolffian ducts, are the original structures of the female reproductive system. Female sexual organs (the fallopian tubes, uterus and vagina) originate from the mullerian ducts, which differentiates within the foetal developmental phase. Initially the foetus contains two mullerian ducts, however by the ninth week fusion of the lower portion of the ducts is complete, creating the fundamental structure of the uterus and the vagina, however the these two organs are not continuous with vagina being solid. The non-fused upper part of the ducts emerge into the fallopian tubes. It is not until the fourth and fifth month of development that the uterus becomes continuous with the vagina, with both organs developing a hollow lumen. The muscular layers of the uterus is also present by this stage. The cervix begins to form within the fifth month, between the continuous vagina and uterus. Also within the same month, the formation of the hymen occurs. The hymen is described as a pouting vertical slit and represents the remains of the mullerian eminence

--[[User:Z3417458|Z3417458]] ([[User talk:Z3417458|talk]]) 21:05, 22 September 2014 (EST) I think it can be added under your heading of historical findings :)

--[[User:Z3417753|Z3417753]] ([[User talk:Z3417753|talk]]) 12:26, 1 October 2014 (EST) hey guys hope you are all enjoying your break :) Hope your assignments are all going well :)

Also, I found this article that might be useful if you havent already found it - it goes under historic findings - it is from 1942!!

Schonfeld WABeebe GW Normal growth and variation in the male genitalia from birth to maturity. J Urol 1942;8759- 777

--[[User:Z3417458|Z3417458]] ([[User talk:Z3417458|talk]]) 21:59, 2 October 2014 (EST) Hey, hope your enjoying your break too. Thats great :). If you any of you guys come across an image that we could use for the first page, post in on here so we can decide if we want to use it. :)

--[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 16:16, 5 October 2014 (EST) Thank you, I'm doing the historical findings and I will have a look into that article. Thanks again. I have just redrawn an image from one of my articles about the Mullerian ducts and forming the female genital system. I will try and upload it following the steps Mark gave to us in the first lab so once it is up please let me know if you guys like it or not. Thanks

--[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 16:57, 5 October 2014 (EST) Also another thing, please let me know if I am being too specific in my part (Historical findings). I still have more to add on other areas of genital development, so if what I am doing is fine then I will continue this way, if not please let me know so I can change what I have. Thanks again.

--[[User:Z3417458|Z3417458]] ([[User talk:Z3417458|talk]]) 16:15, 6 October 2014 (EST) Hey Everyone, I've found a video we could use on our page, the background music is a bit annoying but the drawings are really good, detailed and clear heres a link. Let me know if any of you have found some too. :)
https://www.youtube.com/watch?v=MureNA-RSZM

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*Great progress on the table. Maybe once you've managed to format everything you need into it, don't forget to reference bits you need to
*I liked the diagram you used to show the different pathways of genital development for the different genders. It's just a bit blurry so maybe think of re-uploading a clearer image or of making the image on your page a little smaller
*Good use of dot points under the "current research" section but maybe think of connecting the separate points a bit more as it seems a bit disjointed and difficult to follow. Maybe think of having your write-up as normal and using points in particular parts that show a sequence of events, or separate components of something
*Look to getting more references for the current research and models section because you're just using 1 at the moment
*Proofread. I know maybe you guys are still at the collation of information stage, but I find it's easier to get it right as you go along rather than coming back to it later
*Re-phrase some bits like: female and male fetuses’ external genitalia --> The external genitalia of the female and male fetus
*Great drawn images! They're all so clear, well thought out and identify all relevant components of what you're trying to show all throughout your page
*I liked the detail of your "historical findings" section

Talk:2014 Group Project 3

2014-10-14T13:27:59Z

Z3419587: /* Peer Reviews */

{{ANAT2341Project2014discussionheader}}
==Peer Reviews==

‘GIT system overview’ section is good but requires more information to introduce the GIT and what the page is going to have information on. Timeline could form part of this section and could also preferable be in the form of a student drawn image or even a table. The overview section also contains no in-text citations. It’s a great idea to split the GIT into the three parts: foregut, midgut and hindgut to aid in understanding. There is not much information on recent findings without any mention of current models as well so perhaps it would be best to address this before final submission.

In the foregut section there is not much mention of blood supply or innervation as was done for midgut and hindgut. Student drawn images are very impressive and referenced correctly with the student template, description, title and copyright information. The features of the midgut section could include some histological drawings or images. The ‘abnormalities’ section does not contain many in-text citations in one of the paragraphs and could include more deformities listed and described with more images, as well as information on how to treat and manage such disorders later in life. There is also no information or images addressing historical findings or current models so this needs to be looked into.

The references are correctly done and ordered, and are present at the bottom of the page. Some of the in-text citations aren’t throughout the text like they should be, for example, in the stomach, liver and gallbladder, and oesophagus sections.

Overall, good effort so far but more extensive research needs to be conducted for models and findings and more information for Abnormalities, as well as a few minor edits to make the page present more nicely.

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Good introduction, initial description of fore/mid/hindgut with listing of respective structures gives the reader an anatomical starting point. Fetal development is presented in appropriate depth. There is no acknowledgement of embryonic origin, research or abnormalities. These sections should feature in the introduction to present all parts of the report in the intro. The three separate timelines defeat the purpose of a timeline. These should either be merged into a single large timeline and remain at their present location or moved to introduce the foregut/midget/hindgut sections later on. Recent findings has a single study which is covered in good detail though 2-3 more studies would allow the reader to further understand current GIT Research.

In foregut section the dot-points used should match your subheadings. For example duodenum development is covered in the stomach section but is not mentioned in the subheading resulting in its development being hard to find without trawling through the text or “Ctrl-f”. Additionally you seemed to have missed out on pancreas development entirely. Foregut could also use some more images 2-3 would be suffice. Midgut development has great information, strong table, 8/8 drawings(captions required though). Inclusion of histological features gives viewer a microscopic perspective on development. Hindgut cloaca partitioning content is well worded though references are lacking.

Anorectal deformities sections should be moved under the Deformities section. The type of dot-point style used should be standardized. Too few abnormalities in the deformities section, though after the hindgut deformities are mover there should be sufficient. There are no references supporting the possible causes of Gastroschisis. The referencing it very good unlike other pages there are no random reference subheadings. In overview format wise quite attractive, information is adequately in-depth in all sections, introduction fails to address whole page, referencing is great for a draft (exceptions being “introduction” “Liver, Gallbladder and Bile Duct”), some captions aren't present, abnormalities in development section should be moved into deformities/abnormalities section.

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The introduction is good as it accurately describes what the GIT system is about and the anatomical positions of the features in this system. It also briefly highlights the development stages at embryonic and fetal stages, however ‘embryonic development’ should be mentioned in a little more detail to understand how far in development the fetal stage begins. I also think the introduction should include a sentence or two describing how abnormalities in such organs can lead to these diseases. Basically a bit from each major subheading should be incorporated including current research as an introduction is a summary of the whole page. As for the ‘timeline’, it would’ve been more appropriate to place the timelines under each section, e.g foregut timeline under the ‘foregut’ subheading. This is because viewers would be confused on why there is so much difference in development in one section of the page. A glossary list should be incorporated in a separate subheading to define some of these words such as hematopoiesis so that viewers can fully grasp the information.

The information under recent findings is quite interesting and relatable to the content which is GIT fetal development. However, I believe more findings could be incorporated under this subheading. The information under each organ of the three ‘guts’ are quite detailed in fetal development which is good and shouldn’t be too difficult for the viewers to understand. However, I believe the group could include information on the function of these organs as well. The structure of the information under ‘guts’ does not flow in the sense that the midgut includes features and structure whereas the other ‘guts’ do not. The innvervation and bloody supply of the hindgut should be incorporated in a paragraph instead of being listed like that. All the deformities should be places under one subheading to make it easier for viewers to navigate. The abnormalities were also concise and related to the topic. Overall, the content is relating to the topic of the project and addresses key points. It also shows good amount of research, however there seems to be too much information in some parts which could be reduced a bit. The project needs a coherent flow of the structure.

As for images, there needs to be an image under introduction which includes all features of the GIT tract. There are a lot of potential images missing under each subheading except for the ‘midgut’ section. This shows that there has been one person working on this section or one section being focused on in comparison the others. The information used to reference the images is missing in some images such as the ‘Human- fetal week 10 sagittal plane D.jpg’ (although this is uploaded from a different user so this is understandable. However images such a ‘GIT 2.jpg’ need more information including ‘student template’ as well as the reference where the image idea may have come from. Also, if this is a hand-drawn image then please state this as one member did in ‘Week 11 midgut herniation.png’. Overall, I enjoy the use of self-drawn images as it makes it easier to show what the content is saying without going through the stress of looking for an image online that doesn’t relate to the content. However more images definitely need to be added. The use of footnotes is also good and indicates what the images are showing.

There are sections where incite referencing are used, however some sections are void of them such as the ‘introduction’ and ‘Liver, Gallbladder and Bile Duct’ (the [6],[7] should be placed next to the text not above the text. The use of a ‘references’ subheading is good the same references have been combined into one number showing that the group knows how to make the references set out. The use of a table in formatting the ‘Percentage of Foetuses Herniated’ is great and shows more that the group has done research. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

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A good introduction to the page but only outlines the developmental part of the project. Don’t forget to include other sections as well like current findings, abnormalities, etc. Also, no need for the hyphen for foregut, midgut, and hindgut. The development timeline is really good. Its very concise and well-referenced. It could be improved by tabulating the whole thing and maybe try to fuse the three sections together. Also, add an image or drawing of the development of the system. It will definitely help in terms of understanding what is happening at each stage. On recent findings, it’s not as good as the other groups but it’s definitely a start. Most groups write about 2-4 research articles for their current findings sections. As for the development section, each section is very detailed and informative. Maybe add a few images for the foregut section because images are really helpful. As for midgut, great to see images and student drawings. Good job on that. The same can be said for the hindgut section. It’s written well but maybe put the deformities in this section with the “Deformities” section. Deformities (abnormalities) section is good. It is detailed and the image used clearly shows what the disease is like. Maybe writing about 1-2 more abnormalities would make this section better.

It terms of citation and referencing, midgut section did the best job. I recommend the other sections to look for a lot more related material. I understand that this topic was divided depending on the region of the GIT, particularly the development section, but make sure to reorganise each section to make the page coherent. As for the images, most of them are well referenced. It wouldn’t hurt to add a few more. It’s great to see a lot of student drawings. Overall, a good project page very detailed in most areas but very little in referencing. In summary, focus on adding more references, making the whole page coherent, and a few more on the abnormalities.

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The introduction provides a good basic outline of the overview of the GIT. Although, there are no in-text citations in the introduction and all sub-headings are not included into the overview. Be wary of spelling errors such as “GIT (Gastrointestinal Track) consist of the Fore-gut, Mid-gut and Hind-gut” that should read Gastrointestinal Tract consists of the foregut, midgut and hindgut. This section would be better it was expanded upon and images were added. The timeline provides good detail, though would benefit by better formatting and organisation of the information, maybe putting it all into a table, by week will tidy it up.

Adding images for the sections will definitely be beneficial. The images hand-drawn are great, although the colours used make it hard to read. If you plan to add anymore drawings, try and use dark colours that allow for easy readability. The images already uploaded are missing copyright, referencing and “student template” information for images such as “fetal week 10 sagittal plane”. I would suggest you look up the tutorial for uploading images on the pages as Mark has extensive information for the proper steps required for uploading images.

The deformities section should be re-titled abnormalities as per the assessment criteria and would ensure the group is following similar structure from the other projects. Again, adding an image per disease would be great. Try and do about 1-2 more abnormalities. Great job on putting all the references at the bottom of the page, it makes it very neat and accessible. Overall, a good project just needs a few edits.

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A good overview of the GIT, very descriptive. This section would need some referencing as most of this info isn’t exactly common knowledge. Some of the sentences seem too short for me e.g. I would reconfigure the third sentence and combine the fourth and fifth sentences into one: ‘The GIT (gastrointestinal tract) consists of three regions: the foregut, midgut and the hindgut. The majority of the organs are located in the foregut, including…..’. You also need to make sure not to use capital letters in the middle of sentences.

The timeline is sort of well organized; it’s good that you have it separated for each region so they’re not all muddled up together, but is the info in dot points under the week, or is it just written next to the week? It needs to be kept consistent. I feel like this section is a bit too spread out as well, a large portion of the left hand side has text, while the entire right side of the screen is empty. You could possible put in a picture showing these 3 regions of the gut to fill in the space? Or maybe format the info into a table, it would make it look more formal and structured. The proper referencing technique should also be used here, not added hyperlinks.

The recent findings area is a little sparse, so you should try to find a few more. The title does say findings (plural), so maybe add at least one more. The foregut section is very extensive on the information provided which is good, a lot of research has been made. Visually however, it looks a little bad as all that can be seen is a mass of text. This can be alleviated if the same thing is done as has been with the midgut and hindgut region: the use of bullet points, a small table and the use of images to offset the slabs of text. It makes it more visually appealing. Unlike the midgut portion of the page, if the images are hand drawn, make sure they are clear, legible, and with colours used that will not strain the eye. For the images drawn in that section are messy and the labels hard to read both due to the colour of the pen used and the handwriting. In both the foregut and hindgut, referencing needs to be done. There are slabs of text in both sections where no references are made.

The deformities section is good, kept simple with no extensive explanations. Are there only 2 possible deformaties? If so, might be good to write a sentence mentioning that. If not, would be good to have at least 2 more deformities listed. The image drawn in this section is very neat, I like it a lot. The only problem with it is that it’s too small, making it hard to read some of the labels.

Overall, I think this page is very well done in terms of content. You have a lot of text, but I think it could do with some more pictures especially to offset some of the large slabs of texts in some areas. Make sure the pictures you have a clear and neat, and make sure you are referencing and doing it correctly.

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Overall this is a good project; I enjoyed the tailored diagrams and presentation of information in a succinct manner. Information is presented in a logical and coherent manner. The presentation of information into specific components such as foregut, mid gut, hind- gut is great.

The quality of research is exceptional and well presented. Specifically, the subsection of mid gut and the use of visual aids assist immensely in the translation of complex concepts into simple ones. The use of dot-points succeeds in summarizing the information into easily digestible sections. This also improves the clarity of the page. The use of subheadings also assists with the logical analysis of the project.

However, the referencing could potentially be more extensive. A further expansion on current research model and findings will prove to be instrumental in generation of a solid understanding of the project hand. I would recommend splitting recent findings into current research models and historic findings.

It would have been beneficial to see more information on the foregut section, as this would have provided a pronounced understanding of the topic at hand. It would assist in the comprehension of the data if the timeline were tabulated. Further expansion of the abnormalities would be needed. It would be great if the abnormalities in the hindgut were moved into the abnormal section. The grammar and punctuation is sound and the readability is good. The presentation of information is lucid and shows a sound understanding of the concepts involved.

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The introduction part of this project provided a good overview of the gastrointestinal tract and its components, also mentioning briefly the changes that occur in the fetal period. However, care must be taken to not capitalise words that are not needed e.g. Foregut, Midgut, Appendix etc. Although the information in the ‘timeline’ section is relevant, its formatting needs a bit of review as there are inconsistencies between the foregut, midgut and hindgut parts. It also seems that the in-text citations have just been arbitrarily placed in chronological order, with each line having a new reference. Also, this information may be better presented in table format to improve readability. Some simple editing may be needed to fix this.

The section on ‘Recent findings’ has some good information, however the reference needs to be properly cited and maybe a couple more articles would help give this part some substance. I thought it was effective to have the GIT split into the foregut, midgut and hindgut and then detail the fetal development under those titles. This gave the page a good structure. However, adding some images, both from online and student-drawn to the foregut and hindgut sections would help improve the aesthetics of the page. The hand-drawn images on the midgut section are effective learning tools to a student, but maybe could be drawn a little neater with darker colours as the blue labelling is difficult to read. They should also be captioned. The use of a table to show midgut herniation of fetuses was a good tool as it makes the information easier to read also.

Lastly, the section on abnormalities was well-detailed and I liked that the deformities were split into a definition and cause. An image of gastrochisis may be helpful for a reader to visualise the condition though. The in-text citations in this part were properly done and a long list of references being at the end of the page made the project look neat overall. Areas of improvement may be some simple formatting changes and evening out the information across sections, however a solid project so far.

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This project overall is very good with a lot relevant information. There is some use of images and hand-drawn images that are excellent. It would be good to see more images, perhaps to complement the timeline section. It is clear the group have worked well together to create a wiki page that flows well and covers all the organs of the gastrointestinal system. All the citations formatted correctly and it is good that all the references appear in one long list at the end of the page. There is still room to add tables, maybe to summarise the timeline. Other groups who presented their timelines in a table achieved an element of wiki-sophistication. There are a few spelling errors in some of the sections (specified below) which need to be corrected so as to not interrupt the flow of information when the reader is reading it. Again, there are only minimal errors or problems with this page, overall it is excellent!

The section on the midgut is well presented and thoroughly researched, well done! It is easy to follow and the way it is described makes it easy to imagine visually. However just double check for typos, for example “to that of” is spelt “tot hat of”. Simple error that is easily fixed. These hand drawn images are excellent. The colour coding and minimal use of words is very effective in supporting the written material.

The hindgut section is also well written and there is a lot of extensive information. Also double check for spelling, mesenchyme is spelt “esenchyme” in one of the sentences. This area of the project is lacking images detracting from its readability and level of interest.

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This project page has thus far been completed with really great effort. The introduction is a good detailed description of the gastrointestinal system consisting of all the corresponding organs. Good to see a timeline of all the events, might be useful to format this into a table since it is so extensive. The ‘recent finding’ section is done well, will however need more info maybe including other studies. Try to look through the GIT development lecture content, there may be some more studies mentioned and these could also refer to others. The ‘foregut’ section is really well detailed and easy to understand, although it would be nice to see some images, drawings or even tables as done in the ‘midgut’ section. The ‘midgut’ section is great, in its formatting, info, visuals and citations, and the drawings in particular are a really good effort. It would be great if you could try to re-upload the drawings, as it is hard to see some of the labeled structures clearly. In the section describing the ‘hindgut’ there is a good use of in text citations, just be careful as some parts don’t have them so they may need to be added. Also there are some minor formatting adjustments that may need to be made with some of the dot points. Lastly the ‘deformities’ section is done well, easily understandable and a good structural layout. Might want to add a few more, maybe the ‘Anorectal deformities’ sub heading could be moved into the big ‘deformities’ heading.

Finally this page is done well considering there are a number of sections that have to be covered. Some suggestions that could be helpful include; adding an additional heading for historic findings which is listed in our assessment criteria. To help find info for this try to search under the “Explore” tab on the left had side of the embryo page, clicking on the sub heading ‘historic embryo’. Also a useful source is the unsw library as it spans a longer period of time and following the unsw search then research the article in the pubmed site. For the in text citations try to add them after the content rather than before as it’s not clear which parts are from certain references that have been found. Adding some more images especially in the ‘deformities’ section would be good to see. There are only a few minor changes that may need to be addressed. Otherwise you just need to do a little more research to complete the page. So far good work everyone, keep it up. Good luck ☺

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I believe more of what the page hopes to achieve could be added to the introduction. These outcomes could add to the overall understanding and experience of the page. Also, remember to at least acknowledge the historical findings, recent findings and abnormalities section in the introduction (just state how this page will attempt to cover those areas- just a suggestion though!)

The development section has an excellent choice of headings and subheadings. There is correct referencing and strong evident of significant scientific research. I do believe however that this section could be summarised with more information presented in a table. There is also an excellent addition of images and hand-drawn diagrams, which adds to the overall understanding of the section. The hand-drawn images clearly display an element of teaching at the peer level and a strong overall understanding.

More recent studies could be added to the ‘recent findings’ section. Only one is currently presented at the moment. It is well explained, correctly referenced and informative though.

I can not find a ‘historical findings’ section?

I believe more abnormalities and deformities could be also added. This section is very informative and correctly referenced. I particularly enjoyed the addition of the hand-drawn diagrams- it was clearly labelled and aided in the overall understanding. Excellent work nevertheless.

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In this review I intend to highlight the positive features of your project while pointing out some areas that need improvement, in light of the marking criteria provided.

I really like the overview on of the topic, it is clear and succinct. However you could elaborate on some of the areas if time permits. I think a developmental time line you have presented is a great way to summaries all the information. I would also like to mention that this summary is very well referenced and gives an over view of the significant event is GIT development. However I think that this information would be best presented in a tabulated form. Perhaps you could use the following layout: Column1: Week, Column 2: Foregut, Column 3: Mid-gut, Column 4: Hind-gut. It would also be a good idea to include images or diagrams. I particularly like the hand drawn diagrams, they really compliment the text and help visualise the different stages of development.

However are two issues with this project, there is little information on current research. I suggest looking up emerging technologies, drugs, treatments for congenital abnormalities in relation to GIT development. You also need to address the topic of Historic Findings, I suggest using textbooks from the library, the UNSW library database and UNSW embryology page to discover how our understanding of GIT development began and how it has changed.

A great start to the project. Make sure you organise and structure the page under the appropriate headings before you submit the project. Good luck!!

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Introduction is good as it describes and gives an overview about what is happening in the fetal period for foregut, midgut and hindgut. However, it would be better if it mentions that the project is focusing on fetal development, abnormalities, current researches, etc.

It is clear to separate the timeline of GIT development for hindgut, midgut and foregut. It is well-researched with much information in this section. However, it would be easier to follow if a table is used and images are included.

The hand-drawn images can explain the development well, however the blue colour for labelling is a bit difficult for reading. It would be better if a darker colour is used.

It is a good idea to explain the abnormalities in definition and the causes. Some more abnormalities can be included as well as images for better understanding.

There is only one reference in recent findings. More researches could be done in this section. Also, a section about historic findings could be included as well.

There are a few spelling errors, such as “esenchyme” in the hindgut section and “tot hat of” under midgut section. Some proof-readings are needed.

The referencing is overall good, but some more researches have to be done under some sections (abnormalities and recent findings). It is easy to follow as there is a reference list at the bottom of page.

It is overall a good project as the development during fetal period is well described. However, more information about recent findings and abnormalities could be included, with the use of images to illustrate the contents.

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--[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 20:38, 13 August 2014 (EST)

Alright so lets choose a topic quickly before it gets taken. I would like all of you to post 3 topics that you would like to do (here) in order of importance and the topic that gets chosen the most will win. This is the only way I could think of in order to decide, so sorry. By the way Cardiovascular is taken so we cannot do that any more. My three choices are: Gastrointestinal System, Immune System and Placenta. What are yours?

i choose renal, head and neck, GIT --[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 22:22, 14 August 2014 (EST)

Im thinking GIT. Everyone so far has said GIT so I reckon that might be the best option as i think it will be relatively easy to understand and follow with the whole mid gut, hind gut formation ect.
--[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 12:58, 15 August 2014 (EST)

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 10:16, 16 August 2014 (EST) I have just reformatted your project page heading as the major heading (single =) and capitalised the words). All page sub-heading (two ==).

z3415141: I am going to be looking up research of the midgut.--[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 13:08, 20 August 2014 (EST)

I choose to research on abnormalities of the GIT system--[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 13:14, 20 August 2014 (EST)

z3375627: I'm going to be doing Hind gut development research --[[User:Z3375627|Z3375627]] ([[User talk:Z3375627|talk]]) 13:10, 20 August 2014 (EST)

z3414515: I will be researching foregut. --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 13:12, 20 August 2014 (EST)

Alright people lets get some work done on this project. I hope everyone could at least write up few paragraphs on their chosen section by Tuesday. Thanks :) --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 22:18, 30 August 2014 (EST)

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 22:47, 30 August 2014 (EST) I agree, times a wasting. While you have met the required addition of references, tarts all that is currently on your project page.

--[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 12:23, 2 September 2014 (EST)The reference below might help you guys.
<pubmed>12943221</pubmed>
--[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 12:23, 2 September 2014 (EST)

Is it only me or is everyone finding it hard to differentiate between embryo and fetal development?--[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 12:23, 2 September 2014 (EST)

Yeh I agree there are so many times where they talk about it as one in the same thing. Just have to read really carefully as we don't want to cross over. --[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 14:46, 2 September 2014 (EST)

Also with what you have written so far about the oesophagus, it looks good but what are you doing about referencing. Are you just keeping a list that you will put down later or are you getting the information from the resources that you found last week?? --[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 14:53, 2 September 2014 (EST)

I have my references saved on my laptop so when the time comes I can relate the information to specific reference. How are you coming along with your research so far?--[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 00:08, 3 September 2014 (EST)

Just been reading heaps to make sure I get the information right. I'm trying to get a really good understanding of the midgut rotation as I believe it is a critical part in the development of the ftus. --[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 09:31, 3 September 2014 (EST)

I am still waiting for some information from z3375627 and z3415242. Common people get moving!!! Also I meant that in the nicest way possible :) --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 10:52, 3 September 2014 (EST)

I have found a picture to go with the adnormality that i am doing however i will not upload it until everyone is ok with it. I will work to add on the first abnormality i have started and done and continue to research on a second one. If i come across any useful articles for you guys i will post it on this. --[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 19:02, 9 September 2014 (EST)

Show the group in class your image so we can discuss on it. Also I know everyone must be busy with mid semester exams or assessments so I appreciate the effort you guys are putting in so far. BUT do remember as soon as the mid semester exams are over we need to pick up the pace or pull up our socks for this embryology project. --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 09:27, 10 September 2014 (EST)

Common people lets get a move on. I have put up some information on my section though it is on the embryo period, the fetal period is in progress and in detail. The embryo period is only there as a guideline to understand how the stomach actually attains its shape. --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 12:47, 16 September 2014 (EST)

i have come across some research articles on omphalocele (abnormality occurs in week 10-12 YAY ) just reading through them as they are pretty long and abit difficult understanding so i'm trying to put some stuff into a paragraph or two will try and upload the stuff for it by this week sometime. cheers --[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 21:50, 16 September 2014 (EST)

Alright this is the week to really get a good chunk of it done now that most of our mid sems are over. Not sure if anyone else has any good youtube videos, but because we only get one I'm gonna put this one out there relating to midgut rotation: https://www.youtube.com/watch?v=AscKR_cQExY --[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 08:09, 17 September 2014 (EST)

Also we need to start our list of references so I reckon we just put them down under this heading. Leave the references at the bottom of the page ie. write above the heading references.--[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 08:18, 17 September 2014 (EST)

i found a simple sketch drawing of omphalocele just so we have some picture on our page but i don't want to put it on the page yet incase you guys don't like i and since we cant delete it once its up so after your approval i will put it up also i am trying to find good video on organ development since im sure alot are formed by week 10 as i have read in articlese. --[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 00:42, 24 September 2014 (EST)

Apologies with my lack of input on this. I’ve added a bit of the Cloacal partitioning and deformities that I’ll expand upon. I’ve also found some great pictures on some of the other GIT deformities. If I’m unable to source permission for them, I’m happy to recreate them --[[User:Z3375627|Z3375627]] ([[User talk:Z3375627|talk]]) 07:55, 24 September 2014 (EST)

Definitely put that picture up about Omphalocele. That will work well because I'm talking about midgut herniation so if I talk about it in my stuff then I can just link it so that when you click on it goes down to the bottom of the page to where you talk about it in abnormalities. Not exactly sure how we do that but I'm sure we will work it out.--[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 13:02, 6 October 2014 (EST)

Hey all just wanted to note that when your referencing from now look at the editing page to see what mark does so that the references are footnotes down the bottom of the page. Obviously you will need to change the reference in the brackets but you get the point. This means that when you do this all the references will come up down the bottom of the page. --[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 23:34, 6 October 2014 (EST)

Not sure if we are supposed to get rid of the references that we used for our group assignment but I just did because they were taking up uneccesary space on our page. Just thought i would say this here just in case we were not meant to.--[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 09:17, 8 October 2014 (EST)

Everyone please take off your student signature from the group page as it looks unprofessional. Thanks guys and girls :) --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 10:07, 8 October 2014 (EST)

'''References'''

Won Kyu Kim, Hyun Kim, Dae Ho Ahn, Myoung Hee Kim, Hyoung Woo Park Timetable for intestinal rotation in staged human embryos and fetuses. Birth Defects Res. Part A Clin. Mol. Teratol.: 2003, 67(11);941-5 PMID:14745932. I used this in describing midgut rotation.
<gallery>

</gallery>

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*References are missing from the overview section. Although it serves as an introduction, you can still include references to support what you're saying. Also, maybe the language of this section should be edited to be a bit more formal, like the 2nd sentence in particular
*GIT = Gastrointestinal tract, not track
*The hyphens between "foregut" etc are not needed
*The timeline is a good idea! Everything was simplified. Maybe look to see if you can add some images to this section
*Week 6 of timeline: I don't think a liver can "obtain" a colour. Look to change the wording
*Maybe to simplify the timeline section better, tabulate the findings according to time (weeks), rather than dividing it by the midgut, foregut and hind gut section. It makes it hard to follow
*Need some more work on the recent findings section. Just some tips, when researching on pubmed, there's an option to look at recent articles by customising dates to say 2012-onwards
*Many potentials for adding images to the "foregut" section. If you find that copyright is too difficult to get around, then you can sketch or trace images from textbooks and upload them
*Great effort with the drawn images in the "midgut" section! Be wary of colour choice though, as the green highlighter and blue pen can be a bit difficult to see. Otherwise think of adjusting contrast on the images to make the diagram stand out more
*Maybe think of adding a video from YouTube to show some features of GIT fetal development, like the rotations. If you do that, be sure to include the 11-digit cache code as your reference point

Talk:2014 Group Project 2

2014-10-14T12:39:41Z

Z3419587: /* Peer Reviews */

{{Template:ANAT2341Project2014discussionheader}}
==Peer Reviews==

The introduction provides a very informative description of the functions of the kidney and bladder. Perhaps it would be good to give some more details of the embryonic development just to quickly summarise what has been happening with the fetus up until this point. Also, maybe the introduction should introduce what the page’s content is going to cover. The order of historic findings and then developmental timeline is appropriate as historic findings can be used to compile the timeline. It would also be useful to have the timeline in a table format to make the page look neater and more simplified. Also, there is no research done on ‘historic findings’ so need to address that before final submission.

‘Current research models’ section is good but brief and requires more extensive research as only two articles are cited. There should be information on current models used to study renal development as well as current research and findings. The image in this section is well presented, with appropriate titling, referencing, image descriptions and copyright information with the student image template.
Sections 1.5-1.8 should be smaller sub headings under the larger heading ‘System Development’ and perhaps should go at the top of the page, beneath the introduction seeing as in order to understand research and historic findings, it is necessary to understand renal development first.

It is very good that there is a small section on early development, however maybe it would be better to have it more briefly explained, perhaps in the form of a student drawn diagram or presented as a table. There also is a problem with the image uploaded in the early development section, so should fix that before final submission. The ‘abnormalities’ section is also done well however more conditions should be listed and described with pictures for each one. There are also only abnormalities of the kidneys listed, so maybe it would be better to have more of the other components of the renal system as well (bladder, ureter, urethra).

Also, maybe more information regarding the anatomy of the kidneys and renal system should be added, as this is an anatomy course. Some images are also missing the student image template.
Most images are uploaded correctly with the right information, maybe more would make the page look more aesthetically pleasing as well as assist learning.

Referencing is done correctly with a numbering system and in-text citations are also correct. The in-text referencing in the ‘anatomical position’ sub section of ‘fetal development’ of the ‘Kidney’ section is not referenced appropriately so just fix that minor problem.

Overall, this is great work and should just include more information in certain sections and upload more images, preferably some student drawn images as well. Well done!

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The introduction is well addressed as it sufficiently describes what the renal system is about and its function. Not to mention its anatomical structure as well as the difference between the embryonic and fetal stages of development. This differentiation enables viewers to understand what the content will be focused on, which is fetal development. Also, it helps focus the viewer’s attention on how the project will be divided as the group mentions abnormalities in the last paragraph. Overall the introduction has the right amount of information from each subheading and is very easy to comprehend.

There isn’t any information under ‘historic findings’. If there are any difficulties in finding some historic findings, members of the group can go to pubmed and on the side will be dates such as 1920 that could contain key historical events when renal is entered on search. The use of a development timeline was great as they outlined the major events that occur in a concise manner. Although, I believe a glossary is needed for words like ‘metanephros’ since the viewers would not know what that is. The content under current research models is interesting and correctly describes what the studies were about. Overall, the content used in the project was relating to the topic (fetal development of the kidney) and clearly showed extensive research. I really like how the group divided the different parts of the renal system as well as describing their anatomical positions. The abnormalities listed are also interesting and very easy to understand. I’m hoping to see information under the Horseshoe kidney disease.

In terms of images, there should be an image under introduction perhaps having all features of the renal system. Most images are missing the ‘student template’ aspect of the referencing and needs to be added right away. Other aspects such as description, copyright and referencing were correct. I also like the use of footnotes to describe what the images are about, however some are missing on the page such as the one under ‘anatomical position’ and ‘urethra’. The image used for the ‘development of the kidney’ should be removed from the page as it isn’t permissible. It should be replaced with an image relating to the content and have all the correct copyright and referencing information. Overall, I like the number of images used and its significance to the renal system. They accurately relate to the content of the project.

There is use of in-cite referencing which is good, however some references are just listed and should be placed under the proper ‘references’ subheading such as the ones under ‘ureter’ and ‘renal agenesis’. Some references in the ‘references’ list are used over again and can be fixed by combining it under one reference number. To make the project even more appealing, the group could format the information under ‘developmental timeline’ or even ’historic findings’ in a table. Overall, I think this project is great and by making edits based on the peer-reviews received could enhance their project.

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Really good introduction! It clearly outlines what is in the page. Most key points were done really well except for historic findings. There is a section on the Wikipage that has old books on embryology. It’s under the “Explore” tab and you’ll see “Historic embryo”. The developmental timeline would’ve been better if it was in a table, has an image showing the major steps in development, and is within the development section of the page. Regarding the development section, very detailed and informative. It clearly outlines the development of the renal system in the fetal stage. Dividing this section into the different organs is a very smart decision. It makes it a lot less confusing to the reader. Maybe try to breakdown some of the information and use dot points. There are lots of images to give the readers a visual of the developmental process. Also, the images have captions, which is great.

Great job on the current research section. The articles chosen for current research is highly relevant to the topic and to the project. This section is written concisely and very detailed. The image really helps to understand the findings of the research. The same can be said to the abnormalities section. Each disease was written concisely and is very informative. The images really help in terms of understanding the clinical manifestation/s of each disease. Try to find information on current treatments and/or management techniques for each disease.

Looking at the images included, all of them seems to be properly uploaded except for the “Kidney ascent.jpg”. It is missing its copyright information. From what I know, images from textbooks normally can’t be used because of copyright. Other than that, all the images are relevant and function as an aid to understanding what each section is about. In regards of citation and references, everything looks good. Each section was well-researched and properly cited. Great job on organising most of your references at the bottom of the page. The page looks very clean. In summary, focus on getting the historic findings section done and just minor fixes on images. Well done!

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In this review I will attempt to highlight the strengths of your project and identify some areas for improvement, in light of the criteria provided.

I believe the developmental timeline is a great way to summarise the major events at each stage in fetal development and serves as a simple introduction to the project. However I think it would be best if you presented this information in a tabulated format, and include a little more detail. For instance “Week 8 – Mature kidney is formed” could also mention some structures features seen at this stage, hallmarks that allows us to recognise a mature kidney.

I think the current research section delves into a number in interesting areas, mentioning studies on the treatment of congenital renal abnormalities. However, I think that there needs to be additional discussion on the molecular signalling that drives the underlying process of renal development in the fetus.

The abnormalities associated with renal development in the feral period have been well researched and the information provided is well structured. However this section seems incomplete. I see a number of additional links to interesting scholarly articles. I think you should discuss some more abnormalities at the stages of early and late fetal development. I also suggest including images to supper the text.

There is has been little information added on the historic findings. I suggest looking at text books in the library or searching the UNSW database to find information for this vital section.

I really like how you have selected labeled diagrams to compliment and break up the text. Each image is relevant to the topic being discussed and the small description attached really help the reader orient them selves. Overall this project is coming along nicely. Just ensure that you are making progress on all the sections. Also only include relevant references. Finally proof read and review your work before the final submission.

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This is an excellent introduction and gives a great expectation for the information to come later in the project. The current research models section needs to be checked for spelling and grammar. The information here is good but is also very dense and hard to follow. It would be great if you could break it up a bit with bullet points or more images or tables. This style of writing is very professional and would be perfect for a report or essay, however as a wiki page it is too hard to follow. Breaking up the information into bullet point and tables would allow you to guide the reader through a journey of renal system development.

There has clearly been a lot of research and work put into this project and that is very commendable. However on a whole, there is too much information. It’s difficult to read and grasp a wholesome understanding of the renal system when it delves too deep too quickly. One suggestion is giving a more brief explanation of the timeline of nephrogenesis, urethra, ureter and bladder development and then go into more detail in a subheading called “current research findings”. The references under the abnormalities heading should be incorporated at the very end.

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The introduction delivers a conventional scope of the renal system, allowing the audience to understand the structure and function to the parts of this system. Maybe consider uploading a picture that would illustrate the overall information in the introduction.

The developmental timeline is a great idea that outlines the significant events and in turn helps put major events into perspective, making it more effective for students to study and understand. However maybe consider presenting this information in the table format or see if you can get a vertical/horizontal line to represent the timeline. I feel that there is not enough information in the 'Historic findings' and perhaps you could do some more research.

The "Current research" section is very detailed and shows a great amount of research of recent articles that are relevant. The images included in the current research and the abnormalities section is great as it makes reference to the topic spoken about, giving the student a further understanding of the topic. The images are referenced properly except for “Kidney ascent.jpg”, it's missing a reference.

Overall this page is coming along nicely however you need to work on your development timeline formatting it in order to present a systematic presentation as a means to make it more friendly.

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This so far is a really good. You have all obviously done your research as well as you have got a lot of references throughout your page which again is great. The introduction is well done, clear and concise which is good. Maybe think about adding an image to make it a bit more appealing. You will obviously need to add some historic findings, but I’m sure your aware of that. The developmental timeline I think could be improved if you were to tabulate it as other projects have done that and it looks really good and more professional. The referencing is well done as it looks good having all the references down the bottom of the page. There are some references over the page which have just been listed so it may be a good idea to change this so that they are all down the bottom.

You have made a good start on the current research models. Note the buy in the line ‘One recent research paper buy Al-Odat et al.’ should be by. I don’t think you should actually reference the paper in your writing either. You should reference it but do so by using a footnote rather than actually saying the names of the people. The development of the kidney image has not worked so look at the formatting of that image.

On the bigger picture of this project something that I have noticed is that the balance of writing to images is heavily towards the information writing side. So I think it would be good if you were able to tip this balance with a few more pictures as it would make the page more appealing. I think in doing so you could add some student images as this will make the page more interesting, Also spacing your information out as at times when you look at a whole chink of writing you don’t feel like reading it, so I think spacing it out more will help.

Overall though it is a well done project. A few things such as the references that have been just listed on the page that need to go down the bottom, inclusion of some more student images, and tipping the balance of your page more in favor of images would go a long way in making your project even better. But you have done a good job so far and best of luck with the rest of it.

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At the first scroll of this page it already seemed completely sufficiently. The structural layout is done really well and it’s good to see that it’s done according to the advised sub headings. The introduction is really well done, provides a great explanation into renal development, an abundant overview of the whole page and topics that will be addressed. The info for ‘historic findings’ seems to be lacking content, might be useful to search under the “Explore” tab on the left had side of the embryo page, clicking on the sub heading ‘historic embryo’. Also a useful source is the unsw library as it spans a longer period of time and following the unsw search then research the article in the pubmed site. Might be nice to format a proper timeline or use a table. The ‘current research models’ section is done really well with an abundant amount of detail in each study presented and good use of images. The use of a descriptive caption under each image is done proficiently, it is nice to see that each section has incorporated some form of visual whether histological or from research studies. The ‘kidney’ section is structured really well, the use of the content under early development is unnecessarily but is useful in introducing the stage prior to fetal development. Under the’ anatomical position’ sub heading the in text citations need to be adjusted. For references that are not pubmed use this format; <ref> insert source </ref>. Also the image provided will most likely need to be deleted and then drawn, as we are not allowed to use images directly from textbooks. Just re draw the image if you can and then upload it as you would with any other image. Another suggestion for each of the corresponding organs in renal development, try to format some of the content into dot points or tables so not all lengthy paragraphs. Also noticed one of the images doesn’t have a caption this being under the urethra section. Very well detailed info on the abnormalities, would suggest to add a few more to be completely sufficient.

Lastly, the page has been completed to a high standard in the completion of all the info provided and subsequent images among each section. A few things have been noted, and there are only a few minor modifications that will need to be made these includes; referencing and some formatting as mentioned previously. The use of in text citations throughout the whole page is done efficiently, try to just try keep your references under one main heading. There is great effort noted in the research accumulated so far through the long list of references used to gather the info. Fantastic work everyone, keep up the great work !

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The introduction provided by this project is very good and includes in-text citations. Not only does it introduce the renal system’s components but also discusses its development briefly into the embryonic and fetal stages, focusing more on fetal. Also, by having the references as one long list at the very end of the page, this gives the project a clean and tidy look, which some of the others lack. I thought this was a great idea and very orderly.

While some sections are full of information, others are scarce or empty, such as the ‘Historical findings’ section. Some information on the development of knowledge on the renal system throughout history should be included here, maybe making use of dot points detailing specific year dates. The ‘Developmental Timeline’ provides a good overview of the system’s development, although weeks 3-5 may not be necessary as these are during the embryonic period and the focus here is on fetal development. However, it does provide an overall context which is good. This information may also be effectively translated into a table format for easier readability.

The section on ‘current research models’ was nicely written, with solid analysis of 2 research articles. Using any more articles to that level of depth may be too much information, so this is a good balance. It was very good to see the text actually explaining the accompanying image, which was labelled with a caption too. The introduction to the use of animal models and why these are important was effective also.

I particularly thought the sub-sectioning of the page into the main organs of the renal system was a smart idea rather than having the entire system as a clump of information as this way, it is easier to navigate through the information. The ‘kidney’ section was of a very high standard as the information was relevant and nicely split into different processes of fetal development such as nephrogenesis and renin production. It is very helpful as a reader to have explanations of the images used, making the page more interactive and useful. However, this is a file with a ‘Permission error’ present which would need removal due to copyright infringement; this should be sorted out before the project is due.

The following three sections on the urethra, ureter and bladder were also well-written, referenced correctly with in-text citations and the images used were relevant to the text. However, captioning the image in the urethra section would be good to give the reader knowledge of exactly what it shows. The ‘abnormalities’ section was again, well -researched and full of information, however it seems a little cluttered as lengthy references are placed under the text. Integrating these into the overall reference list at the end of the page would look clearer.

Overall, this project has been well done and there is evidence of consistency throughout the section formatting, suggesting the group members have been communicating between each other, which is good to see. Some improvements I would suggest are the use of hand-drawn images to make it easier for a student to learn off the project, and using tables to summarise some information e.g. timeline.

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The introduction is good and describes the project well. It is good to mention the function of renal system. It would be better if it states that the website will be focused on fetal development, current research and abnormalities to give a better understanding of the content.

Information under historic findings is missing, it would be a good way to start it by looking at textbooks. Images, bullet points and table can be used for an easy understanding of this section.

Using timeline to summarise the development of kidney is a good idea, however it would be clearer if a table is used, more descriptions under each stages and some images are include. Also, some references should be included in this section.

There are a lot of details under development, current research and abnormalities. It would be easier to read if they are written in point form. It is a good idea to divide renal system into several parts (kidney, urethra…) for the explanation of development. For the abnormalities, it is well-researched but some of the details are missing. It would be better if the each type of abnormalities is discussed equally.

Regarding the images, it is good and clear to explain each of them. The only problem is that there is no copyright information under the file “kidney ascent.jpg”.

The project is informative but lacking some information under historic findings and the developmental timeline.

[[RENAL SYSTEM]]

Introduction
Background
Timeline of development - everyone will research first to get general idea of when,what and how long it will develop. Divide this area up from there.
Development of Actual system - all organs and parts that contribute to it (will be divided up later)
Abnormalities

ACTUAL RESEARCH FIRST, THEN DIVIDE. SEE HOW MUCH INFO AND PARTS THERE IS FIRST

==ANNOUNCEMENTS==
http://www.ehd.org/science_main.php?level=a&submit3.x=73&submit3.y=21&s18=on&ops=&re=on&L1=1&L2=0 have a look at this web site, good time line --[[User:Z3463310|Z3463310]] ([[User talk:Z3463310|talk]]) 10:50, 26 August 2014 (EST)

Looks good. There wont be much we can say for all the individual events that occur since all of it is up to the 8th week, but it'll give us a good starting point. We can say 'such and such has been formed during the embryo period' and we can move on from there. I also found the following site which gives a nice intro into the components of the renal system and some general info on each part. Thought we might be able to incorporate a bit of it, talk about what the system/organ does, then follow on how it develops. Use it as a bit of a guide to how we could do our own. http://www.myvmc.com/anatomy/urinary-system-renal-system/ --[[User:Z3465654|Z3465654]] ([[User talk:Z3465654|talk]]) 13:48, 24 August 2014 (EST)

https://docs.google.com/viewer?url=http%3A%2F%2Fpediatrics.med.unc.edu%2Feducation%2Fcurrent-residents%2Frotation-information%2Fnephrology%2Ffiles-1%2FNephrogenesis.ppt this web site goes into quite a lot of detail regarding how the renal system develops.

I think in terms of dividing the work:
*1- urine formation (week 11~12) & amniotic sac
*2- kidneys descending from where they developed to adult anatomical positions (week 9)
*3- development of trigone of the bladder and allantois
*4- structures that arise from the Metanephric mesoderm
*5- structures that arise from the Ureteric bud
*6- abnormalities (developmental and genetic)
*7- introduction
*8- timeline of events in development

I've thought of 8 topics we can divide the work into, so lets choose 2 each?
I preferably want to do abnormalities and urine formation (number 1 and 6), is that ok? we need this sorted out for our lab homework thing for this week. please reply asap. --[[User:Z3463310|Z3463310]] ([[User talk:Z3463310|talk]]) 10:50, 26 August 2014 (EST)

On the actual project page when you expand the bit at the top there are 5 bullet point but the first one is just to come up with our title, shall we divide our project into those 4 different headings?:
Review that system development during the fetal period.
Identify current research models and finding.
Identify historic findings.
Identify abnormalities that can occur in this system during the fetal period

Hey guys, i have now gone and updated the page and added sub-headings as suggested by above, please feel free to add or delete anything you seem unfit for the page. As for the online assessment due tomorrow, i agree that 2 each is appropriate although the timeline will be very long and would be unfair if one person to do the whole thing... We should probably divide the timetable based on weeks and then assign who wants to do what. Although i thought we agreed that i would do the abnormalities as discussed in the last lab...? i have already started to do some research on the topic....

Here is a basic summary of some of the development structures in the renal system, as well as their abnormalities
https://web.duke.edu/anatomy/embryology/urogenital/urogenital.html

--[[User:Z3465141|Z3465141]] ([[User talk:Z3465141|talk]]) 16:52, 26 August 2014 (EST)

Ill look at 4 and 5 if that is alright with everyone (structures that arise from the Metanephric mesoderm
and the Ureteric bud), I think we need to also write a bit about Historic findings and current research models
--[[User:Z5030311|Z5030311]] ([[User talk:Z5030311|talk]]) 17:24, 26 August 2014 (EST)

I can do the descending of the kidneys and the development of the bladder (2 and 3) if everyone is fine with that --[[User:Z3465654|Z3465654]] ([[User talk:Z3465654|talk]]) 18:39, 26 August 2014 (EST)

Uh I guess that leaves 1 & 8 then, since no one wants to do the timeline xD
It doesnt look too hard so i dont mind doing timeline :)
so whoever only took 1 topic, can you please do the intro as well please?
Also im not 100% on the topics, but it'll have to do for now. add as we go i guess.
--[[User:Z3463310|Z3463310]] ([[User talk:Z3463310|talk]]) 20:26, 26 August 2014 (EST)

yeah no worries, there will most likely be changes to the topics, or at least the headings. It's only set out the way it is now just so we can have a general layout, have some idea what to research. I also dont think we'll end up sticking to the subheading we chose, as there is a lot of stuff that will cross over to other topics.
I think we said that the timeline would be one of the last things we would do yeah? cause after we research all the organs and stuff as it develops, it would be easier to determine when it all develops as well, so we could just stick all that info together at the end. --[[User:Z3465654|Z3465654]] ([[User talk:Z3465654|talk]]) 21:04, 26 August 2014 (EST)

--[[User:Z3463310|Z3463310]] ([[User talk:Z3463310|talk]]) 12:53, 27 August 2014 (EST)
*kidney(nephrogenesis0 - Sam
*ureter - Bahar
*urethra & fetal urination - Emily
*bladder - Rachel

*intro - Emily
*historic findings - Emily
*abnormalities - Bahar
*current models - Rachel

*developmental timeline (everyone)

HOW IS EVERYONE GOING WITH THEIR PART????
www.lab.anhb.uwa.edu.au/hsd212/.../KidneyDevelopmentPrint.ppt
--> this powerpoint gives a good general intro to renal development btw if anyone wants to see?

GIRLS
are we going to keep the whole assignment as apa referencing or as harvard? --[[User:Z3463310|Z3463310]] ([[User talk:Z3463310|talk]]) 01:36, 22 September 2014 (EST)

umm i guess APA since thats the actual formal type of referencing. or you can just try and structure it the way its auto generated when you type in pubmed links haha. im gonna try and put some more content up about the kidneys in a couple days and a drawing or two. ill get some historic findings done as well.--[[User:Z3465654|Z3465654]] ([[User talk:Z3465654|talk]]) 21:16, 23 September 2014 (EST)

hey guys, sorry i havent been putting anything up recently. i moved in to my new place over the weekend but the internet isnt up yet so i havent been able to upload anything. i dont know how much longer until its up, so ill be coming to uni just to use the internet (its where i am now lol). so when did the majority of our content have to be up by? was it friday or sunday? i cant remember. --[[User:Z3465654|Z3465654]] ([[User talk:Z3465654|talk]]) 12:48, 1 October 2014 (EST)

i found this really good article. it mainly focuses on the kidneys but there are a couple of lines here and there where it mentions some facts about the rest of the renal system. thought u guys might wanna take a look. i dont know whether full access to the article is normal or whether i only managed it because im using the uni library internet, but if u cant access it just let me know and ill send u the article (i downloaded it haha). --[[User:Z3465654|Z3465654]] ([[User talk:Z3465654|talk]]) 14:15, 1 October 2014 (EST)
oh i also just found this book, it has A LOT of info about the embryology of the renal system, though half the chapters seem to be focused towards abnormalities and defects of the organs http://books.google.com.au/books?id=IKexq6xCRmIC&pg=PA542&lpg=PA542&dq=rotation+of+fetal+kidney&source=bl&ots=0O-4VfybHS&sig=3VeDlTrB9HnJsdYQLP66IKNGPDU&hl=en&sa=X&ei=1ocrVPuiIoKUoQSyroEQ&ved=0CCoQ6AEwBA#v=onepage&q=rotation%20of%20fetal%20kidney&f=false --[[User:Z3465654|Z3465654]] ([[User talk:Z3465654|talk]]) 15:10, 1 October 2014 (EST)

Hey Girls hows the "break" going? :) i was wondering how many abnormalities we should have? 3/4? Also, is it just me or can we not access some of the journals that are free on Pubmed for e.g.
http://www.ncbi.nlm.nih.gov/pubmed/11458035 ?? --[[User:Z3465141|Z3465141]] ([[User talk:Z3465141|talk]]) 19:20, 1 October 2014 (EST)

Sorry this is way too late but I think 3/4 abnormalities sound good and for references I have just been doing the automated way of the references --[[User:Z5030311|Z5030311]] ([[User talk:Z5030311|talk]]) 23:07, 7 October 2014 (EST)

Also at the moment I have done 2 research models, do you think that is enough or shall I do another one? --[[User:Z5030311|Z5030311]] ([[User talk:Z5030311|talk]]) 00:01, 8 October 2014 (EST)

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*Great introduction! Your entire page's contents was introduced well and simple. I'm just wondering if you'd have to include more references to further justify some of the aspects you've mentioned in your explanation of the renal system development
*I noticed the historic findings have been left untouched. This section is in my opinion the trickiest because of the difficulty in finding information out there. My suggestions are to go onto pubmed and use key words like "Renal system development: a historical perspective" and then work from there. You can also adjust years to look at earlier papers from the 1920s and onwards. Also use Mark's historical textbooks on this website as a starting point, it's helpful too to see how ideas in fetal development have changed over the years
*I like how the timeline overview has been simplified. Maybe think of tabulating the findings? You can get the template for doing that off any other group project that has tables by copy and pasting, then just editing in what you need
*I wouldn't add that first like under "Current research models" but if you wanted to do that, maybe think of rewording it. An example could be: "Animal models are ideal to work with when researching renal system development due to their short gestation periods, making the identification of mutations much quicker." Although what you've said about ethics is technically true, the ethics of working with animal models are still lengthy considerations and the fact that our pages are accessed to the public, maybe something like ethics don't need to be mentioned
*Include the years of when the current research findings were discovered. Otherwise, good work on this section. Just proofread over it to fix minor errors
*Great images used throughout
*Maybe think of having some sections more concise rather than wordy by including dot points

Talk:2014 Group Project 1

2014-10-14T11:21:02Z

Z3419587: /* Peer Reviews */

{{ANAT2341Project2014discussionheader}}
==Peer Reviews==

The introduction is very informative and I particularly like how it describes the embryonic development of the respiratory system as well, since in order to understand what is happening in the fetal period, it is important to first understand what happened before that in the embryonic period. Perhaps the introduction could also introduce what information the page is going to contain.

The timeline is well presented in a table form, however maybe it would be better suited to be in the introduction section. The table could also incorporate the use of histological images to illustrate the differences between the time periods. Also, the sub sections titled ‘current models’ and ‘current research and findings’ could be part of a larger section and not fall under the ‘Lung Development Stages’ section.

There is no information as yet under ‘Current models’ however extensive research seems to be conducted on ‘current research findings’. Perhaps it would be better to include more journal articles in this section. The use of dot points and numbering systems is also very effective in allowing the information to be easily read and flow. More articles also need to be covered in the ‘Historic findings section’ as it is very brief at the moment with only a few sentences on each article.

The ‘abnormalities’ section is very well done with an abundance of conditions however more images should be uploaded for each abnormality in order to see what it visually presents as in the fetus and also to make the page look nicer.

The images uploaded onto the page contain adequate information explaining them, copyright information as well as the student image template, which is good. There is one student drawn image, which is also great, but maybe some more would further illustrate the group’s understanding of their topic.

The referencing is done correctly mostly throughout the page but is scattered throughout every section so perhaps it would be better to have them in one section at the bottom of the page under the heading entitled ‘References’ and numbered as they appear in the text. In-text citations are throughout and appear to be done correctly.

Overall, this is a very good effort and a bit of editing will make the page look much more neater and organized. Keep up the great work!

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The introduction was written quite well as it explains what the respiratory system is about and the origin of its development. It also briefly highlights the difference between the embryonic and fetal stage which is important in enabling the viewers to have an understanding on what the project will be focusing on. I also like how the group distinguished between the two zones of the respiratory tract and adequately described the features and function of each. The content in the lung development stages clearly relates to the topic and underlines fetal development. The group briefly mentioned the key features in each stage instead of pasting a whole lot of information; this makes it easier for viewers to understand. Overall the content relates to the learning objectives of embryology and the level of research is good as exemplified under ‘Current Research and Findings’ and ‘abnormalities’ (many forms of diseases described). The project however could benefit from having a ‘Glossary’ list so that viewers can understand some uncommon words.

The images under introduction and the image used for Meconium aspiration syndrome have not been referenced properly as there is missing information such as ((Template: Student Image)), description, copyright information and proper references for some. The image used under the ‘current research and findings’ subheading is a good example for the group to copy the referencing style. It is also vital that the group adds a brief description of what the image illustrates as a footnote to help viewers understand the relation of the content and image (this is seen in the image under ‘surfactant’). More images could be added such as in the ‘lung development stage’ and under abnormalities. If images for lung development stages aren’t easily accessible, it is perhaps a good idea to draw them. The table format used for ‘lung development stages’ makes it easy for the viewers to navigate which is a good feature used in the project.

In terms of referencing, there are many in-cite references missing such as in the ‘introduction’ and in ‘lung development stages’. It is important to have these references formatted correctly under the one ‘references’ subheading. There seems to be many ‘references’ subheadings making it harder for viewers to navigate. Some references are shown as ‘ </li> which needs to be fixed right away. Overall, the content seems well written, formatted and concise making it easy to understand. However the problems related to referencing needs to be corrected as this is inconsistent throughout the project.

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This project was done really well. All key points, i.e. development, historic findings, etc., were clearly described. In terms of content, this group did a great job. It is very informative and all information they have included are relevant to the topic. There are a few mentions of embryonic stage but I do understand why, particularly for the development of the respiratory system. The developmental timeline is good but an image about the development would make it better. Remember to add in-text citations for this part. Historic findings section is very detailed and exceptional. Abnormalities is done well. A couple or more images would make this section really great. There are images that help with understanding the content. Try to find information on current treatments and/or management techniques for each disease.

However, some images have no captions and so some seem vague as to what they’re about. There are a few images missing copyright, specifically the 2nd photo on the project page and the historical image of lung development. From what I know, images from textbooks normally can’t be used because of copyright. The content is cited and referenced correctly. A bit messy with the references right now but I understand why. Just don’t forget to organise it before submission. Also, don’t forget to mention the other sections in the introduction. Overall, this project is done really well. It is very informative and easy to understand. In summary, just a few more images and correction of typos and this project would be remarkable. Well done!

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Firstly, great job on the layout and formatting of the project, everything is easy to find and overall, it reads well. The introduction provides great insight of what to expect on the page. However, it lacks in-text citations for the first three subheadings of the page, as well as the table of lung developmental stages. The first two images also don’t have a description when I click on it, I don’t know what I’m looking at. The “student template” is also missing for the images. I would suggest you look up the tutorial for uploading images on the pages as Mark has extensive information for the proper steps required for uploading images. Otherwise, the lung developmental stages table is informative and easy to read. I would also recommend adding an image for better visualization of the developmental process.

The historical findings and current research models have very detailed content, and look as though they have been referenced correctly using in-text citations, I’m impressed. Although, I would suggest you leave all the references to the end by simply putting </references> at the bottom of the page, as it looks neater to have them all in one place, rather than at the bottom of each sub-heading. The abnormalities section is done well and there are a wide number of abnormalities covered. The detail of the first two is more in depth than the rest, I’m unsure whether they was more information on those particular abnormalities or their still needs to be information added, but I suggest to have the same amount of information on each disease, if possible.
Overall, the project is very informative and presented well. It just need a few minor edits.

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The pages structure is well done, with appropriate use of heading. The introduction explains the general development of the respiratory system, differentiating embryonic, fetal and postnatal time-span. Like division of conducting and respiratory zones with strong general description of each zones components. The referencing of the first three heads content and images was not present though I presume this could be easily resolved. The Development stages table gives is simple yet informative, particularly liked how the stages during the fetal period had more in-depth feature description then the embryonic and postnatal stages.

The Current research and findings section was in-depth with strong explanations and in-text referencing; only part lacking referencing is the Functional unit section. Some sentences should be broken up to avoid excessive use of commas “However, a study conducted…”. There seems to be a picture missing or placed incorrectly for one of the 2013 studies. The Lung Model picture is relevant but with no caption, though the description and referencing when clicking on the image is solid. Little improvement is needed for the Historical findings and Abnormalities sections, great referencing and content. Particularly impressed with the sheer amount of abnormalities presented, with information being sourced from 2-3 references for each abnormality.

To improve further, referencing needs to be added particularly to the introduction, conduction and respiratory zone. The references need to be collected at the bottom of the page instead of after every couple of sections. The removal of the multiple reference subheadings would make the content and page in general easier to navigate. Many of the earlier images should be captioned properly and referenced properly, with missing info like ((Template: Student Image)), description, copyright info. The content of Respiratory and Lung Development Stages could be slightly more in-depth though not too significant of an issue. Overall content is written well, providing information on all the important objectives, only place improvement is properly required is referencing and some formatting.

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The introduction provided good background information about the lungs and its general development, however seemed to lack any further explanation as to what else would be covered on the page (current research, abnormalities). I found most of the sentences to be short and abrupt, and more in the form of statements rather than an explanation. This is the same for the following paragraphs regarding the two zones. I would combine several of the sentences together, and restructure them so that they do not start in the same manner e.g. of the first four sentence in your introduction, three of them begin with the words ‘The respiratory system’, and over half the sentences in the entire paragraph begin with ‘The’. There are a few grammatical errors within the text that should be corrected e.g. ‘till’ of ‘until’, ‘id’ instead of ‘is’. The images used fit well, but there is no caption to explain what they are images of and what they are trying to show. This is also not indicated on the summary of the image, one of which also doesn’t include any copyright information.

The lung development stages were done very well, simplified and tabulated making it very clear. My only concern for this part is that it should be the main part of the project, the area where the development of the lungs is fully explained, yet it is the smallest section of the page. Try to expand on it maybe? Or add a picture or two to enlarge the section?

The current research and findings section seems very thorough, lots of content, good explanations. Very minor problems however; a slight tendency to over use commas in some areas, while not in others. The current models area has not been added to; make sure to fill it in, or will it be scrapped? I have also noticed a picture has been deleted so make sure to get that issue fixed if you still want to use the same image. Is the second picture under this heading part of the section? As it is after the references so I'm not sure where it lies exactly. The image should be captioned as well.

I really like the historical findings section, the information seems more concise when it is presented in bullet points. The second picture within this section is well done and very neatly labeled (I thought it was an image from the internet). The first picture though, needs a caption added as well as copyright information. The abnormalities section is very extensive which can be bother good and bad. For some of the abnormalities there is a lot of detail presented, while for others there is very little. I think maybe that as long as you mention what it is, how you get it/how it forms, some statistics and maybe an image, that should be more than enough. Also, I would remove all the sub-headings under abnormalities and have them just written in bold. Otherwise, when looking at the contents at the top of the page, it looks as though half your page is solely focused on abnormalities.

Overall, I think this page is well done and only a focus on sentence structure, a bit on grammar, and captioning pictures with correct copyright info is needed. Other than these main focus areas, one other point to make would be all the references should be at the bottom of the page.

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In this review I intend to highlight the merits of your project as well as provide some constructive criticism in light of the marking criteria of this task.

The page is well structured and provides perfect balance between written text and images. However some of the included images do not compliment the text. I suggest adding labels or descriptive annotations to these images using paint. You could also include a simple written description of what each image showing. Alternatively you could refer to these images in your text e.g “ as seen in Figure 4a” and use them to make the content more engaging. I found the table on the stages of lung development really effective way of organising the content and I was able to understand much of it in a quick glimpse! I like how the text is summarised and highlights the main developmental changes that are occurring at each stage. Just to make it more engaging, perhaps you could include matching images in a another column.

Under the section of current findings, I believe that most of the information included is relevant and incredibly appropriate articles have been selected. I think its good that this section is delving into the area of molecular signalling underlying the morphological changes that we see. I believe your project would greatly benefit if there was more material discussing the biochemical signalling and recent findings in relation to this. However, I am not sure if the details on cell type should be in this section, this section might need some re-organising.

I understand that the history is a difficult topic to research. The information on our understanding of surfactant is appropriate, detailed and very informative. However I think you need to include more information on our understanding of stages in fetal lung development. Explore the transition in research focus investigating morphology to molecular changes. Perhaps use the library database to find relevant historic journal articles in the database. It was good to see the use of relevant historic images.

A number of abnormalities have been identified and described, I think its great that each section includes a description of the abnormality, and goes on to discuss the cause and implications of each disease. I would only recommend including matching images to make this section more engaging to readers. Great Work!

Overall the project is coming along really well ! Just ensure that you proof read and review before the final submission. Also include in-text references and compile all your references to one section at the end of the page. Good Luck!!

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Well explained introduction and the histological images provided are great.
In the first section the addition of in text citations would be useful. The content is explained really well and a good use of detail in the paragraphs is not too overwhelming. Good use of formatting with the inclusion of the table, helps to keep the content clear and concise. The current research, findings and models is present really well, good use of referencing and in text citations. Current findings, models and research is presented really well, good use of referencing and in text citations. Information is clear and with sufficient detail. There are a variety of formatting techniques used which is great to see. Good use of images, however seems to be missing info, suggest filling it out and maybe fixing some of the formatting errors shown but otherwise really well done. This section shows a good amount of research conducted. The historic findings are also well presented, the use of dot points to format the info is very useful and provides clarity. A timeline for the key historic dates might be helpful and another use of visuals. Great to see a variety of abnormalities, shows an extensive research really well presented. Would be great to see more images for this section and maybe drawings too.

This group overall has done really well, there are only a couple of suggestions for the page to be complete these include filling in the missing info under the sub heading ‘current models’. The in text citations and referencing in the first section should be added in to avoid losing marks. Also try adding captions to some of the images, a brief description of what the image is showing. Evidently the research conducted has been quite extensive and the group has worked well to ensure all parts are completed equally. Overall the page is structured really well and organized in an understandable manner. The use of a variety of images and formatting techniques is really great. Just a few minor adjustments and this page will be really great. Great work everyone !

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The intro is very good and the images are a good size but there needs to be some description to make it relevant to the project. Need to edit ‘Conducting Zone’ info since there are some grammatical and spelling errors. Also should have in-text referencing in this section of the project with a long list of all the references at the end. You can go onto other people’s reports to find the coding for this reference style.

The information on the lung development timeline is fantastic but it is a bit dense. Splitting it into bullet points might be a better way of organising it so peers get a more effective learning experience when they read it. In the conducting system under current findings it looks like there has been an attempt to upload an image called “400px” however the link leads nowhere. It has great information, very interesting and concise. However the references at the end of this section should be incorporated at the very end of the wiki page. This would make it flow better.

Excellent images of the diseased lung compared to normal lung, however it might make more sense for these to be under the lung abnormalities subheading. There is excellent information on the historical findings. It has been written in an easy to understand manner and all the information is relevant. There is also excellent referencing and good use of diagrams. However I still think that the references should all be together at the very end of the project page.

The abnormalities section is very in depth however there is a bit too much information. It would be easier to follow and more interesting if there were images associated with the information, or maybe if the information was tabulated that would make it easier to follow. Well done on this project! It is clear that a lot of research has been done outside.

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This is a really good project. First thing noticeable on the page is the amount of information you have which is great. The introduction is really well written and I like the fact that you have included images in this part as it makes it so much easier to understand. I also found it quite easy to grasp the difference in fetal and embryonic periods so well done as this is an important part of the project. This table of the lung development stages is great and really well done.

One thing you could maybe do here is add a few diagrams. I know you have more diagrams down below but I think it’s something that might make it even easier to follow. You obviously haven’t found any current models at the moment. Don’t know if this helps but it may for the models: PMID: 22876201. Current research and findings again is good. Something which seems to be reoccurring with your page is the fact that the references are spread all over the page. I think it would look much better if all the references were at the bottom of the page as this makes you page look more professional and aesthetically pleasing.

Maybe add some student drawings as I think this would more interesting for your page and be a bit more unique. Something else to note is the abnormalities part. It’s great that you have a lot of different abnormalities but I feel as though some of them such as cystic fibrosis and laryngeal atresia could have been given a bit more of information to supplement what you are saying. Also adding a diagram would be good to make it easier for the viewer to understand.

Overall it’s a well presented page with some quality information. Maybe look at your referencing technique, adding some more student images and a bit more detail to the abnormalities to take what at the moment is a good project to a great project. Best of luck!!

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Overall, the project at this stage consists of a good integration of text, images and references throughout. The introduction is well-written and gives an overview of the two parts of the respiratory system (conducting and respiratory zones). I think it is a good idea that your group has split this up and explained both parts separately as it helps to orient an unknowing reader, especially as the gross anatomical structures are also described (e.g. trachea, larynx, bronchi). However, in-text referencing is needed in this introductory segment to provide the reader with the source of all information, exactly where it appears. You could refer to Dr Hill’s instructions on how to do this if needed, or see another group’s page on Edit mode. Also, the images used in the introduction should have a small caption beneath them, otherwise it is hard to tell what the images show exactly and how this may be relevant to the complementary text.

In terms of heading and subheading organisation, I like how you have split the content up into 5 main areas of introduction, lung development stages, current research models/findings, historic findings and abnormalities. This makes the page easy to navigate and the subheadings under each section are relevant. The use of a table in the ‘lung development stages’ section is very well done and appropriate, as it segments the information into a clean, readable format that a student could simply refer to if they were learning from scratch. The information in the table is succinct and provides all the main points. The only improvement here I would suggest, is aligning the content to the left, as it may seem more pleasing to the eye to have even spacing rather than centre alignment. Also, the ‘references’ have been placed as subheading 2.1, whereas the other ‘reference’ sections have not been given a separate subheading, so I would consider making this consistent throughout the project page.

The section on current research models and findings is concise and informative, with good use of numbering to make the information easier to read rather than having long and chunky paragraphs. Although a minor detail, there is one part that says “a study conducted last year”. Since these Wiki pages will be left online, it is important to specify the exact year here, and provide an in-text reference to the study mentioned so a reader can easily locate it. I like the use of dot points in this section, making it look appealing, however the image used should also include a caption, as should the others on the page. Be careful of copyright infringement regarding image use, as there appears to be a file with a ‘Permission Error’ in this section, which may need to be manually removed.

The ‘historic findings’ section was also well-done, especially because it used dot points to segment the information and show the exact years of each discovery. Once again though, the image requires a caption and the references for this section seem to be split into 2 parts; one list from 1-14 then another from 1-4. I think the list from 1-4 needs a subheading to show how those sources are different to the ones above it, otherwise both lists need to be integrated into one.There are also some parts that have coding showing </ol> and </li> which just need to be removed with editing.

Lastly, the section on abnormalities is also of a high standard as each abnormality begins with a brief description then goes into details by using dot points. There is good use of in-text referencing followed by a reference list which is correctly formatted too. The image included has a caption which is good, as other sections lack this, however I would consider adding more images to make this part more visually appealing and engaging to the reader.

It is evident that a lot of work has been done on this page as each section is detailed and referenced well, with relevant information. Maybe just consider adding some student-drawn images too, but otherwise, the project is of very good quality so far.

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The product was done well overall with lots of information and a good structure. However, I am a bit confused about the sections “respiratory” and “lung development stages”. I guess “lung development stages” is also under “respiratory”, but it seems that they are separated into two big sections.

The introduction clearly explains the development of respiratory system. It is good to divide respiratory tract into 2 main parts and explain them separately. It would be better if it includes a sentence like ‘this website will focus on fetal development of respiratory system.

Using table to explain different stages of lung development is a good idea. It would be easier to read if they are typed in point forms with some images included.

More images could be added under current research, models and findings for easier understanding. Some information should be added under current models.

The historic findings and abnormalities are good and informative.

Some images do not have the information about copyright. It would be better if there is a title for each image included.

In terms of referencing, they are missing in the sections under introduction, conducting zone and respiratory zone. In-text references are also missing in the table about the stages and features of lung development. Also, the images used have not been referenced. Reference list at the end rather than under each section should be used instead.

It is overall a good project and well-researched. More images can be included to balance with the huge amount of text.

--[[User:Z3333429|Z3333429]] ([[User talk:Z3333429|talk]]) 16:13, 17 August 2014 (EST)
Hey guys, it's Emanuel
I've had a look into the systems and respiratory caught my interest. I wanted to do cardio but another group has already chosen it so I think we should choose a system ASAP.

Respiratory looks like it has plenty of resources and there are some interesting abnormalities gat I found on this page:
[http://embryology.med.unsw.edu.au/embryology/index.php?title=Respiratory_System_-_Abnormalities Respiratory Abnormalities]

Do you guys have any other systems you would like to do or do you like respiratory?

--[[User:Z3372817|Z3372817]] ([[User talk:Z3372817|talk]]) 20:07, 17 August 2014 (EST)
Hey Emanuel, its Ish here.

As we said on the day, we're fine with anything. So if it's still free, let's lock it in before another group claims it?

--[[User:Z3333429|Z3333429]] ([[User talk:Z3333429|talk]]) 20:59, 17 August 2014 (EST) Alright awesome, well I guess we're the Respiratory group. How do we let Dr Hill know?

--[[User:Z3330991|Z3330991]] ([[User talk:Z3330991|talk]]) 22:30, 17 August 2014 (EST) Hi guys, it's Nadine. I'm happy to do the respiratory system :) I'm sure we have to email him, I'll do that now, since we all seem to be on the same page and in agreement with the respiratory system.

--[[User:Z3330991|Z3330991]] ([[User talk:Z3330991|talk]]) 22:56, 17 August 2014 (EST) Just emailed Dr Mark and put a heading "respiratory" on our group page :)
Also we each need to pick one of the following;
# Review that system development during the fetal period.
# Identify current research models and finding.
# Identify historic findings.
# Identify abnormalities that can occur in this system during fetal period.
I'm happy to do number 1. Unless someone else wants to?

--[[User:Z3333429|Z3333429]] ([[User talk:Z3333429|talk]]) 06:09, 18 August 2014 (EST)Thanks Nadine, I'll do number 4 if that's all good with you guys?

--[[User:Z3372817|Z3372817]] ([[User talk:Z3372817|talk]]) 19:54, 18 August 2014 (EST) Great work with allocating Nadine. I'd love to do the historic findings (number 3) that sounds interesting! Only if that's okay with you all though?

--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 15:17, 19 August 2014 (EST) Hey Guys! It's marina here :), I'm happy with number 2. If anyone comes across information for other parts of the project, let's let each other know :)

--[[User:Z3330991|Z3330991]] ([[User talk:Z3330991|talk]]) 21:07, 26 August 2014 (EST)Hi guys its Nadine, just wanted to let you guys know that i added in subheadings to our page :) So feel free to add to your sections -pictures -articles -tables

--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 23:58, 26 August 2014 (EST)Marina: Thanks Nadine :) I'm just going to add our names next to each section that we are looking at so its easier to communicate with with one another and who's doing what :)

# Review that system development during the fetal period-Nadine
# Identify current research models and finding-Marina
# Identify historic findings-Ish
# Identify abnormalities that can occur in this system during fetal period-Emanuel

--[[User:Z3333429|Z3333429]] ([[User talk:Z3333429|talk]]) 12:58, 27 August 2014 (EST)
'''Topics to cover'''
#Major stages of development - all fetal (only primordial embryonic development)
#Histological findings
#Separate into Functional elements (alveoli) and Tract (conducting system: upper and lower)
#Include diaphragm (musculoskeletal)
#Changes after birth

--[[User:Z3333429|Z3333429]] ([[User talk:Z3333429|talk]]) 12:20, 2 September 2014 (EST) Emanuel: Hey guys just letting you know that I spoke to Dr Hill before the lecture with Carl from the cardio group about using review articles. He said we are allowed to use them as long as we refer to them appropriately (e.g as reviewed in..., according to review by..., etc).
He also said that any direct findings need to be referenced from the original article and not a review article.
We can reference to them as mentioned above and we can also add a subheading under references titled "review articles" if we want. When we start to formulate the page we can look at what previous projects have done when organising their review article references for ideas.
In regards to using images from review articles - there is no need to cite them as coming from review article.

--[[User:Z3333429|Z3333429]] ([[User talk:Z3333429|talk]]) 15:41, 2 September 2014 (EST) Emanuel: Hey guys just looking through the lecture and I noticed the part about the development of the pharynx. It develops with the foregut (oesophagus) of the GIT. What do you think if Nadine mentions that groups page in an appendix for her section to link the two pages? There is also a relationship between the development of the liver in wk7 that stops the descent of the heart and lungs so it could make our project more interesting in that it links out page with others offering a wider scope of information along with our specific topic.

--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 11:37, 3 September 2014 (EST)Marina: Yeh I agree! I noticed that too Emanuel. The development of the oesophagus from the foregut and how it bifurcated from the common pharynx into the trachea is very much related to our topic. We can definitely include those relationships, and any others we come across

--[[User:Z3333429|Z3333429]] ([[User talk:Z3333429|talk]]) 22:47, 9 September 2014 (EST) Emanuel: Hey Ish, just came across these articles regarding historical findings for pulmonary surfactant:

[http://www.ncbi.nlm.nih.gov/pubmed/18446178 Surfactants: past, preset and future.]

[http://www.ncbi.nlm.nih.gov/pubmed/14509914 The era of pulmonary surfactant from Laplace to nowadays]

Mary Ellen Avery and Jere Mead seem to be the godparents of surfactant discovery.
I also noticed that there is a little tool on the right hand side of the pubmed page when you search for articles called "Results by year". It's a little bar graph showing which years had the most articles and you can click on each year to bring up it's articles. This might be helpful if your looking for articles that sparked an increase in research by clicking on the years just before the spikes in articles.

--[[User:Z3372817|Z3372817]] ([[User talk:Z3372817|talk]]) 15:49, 16 September 2014 (EST) That is just amazing Emanuel, thanks! Just another thing I wanted to ask, I noticed you took notes when Mark came by to talk to our group at the last lab. When he was saying to focus on things like..
Yeah, do you mind just typing up what you had written. That would be so helpful!

--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 23:33, 16 September 2014 (EST)Marina: Hey guys, just uploaded an image onto our page. It's under current research because its something scientists are looking at the moment with tracking abnormalities. The picture compares the normal structure of a lung to a couple of diseased ones. I know this also links to other parts of our project so we can shift it around later if need be. Mark wanted a picture uploaded before tomorrow, so at least we have something up there for now :)

--[[User:Z3330991|Z3330991]] ([[User talk:Z3330991|talk]]) 12:13, 17 September 2014 (EST) Nadine here, just wanted to inform you that we have a new group assessment that will be marked individually we need to pick 2-3 research papers on stem biology and we need to summarize the paper and present it in week 12 as a group. You will get an email in regards to this set assignment, just thought I'd give you a head up.

--[[User:Z3333429|Z3333429]] ([[User talk:Z3333429|talk]]) 12:44, 17 September 2014 (EST) Emanuel: This is for Ish, I found a link on the respiratory pages that should help you out. Just go to one of the pages (e.g Respiratory System - Abnormalities) and there is a 'Historic Embryology' link just after the introduction. It's small and in a blue box so click on it to expand. It has some really good links that will hopefully help you. Something else that was interesting was the disclaimer at the bottom of the links stressing that the content and scientific understanding are specific to the time of publication. You may want to ask Dr Hill if you need to include that at the bottom of the page to make sure that our audience does not get confused.

--[[User:Z3372817|Z3372817]] ([[User talk:Z3372817|talk]]) 13:27, 17 September 2014 (EST) Ish: Yup, I've seen that Emanuel. I sort of wrote a paragraph along those lines as an introduction to my section which serves as a type of disclaimer too, but I'll reconfirm with Mark whether it's necessary to have anything in addition to that. Nadine, thanks for the heads up.

--[[User:Z3330991|Z3330991]] ([[User talk:Z3330991|talk]]) 16:21, 1 October 2014 (EST) Nadine: Hey guys, just wanted to remind you that by the end of this week all information should up for your section. Make sure that references are included, pictures if needed.

--[[User:Z3372817|Z3372817]] ([[User talk:Z3372817|talk]]) 20:34, 1 October 2014 (EST) Ish: Hey guys, anyone else having issues with the website lately? I'm trying to upload an image - can't. I completed my latest lab assessment a couple days ago and saved it - lost it. So just to be safe, once you've written everything you need down in your sections, copy and paste EVERYTHING into a separate word doc. Don't want you guys to lose hours of work like I did.

--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 19:02, 3 October 2014 (EST) Marina: Hey Ish yeh im also having trouble with it as well. Even the "uploading image" button is inactive for me, apparently others are having as few problems with this as well. Can you guys check if you yours is visible at the moment? I know this must be recent as you guys have uploaded images and i was able to before. Maybe it has to do with the website change Dr Mark was talking about.

--[[User:Z3330991|Z3330991]] ([[User talk:Z3330991|talk]]) 21:10, 4 October 2014 (EST) Nadine: Thanks Ish! i had the same problem happened twice to me! But it worked out for me in the end. So i have been looking around -projects from years before us and i really like this layout. Have a look if you get the chance [https://embryology.med.unsw.edu.au/embryology/index.php/2012_Group_Project_3]

--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 22:50, 4 October 2014 (EST) Marina: Hey Nardine, i really like that layout, hopefully we can get something similar to that going for us as well :) I'm sorry I havent been able to upload any images as the tab for me is unavailable, i emailed Dr mark about it though so hopefully that gets fixed soon.

--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 22:51, 4 October 2014 (EST) Marina: I was thinking of adding a heading titled "Glossary" at the very end of our project for us to add any words we want to define.... what do you guys think of this?

--[[User:Z3330991|Z3330991]] ([[User talk:Z3330991|talk]]) 20:33, 7 October 2014 (EST) Nadine: Hey Marina, i like that idea heaps and i was also thinking of drawing for my section i found a great paper with fantastic pictures but i cant find the copyright information its off Nature, or I'll just figure something out

--[[User:Z3330991|Z3330991]] ([[User talk:Z3330991|talk]]) 20:36, 7 October 2014 (EST) Nadine: Hey I was thinking we need to get on top of the week 12 project maybe we can talk about this further tomorrow? I just dont want all of the good papers to go fast and we get left with really hard ones.

2014 Group Project 7

2014-10-08T11:30:33Z

Z3419587: /* Development during fetal period */

2014 Group Project 7

2014-10-08T11:28:31Z

Z3419587: /* Development during fetal period */

2014 Group Project 7

2014-10-08T00:11:03Z

Z3419587: /* Neural - CNS */