2014 Group Project 7
|2014 Student Projects|
|2014 Student Projects: Group 1 | Group 2 | Group 3 | Group 4 | Group 5 | Group 6 | Group 7 | Group 8|
|The Group assessment for 2014 will be an online project on Fetal Development of a specific System.
- 1 Neural - CNS
- 1.1 Introduction
- 1.2 Development during fetal period
- 1.3 Brain Development
- 1.4 Spinal Cord Development
- 1.5 Historical Research and Findings
- 1.6 Current research models and findings
- 1.7 Abnormalities
- 1.8 References
Neural - CNS
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
Development during fetal period
Timeline of human neural development 
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 
- 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 . 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 . The nuclei move between the ventricular surface and the border of the ventricular zone with the subventricular zone .
- 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 . In some parts of the brain, there is the production of a significant number of neurons in this zone . For example, the subventricular zone contributes large number of cells to the neocortex, which is the youngest structure in the brain . In contrast to ventricular zone, the proliferating cells do not move through the cell cycle.
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 
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.
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 , 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
- 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 
During Fetal Period
- Extends from the ninth gestational weeks through to the end of gestation
- 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
- The major fibre pathways make up the brain white matter
Increase in size and weight
Image of brain and ventricular development 
Image of brain fissure development 
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 
Gyration: development of gyrus that occurs late during fetal development until end of the pregnancy or even later after birth 
|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|
|38-40||dark posterior limbs of internal capsules|
table obtained from <pubmed>20608424</pubmed> 
Spinal Cord Development
The spinal cord is formed from parts of the neural tube during embryonic and fetal 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.
|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 
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
Local tissue growth patterns underlying normal fetal human brain gyrification quantified in utero
|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 
Sexually Dimorphic White Matter Geometry Abnormalities in Adolescent Onset Schizophrenia 
Asymmetry of White Matter Pathways in Developing Human Brains 
Cortical Overgrowth in Fetuses With Isolated Ventriculomegaly 
Microcephaly, Macrocephaly and Hydrocephalus
- Primary Microcephaly: Abnormal development is observed in the first seven months of gestation.
- In patients with macrocephaly the head is enlarged.
Fetal Alcohol Syndrome
- 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. 
- 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. 
- 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). 
- 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.
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. 
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. 
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. 
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.
- 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 .
- Since incomplete skull formation occurs, brain tissue becomes exposed due to the absence of bone covering and therefore leading to further complications.
- 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.
- 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 . Intake of certain drugs such as anti-histamines and sulphonamide/tetracycline (antibiotics) have also increases this risk . Furthermore obesity has been shown to have a significant effect on the incidence of iniencephaly with 1.7-3 fold increase .
- 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
- <pubmed> 23307634 </pubmed>
- <pubmed> 23307635 </pubmed>
- <pubmed> 24812082 </pubmed>
- <pubmed> 23508710 </pubmed>
- <pubmed> 23809349 </pubmed>
- <pubmed> 11264481 </pubmed>
- <pubmed> 11589424 </pubmed>
- <pubmed> 22408660 </pubmed>
- <pubmed> 22439066 </pubmed>
- <pubmed> 18538144 </pubmed>