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Children and adults with developmental (intellectual) and learning difficulties may exhibit delayed cognitive development. Some may suffer from profound delays, while others may show minor difficulties in learning. We know, from our current state of knowledge that the functional organisation of the brain, as it develops, may be disrupted at various stages, starting from when the foetal brain is in its early stages of development to post birth, until adolescence. Various genetic and environmental factors may cause such disruption in the regulation of the orderly development of the brain.

It is, therefore, of interest to briefly look at some of the developmental stages in the foetal brain and also look at how a normal brain develops after birth. This gives us a frame of reference for understanding many of the syndromes that unfortunately represent maldevelopment of the brain.

a) Initial Stages in Brain Development
About the 18th day of gestation, the nervous system begins as a plate of tissue. The edges of this plate fold to form a tube, much as one may fold a rolled sheet of dough. The two ends of the tube then close by the 26th day. This closed tube eventually develops into the brain and spinal cord. Disturbances to this process result in errors in the neural tube closure.

The following are some examples:

Anencephaly: In this condition, the head end of the tube has not closed, resulting in the absence of major parts of the skull, brain and brain stem. These foetuses do not survive.

Myelomeningocele: The tail end of the neural tube fails to develop appropriately, resulting in deficiency in the axial skeleton. These infants survive but have major deficits.

b) Middle Stages of Development
During this stage, intense growth of the neural tube takes place resulting in the formation of the face and forebrain. The most intense activity takes place during the 5th and 6th weeks: Much of the nerve tracts associated with the eye and nose develop, as well as the cranial nerves, basal ganglia (inner parts of the brain) and the two cerebral hemispheres. In the 2nd and 3rd months, other structures such as the hypothalamic plate (the centre that controls endocrines, temperature and appetite) develop. Most important, the bridge between the hemisphere called the corpus callosum develops, to be completed by 20 weeks of gestation.

Understandably, disruptions at this stage may cause profound damage; however, some damage may not even be detected during life. Some examples of detectable damage follow below:

Haloprocencephaly: In this condition, the forebrain is severely malformed, resulting in profound retardation.

Agenesis of Corpus Callosum: In this condition, the bridge between the two brain hemispheres is defective, resulting in problems in the communication between the two parts of the brain. Depending on the extent of the damage, the brain may compensate for these defects and the individual may be able to function, albeit with some difficulties.

c) Later Stages of Development
From between two and four months, the basic structure of the brain starts growing. Nerve cells, receptors and the supporting structures start proliferating. Disorders at this stage may result in small brains called micrencephaly or excessive deranged proliferation called macrencephaly. Various degrees of cognitive difficulties result from this.

Apart from growth during this stage, millions of nerve cells move to various specific regions of the brain and settle down. This migration is at its peak around the 5th month. Disturbances can result in serious malformations of the brain to patches of nerve cells found in abnormal places. Seizures are frequent clinical events. Carbon monoxide poisoning at around 22 weeks of gestation may cause some types of migrational problems.

From about the 5th month to several years after birth, the brain goes through an organisational phase. During this stage, the nerve cells and receptors grow in numbers initially but after two years of age are gradually pruned until adolescence to nearly 50% of the original number. This process is very important and enables the infant to adapt to living in the world with all its various demands. This process enables appropriate connections to develop in the circuitry in the brain. The organisation of the brain is dependent on a certain structure within the brain called the subplate. This structure provides a docking site for the connections that flow from the rest of the brain to the future cortex. These neurones also wait in the subplate, like passengers in a railway station, and in the process, mature and get ready for an onward journey. Eventually, they travel to a specific layer of the cortex (the outer brain) which is now differentiating into a six layered structure. If the subplate neurones are damaged during the 2nd and 3rd trimesters of pregnancy, the subsequent organisation of the neural network in the brain is severely disrupted. These networks are the basic wiring needed for cognitive development.

The growth of the brain continues, as alluded to above, even after birth. However, after birth, it is more a process of pruning the excessive wiring, and the development of extensive connections between the neurones and synapses. This process of dendritic connections (dendrites are wiring that sprout from the head of the nerve cell) is most active during and after adolescence. At the same time, the density of receptors in layer II and III of the cortex increases. These are the layers that are involved in information processing. Localised disruption to this process will only become evident clinically after several years, around adolescence. This explains why in some children cognitive abilities decline in mid or later childhood. Disorders of the organisation of neural connections, as described above, are associated with mental retardation with or without seizures; Down's syndrome, Angelman syndrome, infantile autism, Duchene's muscular dystrophy, etc.

Another important development is myelination. Myelin is a sheath that wraps around the neuronal wiring to insulate and facilitate faster transmission of electrical potentials. This process begins prior to birth and continues until adulthood in an orderly fashion. For example, sensory pathways are myelinated first and motor pathways after. The rear lobe (occipital) that is concerned with vision is myelinated first and the frontal lobe (the executive brain) later. This explains why in children sensory efficiency develops before motor efficiency and why complex problem solving and such cognitive abilities develop much later. Disorders of myelination lead to conditions such as cerebral white matter hypoplasia, amino and organic acidopathies, congenital hypothyroidism, periventricular leukomalacia .

Conclusion
I have outlined, very briefly, some of the milestones in the development of the brain and the conditions that may arise if there is disruption of such events.

There are exciting developments in the field of developmental biology and medicine that are gradually unravelling the mystery of brain development. We are gaining an understanding of what may interrupt this complex process of development. Eventually, this knowledge may lead to biological, psychological and social interventions that may provide us more effective preventive and interventional strategies. While on one hand, such complexity is overwhelming, on the other hand, the knowledge that we are acquiring can be seen as the dawn of a new era of hope.

This article first appeared in the Clinical Bulletin of the Developmental Disabilities Programme at the University of Western Ontario Vol 13 - No.4 December 2002

Recommended reading list
1) Miller JC & Freidhoff AJ (1988) Prenatal neurotransmitter programming of postnatal receptor function. Progress in Brain Research; 73, 509-22.

2) Doupe AJ, Patterson PH & Landis SC (1985a) Environmental influences in the development of neural crest derivatives: glucocorticoids, growth factors and chromaffin cell plasticity. Journal of Neuroscience; 5:21, 19-42.

3) Oster-Granite ML & Ebner FF (1996) Developmental processes and the pathophysiology of mental retardation. Mental Retardation and Developmental Disabilities; 2:197-208.

4) Greenough WT (1986) What is special about development? Thoughts on the bases of experience-sensitive synaptic plasticity. In Greenough WT, Juraska A (eds.) Developmental Neuropsychobiology. New York: Academic Press, p. 387-407.

5) Harris JC (1995) Developmental neuroanatomy. In Developmental Neuropsychiatry, Vol. 1. New York: Oxford University Press, p. 26-48.

This article was first published on the site in 2003.