NADD Bulletin Volume VII Number 5 Article 3

Complete listing

Developmental Neuropsychiatry: Embryology and Psychopathology

Jarrett Barnhill, M.D.


The human brain is the culmination of 30 million years of primate evolution. Phylogenetically, major changes have resulted in the transition from a vision centered to language dominated cerebral organization. The evolutionary forces driving this transformation and cerebral expansion remain elusive (Benno, 1995). Ontologically, the CNS begins as a neuroectodermal folding, and then begins a period of exponential growth and bewildering differentiation. Many developmental disorders adversely affect this complex process. I will provide an oversimplified though basic overview, pointing out key times for selected syndromes.

Basic Developmental Neurosciences

Genes signal the differentiation of neuroglial precursors and embryonic neurons from cell lines that also give rise to skin cells. Once activated these genes signal neuronal cell division and the production of a range of neurotrophic factors that guide nerve cell migration and eventual differentiation of various component cells of the nervous system. Neurogenesis is an explosive process that dominates the first 20 weeks of gestation. Shortly after the formation of billions of nerve cell precursors, they begin a massive outward migration in the rapidly developing cerebral cortex. A group of specialized cells, radial glial cells, provide structural scaffolding and a large array of peptide and neurotransmitter trophic factors operate as chemical signposts. The exodus of neurons proceeds from inner to outer layers of the evolving cortex (Harris 1995b).

Once in place, neurons complete the process of axonal connections, and dendritic arborization/stabilization. During this time, nerve growth proceeds along chemically defined pathways, guided by a staggering array of peptides and smaller molecules that will eventually serve as neurotransmitters. The process of differentiation also shapes the eventual identity of these cells. This process depends in part on the interconnections between adjacent neurons. Later, the formation of synaptic connections dominates. Initially, there is a massive overproduction of synaptic dendrites and potential synaptic connections. During development most of these dendrites are pruned or eliminated. In addition, pre-programmed cell death (apoptosis) results in the elimination of approximately 20-40% of infant nerve cells during development (Walsh, 1995). Apoptosis (programmed neuron death), dendritic pruning and resculpting are influenced by an interaction between genetic factors, environmental inputs and local neurochemical factors.

Interestingly, the function of most neurotransmitters also changes during brain development. Neurotransmitters such as norepinephrine, serotonin and dopamine serve as gene activators, trophic factors and stimulants for the growth of dendrites long before they function at the synapse. In addition, variations in the development of autoreceptors, transporter proteins, second messenger systems also follows a developmental trajectory that may explain pharmacodynamic differences between drug responses of children versus adult patients (Harris, 1995a).

Aside from important changes in nerve, a second wave of cell multiplication occurs- glial cell production. Glial cell proliferation appears between the 20-40th weeks of gestation. Glial cell migration and differentiation play key roles in brain development and function. Much of the explosive growth in brain size during the last trimester is related to glial proliferation and neuronal differentiation. In addition to the development of a blood brain barrier and immunological functions within the brain, glial cells are responsible for myelinization in the brain. Failures in glial development may result in ectopic foci during migration, or disturbances neuronal functioning. In children, the blood-brain barrier develops throughout childhood, and the consequences of faulty maturation of these cells further compromises later brain maturation and function. Myelinization plays a key role in brain and cognitive development by accelerating nerve cell communication and interconnections between various brain regions (Huttenbacker & Dabkolar, 1997).

Why Should This Stuff Matter to Clinicians?

Understanding the basic elements of brain development allows the clinician an opportunity to address the relationship between the genes, gestational or embryological insults, and developmental psychopathology. In general, genes may influence cell replication, migration, differentiation, and maturation. It is also apparent that the activation or de-activation of specific genes plays a crucial role in normal development (Thatcher, 1997). But environmental influences are also operating. Learning and experience shape that nature of nerve cell maturation and functioning. These experiential changes result from changes in dendritic architecture, patterns of interconnections, and activity (Long term potentiation or inhibition) or by continuing neurogenesis in selective brain regions (Huttenbacker & Dabkolar,1997). Another form of reaction to environmental input involves apoptosis (programmed cell death), dendritic pruning, and plasticity are constantly re-working the viability of interconnections between nerve cells--"use it or lose it" applies. The development of the hierarchical organization of brain functions, coherence and integration of various cortical and subcortical circuits, contributes cognitive development (Benno, 1990).

Many developmental disabilities occur when these processes go awry. These errors in normal development can result from faulty genes that result in a failure to produce or an underproduction of significant chemical signals for brain development. Other disorders may be the result of gestational, neonatal, or later traumatic insults to the developing brain. Genetic disorders may result in deficiencies in enzymes that are critical for nerve cell survival and functions. Insults occurring later in gestation may result in problems with neuronal migration, differentiation, and maturation, and later problems growing out of deficits in glial cell function, dendritic connections, and pruning/apoptosis (Harris, 1995a; Walsh 1995).

Most psychiatric disorders are associated with a combination of these errors. There appears to be a combination of genetic vulnerability, structural and functional differences in brain function, cognitive and behavioral manifestations, and adverse environment (Benno, 1990). For example, many primary psychiatric disorders present with subtle structural or functional abnormalities in limbic and frontal systems that suggest faulty neuron interconnections as well as the emergence of higher level of neurocognitive dysfunction (Thatcher, 1997). These developmental changes disrupt the process of hierarchical organization of higher cortical functions. These expanding cognitive capacities parallel the emergence and integration of higher level association and prefrontal functions Integration of these regulatory regions with limbic and memory circuitry also serves as the substrate for temperament and normal personality development (Huttenbacker & Dabkolar,1997; Thatcher, 1997).


The impact of abnormal brain development plays a pivotal role in the lives of many people with intellectual disabilities. These deviations profoundly influence not only brain function but also sensitivity to environmental stress, deficits in adaptive skills, affect regulation, impulse control, and communication skills. These developmental brain abnormalities affect genes associated with neuropsychiatric disorders and influence risk, clinical presentation, treatment response, and prognosis. Clinicians need to consider these observations to diagnostic and treatment models of psychopathology. It is increasingly important that clinician apply this understanding to clinical problems, especially the relationship between brain disorders, intellectual disability, differences in temperament, behavioral phenotypes, and neuropsychiatric disorders and treatment planning. Lastly the clinician should attempt to integrate findings from the neurosciences into a transactional or biopsychosocial model.


Benno, R. H. (1990). Development of the nervous system: Genetics, epigenetics, and phylogenetics. In M. E. Hahn, J. K. Hewitt, N. D. Henderson, & R. Benno (Eds.), Developmental behavioral genetics (pp. 113-142). New York: Oxford University Press.

Harris, J. C. (1995a). Development of neurotransmitter signaling systems and neuronal signaling mechanisms, Developmental Neuropsychiatry (Vol I) (pp. 49-77) New York :Oxford University Press.

Harris, J. C. (1995b). Molecular neurobiology: The new genetics. Developmental Neuropsychiatry (Vol I) (pp. 3-26). New York: Oxford University Press.

Huttenbacker, P. R. & Dabkolar, A. S. (1997). Developmental anatomy of prefrontal cortex. In N. A. Krasnegor, G. R. Lyon, & P. S. Goldman-Radic (Eds), Development of the prefrontal cortex (pp. 69-82). Baltimore: Paul H. Brookes.

Thatcher, R. W. (1997) Human frontal lobe development. In N. A. Krasnegor, G. R. Lyon, & P. S. Goldman-Radic (Eds), Development of the prefrontal cortex (pp. 85-112). Baltimore: Paul H. Brookes.

Walsh, C. A. (1995). Neuronal identity, neuronal migration, and epileptic disorders of the cerebral cortex. In P. A. Schwatzdroin, S. L. Moshe, J. L. Noebels, & J. W. Swann (Eds.), Brain development and epilepsy (pp. 122-143). New York: Oxford University Press.

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