What we know of the nervous system in the germinal and embryonal periods has been derived from the anatomical study of fetuses. Neuroblastic differentiation, migration, and neuronal multiplication are already well under way in the first 3 weeks of embryonic life. The control of each of these phases (and, later, of connectivity of neurons) is determined by the genome of the organism. Primitive cells destined to become neurons originate in, or close to, the neuroepithelium of the neural tube. These cells proliferate at an astonishingly rapid rate (250,000 per minute, according to Cowan) for a circumscribed period (several days to weeks). They become transformed into bipolar neuroblasts, which migrate in a series of waves toward the marginal layer of what is to become the cortex of the cerebral hemispheres. The first glial cells also appear very early and provide the scaffolding along which the neuroblasts move. Each step in the differentiation and migration of the neuroblasts proceeds in an orderly fashion, and one stage progresses to the next with remarkable precision. The process of neuronal migration is largely completed by the end of the fifth fetal month but continues at a much slower rate up to 40 weeks of gestation, according to the classic studies of Conel and of Rabinowicz. Because the migration of most neurons involves postmitotic cells, the cerebral cortex by this time has presumably acquired its full complement of nerve cells, numbered in the many billions. This concept was, however, revised with the discovery that active stem cells in the adult brain generate neurons in the hippocampal formation and in the subventricular matrix zones, giving rise most evidently to olfactory neurons in the adult brain but possibly also to other nerve cells (see the reviews by Alvarez-Buylla and Garcia-Verdugo, Kempermann, and also Bond and colleagues).
Despite the almost universal acceptance of the presence of neurogenesis in the human brain, the methodology that demonstrates it is complex (see review by Kuhn and colleagues) and has been questioned by authoritative individuals such as Rakic, whose perspective should be consulted for a complete portrait of the subject. Actually, we have little idea of the number of nerve cells in the cerebral and cerebellar cortices at different ages. Many more are formed than survive, as programmed cell death (apoptosis) constitutes an important component of development.
Within a few months of mid-fetal life, the cerebrum, which begins as a small bihemispheric organ with hardly a trace of surface indentation, evolves into a deeply sulcated structure. Every step in the folding of the surface to form fissures and sulci follows a temporal pattern of such precision as to permit a reasonably accurate estimation of fetal age by this criterion alone. The major sylvian, rolandic, and calcarine fissures take on the adult configuration during the fifth month of fetal life, the secondary sulci in the sixth and seventh months, and the tertiary sulci, which vary slightly in location from one individual to another, in the eighth and ninth months (see Fig. 27-1 and Table 27-2).
Concomitantly, subtle changes in neuronal organization are occurring in the cerebral cortex and central ganglionic masses. Involved here are the processes of synaptogenesis and axonal pathfinding. Neurons become more widely separated as differentiation proceeds, owing to an increase in the size and complexity of dendrites and axons and enlargement of synaptic surfaces (Fig. 27-2). The cytoarchitectural patterns that demarcate one part of the cerebral cortex from another (as described in Chap. 21) are already in evidence by the 30th week of fetal life and become definitive at 40 weeks and in succeeding months. As the maturational process of cortical neurons proceeds, the patterns of neuronal organization in different regions of the brain (motor, premotor, sensory, and striate cortices, Broca and Wernicke areas) continue to change.