Chapter 81. Brain Development and Behavior

This chapter provides an overview of brain development and the role of experience in sculpting the developing brain that provides a construct for understanding the neural basis of cognitive development.

The brain develops over a prolonged period of time; the most rapid period of development occurs prenatally and during the first few postnatal years. The major events that occur prenatally include the construction of the neural tube, cell proliferation and migration, and cellular differentiation. Although myelination and synaptogenesis both begin during the last trimester of pregnancy, these events extend well into postnatal life.

Neurulation

Between the second and third weeks of gestation, the dorsal region of the ectodermal layer of the embryo begins to thicken and form a pear-shaped plate. As cell proliferation continues, this plate becomes a groove and then a tube. Toward the end of the third week of gestation, the anterior end of the neural tube forms a set of swollen enlargements that give rise to 3 primary vesicles: the forebrain (which will become the cerebral hemispheres), the midbrain (which will contain important pathways to and from the forebrain), and the hindbrain (which will consist of the brainstem and cerebellum). The remainder of the neural tube gives rise to the spinal cord, peripheral nerves, and certain endocrine glands in the body. The neural tube completes its closure by the end of the third prenatal week.

This phase of development may be compromised, leading to a class of disorders called neural tube defects, which are further discussed in Chapter 549.2

Neurogenesis

After the neural tube has closed, a new phase of brain development commences. Within the neural tube, the innermost cells divide rapidly and repeatedly, giving rise first to the cells that primarily become neurons and later to precursors of both neurons and the supportive tissue components called glia (which will include elements such as astrocytes, oligodendrocytes, etc). In most areas of the brain, the process of neurogenesis is completed by the third trimester of pregnancy, with 2 known (and accepted) exceptions. First, cells that line the olfactory bulb turn over on a near-weekly basis for the entire life span. Second, postnatal neurogenesis is known to occur in a region of the hippocampus known as the dentate gyrus.3-5 In this region, new neurons are born through at least middle age. Interestingly, these new neurons possess all the functional properties of prenatally derived neurons (eg, developmental processes); in addition, they appear to be influenced by experience. For example, when learning and memory functions are challenged in the rodent, the number of new cells produced in the dentate increases; by contrast, if the rodent is reared in a stressful environment, there is a reduction in the number of new cells produced.6

Although there have been reports of postnatal neurogenesis in other regions of the cortex, there is controversy as to whether these new cells are actually neurons or supporting elements. Currently, it appears that postnatal neurogenesis is limited to the olfactory bulb and the hippocampus.

Cell Migration

The cerebral cortex is composed of 6 layers, which form in what is called an inside-out fashion, with the deepest layers formed first, and subsequent layers formed later. These layers are created through the process of cell migration. Specifically, the wall of the recently closed neural tube consists of a single layer of epithelial cells. These cells are connected to each other, and they rapidly proliferate, causing the layer to thicken. The neuroblasts that line the neural tube attach themselves to a specialized type of glial cell, the radial glia fiber, and essentially climb along this fiber until the cell has reached its target destination. Once this has occurred, a process that takes 10 to 20 hours, the neuroblast essentially detaches itself from the glial fiber and begins the process of differentiation. See Figure 81-1 for an illustration of cell migration; note that some cells migrate using a form of radial migration, although this does not account for the bulk of migrating cells.

The initial formation of the cortex occurs by migration of cells to the deepest layer (VI) of the cortex, and subsequent migrations follow in an inside-out pattern. In this manner, young (postmitotic) neurons leave their zone of origin and typically migrate past older cells to reach their final position. As a result, the earliest formed cells come to inhabit the deepest cortical layer (VI), whereas progressively later-formed cells will occupy positions at progressively more superficial layers. An exception to this is in the cerebellum, where granule cells are formed in the external germinative layer and move in an internal direction.6

The cells trapped between the ectodermal wall and the neural tube are neural crest cells. This intermediate zone of cells will extend effectively from the forebrain downward along an axis. The cells on each side of this axis migrate to the dorsolateral side of the neural tube and eventually give rise to the sensory ganglia (or dorsal root ganglia) of the spinal and cranial nerves (V, VII, IX, and X).

After cell migration is complete, usually by the sixth prenatal month, neurons must begin the arduous process of differentiating (making processes, or axons and dendrites) and then making connections. The first axons and dendrites form shortly after the 20th week of gestation, with the first synapses to follow. Dendrites typically begin as small, stubby protuberances that gradually become more refined and sophisticated. Axons form at one end of the cell and, once mature, must seek out an adjacent dendrite (or in some limited cases, another axon). They move through the brain with the help of small extensions (lamellipodia and filopodia) that sample the local biochemical medium until they find their target destination. Once they have done so, a synapse can form.7

Synaptogenesis

After neurons have differentiated, their axons begin to reach out to neighboring cells. Here they typically form the synaptic connections through which they can communicate with the target cell, with another neuron, or with a nonneuronal cell such as a muscle. In most parts of the nervous system, the stability and strength of these synapses are determined to some degree by the activity (neural firing) of these connections.

Not surprisingly, the formation of synapses to some degree follows the form-followed-by-function rule in which those regions of the brain that are the first to develop functioning synapses become functional first, and those that develop synapses later function last. In addition, in all areas of the cortex, there is an initial overproduction of synapses that far exceeds adult numbers, followed by a pruning back or retraction of synapses. For example, the peak of overproduction in the visual cortex occurs between 3 and 4 postnatal months, with maximum density reached at 4 months. Synaptogenesis in the Heschl gyrus, the primary auditory cortex, follows a similar timetable and is 80% complete by 3 months of age. In contrast, overproduction in the middle frontal gyrus is not reached until middle to late adolescence.8-11

Collectively, synapse elimination in the human brain appears to occur late in gestation and early in the postnatal period, during a time when the nervous system is highly sensitive to environmental influences. It has been suggested that the main purpose of this overproduction followed by retraction is to “capture” synapses on a systemwide basis. In so doing, there is both selective confirmation and elimination that is based on experience.

Myelination

Like synapse development, the development of myelin is a protracted developmental process that extends well into the postnatal period. Myelin in the central nervous system is produced by a specialized glia element called oligodendroglia, whereas Schwanncells produce myelin in the autonomic nervous system. Myelin essentially insulates the cell and increases conduction velocity. The formation of myelin is a genetically defined process that is preceded by the proliferation and differentiation of glial cells proximate to the pathways to be myelinated and is most prominent during the period of rapid brain growth. Although this process is genetically determined, it can be influenced during the postnatal period by environmental factors such as diet.

As a rule, motor roots myelinate first, followed by sensory roots, followed by primary somesthetic, visual, and auditory cortices. Next to myelinate (during the first postnatal months) are the secondary association areas that surround the primary sensory or motor cortices. Myelination of the classic association areas that are involved with higher cortical functions, most notably in the frontal cortices, extends well into the postnatal period and possibly into adolescence.12

The degree and location of myelination can be accurately measured by the level of signal intensity inferred from magnetic resonance images. Great advances have been made using magnetic resonance–based imaging tools. For example, we now know that there is a large increase in intracranial volume in the first year, and that by age 1, intracranial volume is about 75% of adult volume, and at 2 years, it is 80%. Males in general have larger intracranial volumes than females, and in contrast to the adult, there may be no sex differences in white matter in newborns.13,14

We now know that there is a linear increase in white matter from postinfancy through 20 years of age and there are nonlinear changes in gray matter during this same time period. There is an increase in gray matter in the frontal and parietal lobes until about the age of 12 years, thereafter followed by a decrease. In the temporal lobes, the increase occurs until age 16, and then again is followed by a decrease.15,16

Overall, changes in gray and white matter continue across the first 20 years of life. Gray matter reaches its peak around the age of 12, and myelination reaches its peak around the age of 20 years.

Although most aspects of prenatal brain development are not dependent on experience (with the exception of obvious deleterious experiences, such as exposure to poor nutritional environments and teratogens), the same cannot be said of postnatal development. Indeed, many elements of postnatal development depend critically on experience.17 For example, although the initial formation of ocular dominance columns in the visual cortex occurs independent of experience, full elaboration and differentiation of these columns depends heavily on experience; thus, untreated strabismus inalterably leads to abnormal visual development. Furthermore, several aspects of language development depend on experience. For example, the infant’s ability to discriminate speech sounds from the infant’s native language depends considerably on hearing the sounds of that language. Before 6 to 12 months of age, infants from around the world are adroit at discriminating the sounds of most of the world’s languages. However, after this age, infants behave more like adults and discriminate best the sounds of their native language.18 Moreover, we know that infants begin to profit from hearing their mother’s voice weeks before they are born (assuming a term pregnancy) because they can recognize this voice within hours of being delivered. Finally, it is currently believed that an infant’s or toddler’s vocabulary can vary as a function of the words heard in the child’s home.

A similar phenomenon occurs in the visual domain. For example, 6 month olds, 9 month olds, and adults are all equally effective at discriminating 2 human faces, but only 6 month olds can also discriminate 2 monkey faces. However, if 6 month olds are given 3 months of experience viewing monkey faces, they retain the ability to discriminate monkey faces.19,20 Thus, for both speech and face processing, infants appear to pass through a sensitive period whereby experience or the lack thereof has a pronounced impact on whether an ability is retained or lost.21

It appears that visual acuity passes through a similar developmentally sensitive period. For example, infants who have congenital cataracts removed within the first few months of life show a tremendous improvement in visual acuity; however, the more time that passes without replacing the cataract with a normal lens, the more acuity will permanently suffer.22

Outside of the sensory development, little is known about the specific role of experience, and the timing of such experiences, in influencing brain development. Based on studies of deprivation, such as in children who are neglected or abused, a very broad sensitive period may exist for the formation of initial human attachments. For example, children reared in Romanian orphanages and adopted into homes in Canada, Britain, or the United States typically have better developmental outcomes if they were adopted before the second year of life.23,24 Here it is assumed that the myriad deprivations that occurred in those first months derailed the infant from a normal trajectory and that the longer such deprivation continues, the worse the outcome and/or the harder it is to bring the infant back onto a normal trajectory.

Moving beyond basic abilities such as seeing, hearing, and forming attachments, we know that there is considerable plasticity in both the cognitive and motor domains. With regard to the cognitive domain, we know that learning and memory are possible throughout the life span; we also know that in the rat, these experiences can be powerfully influenced by how the rats are housed. Thus, rats living in so-called complex environments (those with lots of toys and other rats) perform better on maze tasks and have more synapses per unit area in the areas of the brain that underlie memory and visual function than do rats housed in single cages (the typical laboratory rat environment).17 With regard to motor skills, we know that the area of the somatosensory cortex that represents the fingers of the left hand in trained right-handed musicians is larger than both their right hand and the left hand of nonmusicians.25 Similarly, we know that motor training following an ischemic stroke can recruit neighboring areas of the motor cortex that lead to recovery of motor ability.

Overall, the most rapid period of brain development occurs shortly after conception through the first few postnatal years. However, the establishment of the extensive network of interconnections that underlies behavioral change occurs for many years thereafter. More importantly, many forms of plasticity occur throughout the life span.