The Wiley-Blackwell Handbook of Childhood Social Development

Reproduced under the Creative Commons Attribution License, PLoS ONE.

As implied in Figure 3.1, to achieve the in‐utero endpoint of neural growth that forms the brain by the time of birth, multiple factors occur almost simultaneously at a phenomenal rate. Both neurons and glial cells develop in concert, with amazing speed, including epochs where tens of thousands or more cells develop every minute . Since neurons have to create synaptic contacts to become functionally active, synaptogenesis occurs at an equally astonishing rate. This also begins the process of neural connectivity and the development of networks (see Figure 3.2). Under genetic control, there is also a migration (see Figure 3.1) of certain cells to form regionally and then connect with their counterparts either within a hemisphere or the opposite hemisphere. This means there is axonal growth where the axon has to navigate to find its destination, which also means neural guidance of projecting axons from each of the 100+ billion neurons to appropriately and precisely connect. Like any integrated circuit, there has to be feedback, so all of these 100‐trillion synaptic connections must have some element of a reciprocal feedback loop as well.

Physiological function requires metabolism, which means that each neural cell has its own metabolic needs, but has to function interactively and in concert with all other cells with which it comes in contact. Metabolic function occurs within the mitochondria located within the cell body or soma of the neural cell, dependent on the delivery of oxygen, glucose, and other nutrients from the blood supply. Accordingly, the dynamics of neural cell metabolism and regulation, including autoregulation is as complex as synaptic functioning and connectivity, for all 200–300 billion cells. This means vasculature development in speed and complexity parallels neural cell development. The orchestration of neural cell growth tied to the vascular supply and metabolic functioning is what literally gives life to a functioning neural network. Examining each of these neurodevelopmental feats – cell growth, vascularization, and metabolism – that occur in stages, furthermore means that with each stage, if a development error or adverse event occurs, it may alter the trajectory of development.

Neural cells and their components are infinitesimally small, measured in microns (micron = one‐millionth of a meter) to nanometers (nanometer = one billionth of a meter), depending on the structure. At the level of the synapse, neurons do not touch, where the synaptic cleft is measured in ångströms (Å = one ten‐billionth of a meter). The gap across the synaptic cleft is where neurotransmitters are released, allowing one cell to communicate with another. The myelin that coats the axon, which facilitates the speed of neural transmission, actually arises from a separate glial cell, the oligodendrocyte. Since fat is a major constituent of the myelin sheath that coats the axon, this represents the origin of brain “white matter” or WM classification. “Gray matter” or GM (non‐white) is where cell bodies are densely compacted. The microvasculature is so small and contained within both WM and GM, that it cannot be visualized by gross inspection of brain tissue at post‐mortem or with neuroimaging. Cipolla (2009) estimates that the total length of capillaries within the human brain, if laid end‐on‐end is approximately 400 miles. The co‐development of cerebral vasculature is equally important because neural cells have no capacity to store glucose or oxygen, and myelin development requires delivery of critical nutrients to build and maintain the fatty sheath that coats the axon for neural transmission. Since each brain cell is dependent on the oxygen and nutrient exchange that occurs within this capillary bed, any disruption in vascular development or intactness also implies disrupted cellular integrity.

The importance of the vasculature to supply glucose for brain development cannot be overstated. As pointed out by Steiner (2019, p. 8): “It has been estimated that during childhood the brain may account for up to 60% of the body basal energetic requirements.” Returning to Figure 3.1and the proportional development of the brain in relation to the fetal/infant body is information enough to implicate the enormous requirements for energy, more‐so than any other body part. The cellular processes combined with nutritional demands to meet the energy needs of the growing brain are complex, essential for healthy brain growth and age‐typical social brain development (Laffel, 1999; McKenna et al., 2015).

Prior to modern methods of brain imaging, the head circumference (HC) measurement was the only possible metric to directly assess head size development, indirectly allowing inferences about brain development. Essential for subtle skull displacement as the head passes through the birth canal, the fetal skull is soft, necessarily pliable because of hinge‐like sutures with corresponding incomplete bone coverings – the anterior and posterior fontanelles (“soft spots”). Brain growth stimulates skull expansion, both in‐utero and postnatally, that will not stop until brain volume reaches its apex. Accordingly, the HC chart as part of every pediatrician’s well‐baby checkup represents an indirect measure of brain development. However, this is only informative for first few years of life and provides no information about age‐mediated dynamic changes within the brain, only implied information about its overall size. HC findings in terms of social development are important in terms of certain perinatal disorders such as prematurity and birth injury as well as genetic conditions and nutritional deficiencies, but only as a coarse indicator of brain development. Importantly though, the expansion rate of HC from birth to 3 years of age has been shown to be a modest predictor related to intellectual development (Flensborg‐Madsen et al., 2020), which has implications related to health care and nutritional and socioeconomic status, all of which play a role in the development of social behavior.

Historically, human developmental neuroscience research was entirely dependent on postmortem examination (Ernhart, 1991; Eskenazi et al., 1988; Towbin, 1978) and animal studies (Rakic, 1978). These early postmortem investigations often examined specific regions of interest (ROI) involving certain brain structures, often reporting size, type of cells, and cellular configurations, but such procedures were extremely time‐consuming, requiring meticulous dissection and effort (Blinkov & Glezer, 1968). Of course, since this was all postmortem, none of this could be related to social‐emotional functioning in the living child, unless an antemortem, anecdotal record had some information about social behavior. Despite these pre‐neuroimaging limitations, it was established that there were a minimum of four key features of brain growth that related to its size and assumed importance for social development: (1) myelination increased throughout childhood and adolescence, (2) changes in cellular density within GM occurred during development, which actually included apoptosis (see Figure 3.1) and pruning, (3) synaptic complexity increased along with neural connectivity, and (4) the development of integrated neural networks (Davison & Dobbing, 1966; Herschkowitz & Rossi, 1971).

The ability to study these four areas and their relevance to social brain development, all changed with the introduction of computed tomography (CT) in the early 1970s, followed by magnetic resonance (MR) a few years later. These neuroimaging technologies permitted in vivo assessment of brain structure, providing the first direct visualization and quantitative metrics to investigate brain development. The initial problem was that CT involved radiation exposure, so not a brain imaging method possible for normative, and especially longitudinal studies of children, brain, and social development. Nonetheless, CT rapidly became instrumental in identifying various aspects of brain pathology in pediatric neurological and neuropsychiatric disease and acquired injuries, which in turn, permitted the study of the developing brain in the living child who had a change in social behavior (Bigler et al., 2013; Yeates et al., 2007). With CT, the first in vivo studies emerged showing how acquired lesions, especially from trauma, altered social‐emotional functioning in children (Bigler, 1999). Now with contemporary neuroimaging methods this approach to studying damage to the social brain network has become commonplace as reviewed by Ryan et al. (2021).