with specific reference to the prefrontal cortex (PFC) (Reproduced with permission from Chini and Hanganu‐Opatz, 2021). Cortical brain development is initially guided by molecular cues, whose importance declines with age, while the relevance of electrical activity, as a reflection of brain connectivity increases throughout development. Abbreviation: GW, gestational week.
Reproduced with permission from Elsevier.
Once the ovum is fertilized and cells begin to congregate, the neural plate forms, which in turn, folds to become the neural tube, the process referred to as neurulation. This, in turn sets the stage for rapid proliferation of cells and neurogenesis. The folding of the neural tube is essential for dividing the brain into two halves. The brain is a symmetric organ, from the brainstem to the cerebral hemispheres, with two sides that parallel one another – a left and right. So, the early neurulation that occurs is an essential process in generating two halves of the brain, which in turn controls and integrates the two sides of the body. By gestational week ~5, the appearance of what will become a recognizable head and brain has occurred (see Figure 3.1). Nine months later, a fully formed brain.
Proportionally, from its embryonic, in‐utero start, head and brain constitute the largest body parts for growth. Nonetheless, this fetal head growth must be kept small enough to pass through the birth canal to limit injury (Towbin, 1978). The astonishing initial in‐utero growth of the brain is followed by an equally rapid post‐natal growth as shown in Figure 3.2, which also introduces magnetic resonance imaging (MRI) of the developing brain (Gilmore et al., 2018). Since the scan images in Figure 3.2 are in proportion to actual size in reference to the adult scan on the right, rapid expansion of the brain is evident.
However, it is not just expansion in size, but an incredible matrix of dynamic, maturational, cellular processes that interconnect and become functionally active that form the social brain in the first 25 years of life.
Figure 3.2 Maturation of the “baby connectome”: examples of brain networks at three different ages. (a) Anatomic MRI images (3T, T2‐weighted) (b) Tractograms reconstructed based on diffusion tensor imaging (DTI) data. (c) Brain networks represented as weighted graphs. The size of the nodes is proportional to the node degree. The edge weights are proportional to the streamline count. (From Tymofiyeva et al., 2013).
Reproduced under the Creative Commons Attribution License, PLoS ONE.
Brain Development by the Numbers
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 3.1 and 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).
The Developing Brain and Neuroimaging
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
