Biological Basis of Emotions: Brain Systems and Brain Development

DEVELOPMENTAL PATTERNS OF CEREBRAL GLUCOSE METABOLISM

The pattern of glucose metabolism in the newborn brain is fairly consistent (Fig 1), with the highest degree of activity in primary sensory and motor cortex, thalamus, brainstem, and cerebellar vermis.^2–4 The cingulate cortex, amygdala, hippocampus, and, occasionally, the basal ganglia also may show a relatively high glucose metabolism compared with most of the cerebral cortex in the newborn period.⁵ The relatively low functional activity over most of the cerebral cortex during the neonatal period is in keeping with the relatively limited behavioral repertoire of newborns, characterized by the presence of intrinsic brainstem reflexes and limited visuomotor integration.^6,,7However, the relatively high metabolic activity of amygdala and cingulate cortex in newborn suggests an important role of these limbic structures in neonatal interactions and, possibly, in emotional development.

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Fig. 1.

Newborn pattern of cerebral glucose metabolism. At this stage of development, glucose metabolism is most apparent in the sensorimotor cortex (a), cingulate cortex (b), thalamus (c), basal ganglia (d), brainstem (e), medial temporal region (f), and cerebellar vermis (g). Metabolic activity is low in most of the frontal, parietal, temporal, and occipital cortex, as well as in the cerebellar cortex.

Increases of glucose utilization are seen by 2 to 3 months in the parietal, temporal, and primary visual cortex, basal ganglia, and cerebellar hemispheres (Fig 2). These changes in glucose metabolism coincide with improved skills involving visuospatial and visuosensorimotor integration, the disappearance or reorganization of brainstem reflex neonatal behaviors, and evidence of increasing cortical contribution to the electroencephalogram.^6,8–10

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Fig. 2.

Pattern of cerebral metabolism in a 3-month-old infant. Glucose metabolism has increased in the parietal cortex (a), occipital cortex (b), temporal cortex (c), basal ganglia (d), and cerebellar hemisphere (e). Metabolic activity remains low in the frontal cortex (f).

The frontal cortex is the last brain area to display an increase in glucose consumption. Starting between 6 and 8 months, lateral and inferior portions of frontal cortex become more functionally active (Fig 3) and eventually, between 8 and 12 months, the dorsal and medial frontal regions also show increased glucose utilization. These changes of frontal cortex metabolism come at a time when cognitively related behaviors, such as the phenomenon of stranger anxiety and improved performance on the delayed response task, begin to appear.^11–13 Increased glucose requirement in frontal cortex also coincides with the expansion of dendritic fields and the increased capillary density observed in frontal cortex during the same period of development.^14,,15 By ∼1 year of age, the infant's pattern of glucose utilization resembles qualitatively that of the adult.

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Fig. 3.

Pattern of cerebral metabolism in an 8-month-old infant. Glucose metabolism has increased in the lateral portion of the frontal cortex (a) prior to the medial portion (b).

From these observations, it appears that in the first year of life, the ontogeny of glucose metabolism follows a phylogenetic order, with functional maturation of older anatomic structures preceding that of newer areas.^2–4 In addition, the suggestion by Kennedy and colleagues that “at any given developmental age, structures having metabolic rates equal to or exceeding their mature levels are those that dominate the behavior at that age” appears to be the case in human infant development because there is at least a general relationship between the maturational sequence of regional glucose metabolism and the behavioral maturation of the infant.¹⁶

GLUCOSE METABOLIC RATES

An important aspect of the PET technique is that it allows for the quantitative measurement of biochemical and physiologic processes. Thus, although the brain of a 1-year-old infant shows a similar distribution pattern of glucose utilization as that of an adult, the rate at which glucose is being used by various brain regions is different. In fact, a dynamic, protracted, and nonlinear process of metabolic maturation is apparent at birth and lasts until early adulthood (16 to 18 years).

Birth to 4 Years

At birth, the regional or local cerebral metabolic rates of glucose utilization (LCMRglc) are ∼30% lower than those seen in normal healthy young adults (Fig 4). Between birth and ∼3 to 4 years, the cerebral cortex shows a dramatic increase in LCMRglc to reach levels that exceed adult rates by greater than twofold (Fig 4, A, B). Such changes in LCMRglc are not observed in brainstem (Fig 4, C), but a less dramatic increase is seen in the basal ganglia and thalamus (Fig 4, D).

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Fig. 4.

Absolute values of LCMRglc for various brain regions versus age in normal infants, children, and young adults. A, Cerebral cortex (lobes); B, selected cortical regions; C, brainstem and cerebellum; and D, basal ganglia and thalamus.

REGRESSIVE PHENOMENA IN DEVELOPMENT

Since the initial description of the ontogeny of cerebral glucose metabolism in children, the relevance of these dynamic changes has been under active investigation.³ For more than half a century, it has been recognized that the brain of an immature rat consumes more oxygen and glucose than an adult rat brain.^18,,19 For example, the utilization of both oxygen and glucose in excised rat cerebral cortex, striatum, cerebellum, and brainstem was shown to be higher during the period between the 4th and 7th postnatal weeks compared with adult values.¹⁹ Studies performed in other species using either in vivo autoradiography or PET have confirmed the presence of a developmental period during which local cerebral energy demand, as measured by local cerebral blood flow, and, more directly, LCMRglc, exceeds that of the adult.^20–22

The ontogeny of cerebral glucose metabolism described in Figure 4 is not surprising, considering the fact that regressive phenomena are not uncommonly seen during development of the nervous system.^23–25 Thus, there are periods during development when neurons, neuronal processes, synaptic contacts, neurotransmitters, and various receptors are in excess of those seen in the adult. The proliferation and overproduction of neurons in humans occur prenatally, whereas programmed cell death (apoptosis) begins prenatally and continues until approximately the second postnatal year.²⁶Surviving neurons undergo a similar phenomenon postnatally, characterized by overproduction of their arborization and synaptic contacts, followed by an elimination or “pruning” phase.^27–29 Synaptic elimination in humans probably continues well into adolescence; for example, synaptic density in frontal cortex of children to 11 years of age has been shown to exceed that in adults.²⁷

Synaptic pruning is not a random phenomenon, but rather is based on activity-dependent stabilization. In other words, repeated neuronal activity involving certain circuits during a critical period will result in stabilization of those circuits rather than in elimination during the pruning process.³⁰ The advantage of activity-dependent stabilization of neuronal pathways is that there will not be an unnecessary expenditure of genes to code precisely for the large number of connections in the brain. Rather, repeated early environmental exposure will serve to guide the molding of an optimum cortical cytoarchitecture for the individual's future needs. The molecular basis for the stabilization and retention of some pathways and vulnerability of others to be pruned or eliminated is an area of intense investigation. Recent studies have suggested that in the visual cortex of kittens, activity-dependent stabilization may involve activation of the N-methyl-d-aspartate subclass of glutamate receptors, associated perhaps with the expression of specific neuronal proteins.^31,,32

NEUROBIOLOGICAL CORRELATES OF GLUCOSE METABOLISM ONTOGENY

CLINICAL IMPLICATIONS OF GLUCOSE METABOLISM ONTOGENY

The ontogeny of cerebral glucose metabolism appears to have profound implications in the study of human brain development, plasticity, and, possibly, child psychopathology. A central hypothesis in our laboratory is that at ∼10 years, when LCMRglc in cerebral cortex begins to decline (Fig 4), developmental brain plasticity also begins to diminish in children. There is much support for this hypothesis in the clinical literature, only some of which will be reviewed below.

Children who have been deprived of exposure to language since birth, as, for example, those raised in the wilderness (so-called feral children), can still acquire reasonably normal language skills but only if intense speech and language therapy is introduced before the age of 10 years.⁵⁰ After damage to the language-dominant hemisphere, there is better recovery of language skills if the injury occurs before ∼8 to 10 years than if the injury occurs later.^51,,52 In fact, based on an extensive review of this subject, Lenneberg postulated that there must be a “critical period for language acquisition” ending at approximately the age of 10 years, after which there is a more limited (but not absent) potential to acquire language skills.⁵³

Analyses in the human visual system also have suggested a similar timing of diminished plasticity in children. A number of studies have evaluated the upper age limit beyond which stimulus deprivation of one eye in young children, caused by monocular occlusion such as a cataract or certain kinds of strabismus, will induce an irreversible reduction of visual acuity known as amblyopia.⁵⁴ Two large clinical surveys have found that amblyopia can be prevented from occurring if the monocular occlusion is corrected before ∼8 to 10 years of age, but not after.^55,,56 In addition, the compromise in visual depth perception induced by unilateral enucleation (eg, for orbital tumors) can be minimized if enucleation is performed before ∼8 years of age.⁵⁷

The notion of an extended period during childhood when activity-dependent synaptic stabilization occurs has received considerable attention recently by those individuals and organizations dealing with early intervention to provide “environmental enrichment” and with the optimal design of educational curricula. Thus, it now is believed by many (including this author) that a biological “window of opportunity” when learning is efficient and easily retained is perhaps not fully exploited by our educational system.

Finally, there are investigators who believe that the onset of some forms of psychopathology may be related to various segments of the synaptogenesis curve. For example, Feinberg and colleagues have noted that the maturational curves for LCMRglc, synaptogenesis, and δ wave amplitude during sleep in children are similar and can be described best with a γ distribution model.⁵⁸ The proposal is made that because the early symptoms of schizophrenia occur at early adolescence when the maturational curves begin their downslope, errors in synaptic pruning localized to certain areas of the brain (eg, frontal cortex) may play an important role in the pathophysiology of this disorder.