The developing amygdala: a student of the world and a teacher of the cortex

Although the amygdala’s role in shaping social behavior is especially important during early post-natal development, very little is known of human amygdala functional development before childhood. To address this important gap, this study used resting-state fMRI to examine early functional network development of the amygdala and its subregions in 80 participants from 3-months to 5-years of age. Whole brain functional connectivity with the whole amygdala and its laterobasal and superficial nuclear groups were largely similar to those seen in older children and adults, and functional distinctions between subregion networks exist already. These patterns suggest many amygdala functional circuits are intact from infancy, especially those that are part of larger motor, visual, auditory and subcortical (basal ganglia especially) networks. Notably, these observed robust amygdala functional networks in infancy precede reports to date of elicited amygdala reactivity in development. Developmental changes in connectivity were observed between the laterobasal nucleus and bilateral ventral temporal and motor cortex as well as between the superficial nuclei and medial thalamus, occipital cortex and a different region of motor cortex. These results show amygdala-subcortical and sensory-cortex connectivity begins refinement prior to childhood, though connectivity changes with associative and frontal cortical areas, seen after early childhood, were not evident in this age range. These findings represent early steps in understanding amygdala network dynamics across infancy through early childhood, an important period of emotional and cognitive development.

An outstanding issue in our understanding of human brain development is whether sensitive periods exist for higher-order processes (e.g., emotion regulation) that depend on the prefrontal cortex. Evidence from rodent models suggests that there is a sensitive period before puberty when acoustic stimuli, like music, shape medial prefrontal cortex (mPFC) responses that regulate affect in the context of acute stress in adulthood. The present study examined whether a homologous sensitive period for the mPFC occurs during human childhood. In the context of acute stress, adult behavioral preferences were observed only for music experienced during childhood, not preschool or adolescent periods. Childhood music increased mPFC activation and modulated connectivity with the amygdala, which was associated with enhanced emotion regulation and lowered autonomic arousal. Moreover, the timing of this sensitive period could be moved by early-life stress. These findings indicate that childhood is a sensitive period for mPFC encoding of regulatory stimuli.Sensitive periods are developmental moments of heightened neuroplasticity when experiences shape brain function and behavior with lasting effects (1). They are fundamental to human cortical ontogeny, and yet, the timing and nature of sensitive periods for human prefrontal cortex functions remain unknown (2–8). In the rodent, Yang and colleagues have shown that the medial prefrontal cortex (mPFC) exhibits a sensitive period during the prepubertal juvenile period, with heightened responsivity to complex auditory stimuli (i.e., music) (9). Specifically, initial exposure to music during the open (juvenile) sensitive period or a pharmacologically re-opened sensitive period in adulthood was followed by that music uniquely producing a behavioral preference in adulthood, increasing mPFC activity, and reducing anxiety-like behavior. This finding and others converging on the same prepubertal period of plasticity in the rodent (9, 10) may have important implications for human development; the complementary prepubertal period in humans (i.e., school-age childhood) also exhibits developmentally-unique mPFC circuitry phenotypes (11–17) that make childhood a strong candidate for a human mPFC sensitive period. Here, we used Billboard music chart data to identify age-specific exposures to pop songs to test whether music shapes human mPFC responses during a childhood sensitive period as in the rodent. To parallel the approach used in the rodent, we examined whether (i) music experienced during childhood uniquely produced a behavioral preference under stress, (ii) childhood music enhanced emotion regulation behaviorally and physiologically, (iii) mPFC activity was enhanced by childhood music, and mPFC circuitry mediated emotion regulation benefits of childhood music, and (iv) whether the timing of this putative sensitive period could be shifted by early adversity.

30Total amygdala volumes continue to increase from childhood to young adulthood. 31Interestingly, postmortem studies have found postnatal neuron numbers increase in a nuclei 32 specific fashion across development, suggesting amygdala maturation may involve changes to 33 its composition. Thus, the goal of this study was to examine amygdala subregion apportionment 34 in vivo and examine if these patterns were associated with age, sex, body mass index (BMI), and 35 pubertal status in a large sample of typically developing adolescents (N=421, 44% female, ages 36 10-17 years). We utilized the CIT168 atlas to examine the relative volume fraction (RVF) of 9 37 subregions within each hemisphere of the amygdala. Generalized Additive Mixed Models 38 (GAMM) were used to assess how demographic variables (e.g. age, sex) and physical 39 development (e.g. BMI and pubertal status) were associated with amygdala RVFs. Results 40 showed that age associations varied significantly by sex for the RVFs of the lateral (LA), 41 basolateral ventral and paralaminar subdivision (BLVPL), central nucleus (CEN), and amygdala 42 transition areas (ATA). While pubertal development was found to be associated with RVFs in the 43 BLVPL, CEN, and ATA in males, best-fit model comparisons revealed that age was the best 44 predictor of relative volumes of these subregions. These results suggest that the relative 45 apportionment of the amygdala further develops with age in males across adolescence. These 46 findings may help elucidate how sex differences could impact the prevalence of mental health 47Significance Statement: Given the heterogeneity of cytoarchitecture, connectivity, and function 49 between amygdala subregions, naturally more research is needed to understand amygdala 50 composition across human adolescence. Our findings show that males, but not females, 51 demonstrate amygdala composition development across the adolescent years of 10 to 17. In 52 males, there is a relative expansion of the lateral and central subregions, but a contraction of the 53 basolateral ventral and paralaminar subdivision and amygdala transition areas within the 54 amygdala. Distinct maturation patterns of the amygdaloid complex across adolescence may be 55 an important mechanism contributing to sex differences in emotional processing as well as the 56 onset, prevalence, and symptomatology for affective disorders that typically emerge during this 57 developmental period. 58