Bonnie Goff

A Developmental Shift from Positive to Negative Connectivity in Human Amygdala–Prefrontal Circuitry

Recent human imaging and animal studies highlight the importance of frontoamygdala circuitry in the regulation of emotional behavior and its disruption in anxiety-related disorders. Although tracing studies have suggested changes in amygdala–cortical connectivity through the adolescent period in rodents, less is known about the reciprocal connections within this circuitry across human development, when these circuits are being fine-tuned and substantial changes in emotional control are observed. The present study examined developmental changes in amygdala–prefrontal circuitry across the ages of 4–22 years using task-based functional magnetic resonance imaging. Results suggest positive amygdala–prefrontal connectivity in early childhood that switches to negative functional connectivity during the transition to adolescence. Amygdala–medial prefrontal cortex functional connectivity was significantly positive (greater than zero) among participants younger than 10 years, whereas functional connectivity was significantly negative (less than zero) among participants 10 years and older, over and above the effect of amygdala reactivity. The developmental switch in functional connectivity was paralleled by a steady decline in amygdala reactivity. Moreover, the valence switch might explain age-related improvement in task performance and a developmentally normative decline in anxiety. Initial positive connectivity followed by a valence shift to negative connectivity provides a neurobiological basis for regulatory development and may present novel insight into a more general process of developing regulatory connections.

Early developmental emergence of human amygdala- prefrontal connectivity after maternal deprivation

Significance Early adversity has profound and lasting effects on neurodevelopment and emotional behavior. Under typical environmental conditions, prefrontal cortex connections with the amygdala are immature during childhood and become adult-like during adolescence. Rodent models show that maternal deprivation accelerates this development as an ontogenetic adaptation to adversity. Here, we demonstrate that, as in the rodent, children who experienced early maternal deprivation exhibit early emergence of mature amygdala–prefrontal connectivity. Evidence suggests that the adult-like neural phenotype, which is mediated by cortisol levels, confers some degree of enhanced emotion regulation, as maternally deprived youths with adult-like phenotypes are less anxious than their counterparts with immature phenotypes. Accelerated amygdala–prefrontal development may serve as an ontogenetic adaptation in the human in response to early adversity. Under typical conditions, medial prefrontal cortex (mPFC) connections with the amygdala are immature during childhood and become adult-like during adolescence. Rodent models show that maternal deprivation accelerates this development, prompting examination of human amygdala–mPFC phenotypes following maternal deprivation. Previously institutionalized youths, who experienced early maternal deprivation, exhibited atypical amygdala–mPFC connectivity. Specifically, unlike the immature connectivity (positive amygdala–mPFC coupling) of comparison children, children with a history of early adversity evidenced mature connectivity (negative amygdala–mPFC coupling) and thus, resembled the adolescent phenotype. This connectivity pattern was mediated by the hormone cortisol, suggesting that stress-induced modifications of the hypothalamic–pituitary–adrenal axis shape amygdala–mPFC circuitry. Despite being age-atypical, negative amygdala–mPFC coupling conferred some degree of reduced anxiety, although anxiety was still significantly higher in the previously institutionalized group. These findings suggest that accelerated amygdala–mPFC development is an ontogenetic adaptation in response to early adversity.

The development of human amygdala functional connectivity at rest from 4 to 23 years: A cross-sectional study

Functional connections (FC) between the amygdala and cortical and subcortical regions underlie a range of affective and cognitive processes. Despite the central role amygdala networks have in these functions, the normative developmental emergence of FC between the amygdala and the rest of the brain is still largely undefined. This study employed amygdala subregion maps and resting-state functional magnetic resonance imaging to characterize the typical development of human amygdala FC from age 4 to 23years old (n=58). Amygdala FC with subcortical and limbic regions was largely stable across this developmental period. However, three cortical regions exhibited age-dependent changes in FC: amygdala FC with the medial prefrontal cortex (mPFC) increased with age, amygdala FC with a region including the insula and superior temporal sulcus decreased with age, and amygdala FC with a region encompassing the parahippocampal gyrus and posterior cingulate also decreased with age. The transition from childhood to adolescence (around age 10years) marked an important change-point in the nature of amygdala-cortical FC. We distinguished unique developmental patterns of coupling for three amygdala subregions and found particularly robust convergence of FC for all subregions with the mPFC. These findings suggest that there are extensive changes in amygdala-cortical functional connectivity that emerge between childhood and adolescence.

Reduced nucleus accumbens reactivity and adolescent depression following early-life stress

Depression is a common outcome for those having experienced early-life stress (ELS). For those individuals, depression typically increases during adolescence and appears to endure into adulthood, suggesting alterations in the development of brain systems involved in depression. Developmentally, the nucleus accumbens (NAcc), a limbic structure associated with reward learning and motivation, typically undergoes dramatic functional change during adolescence; therefore, age-related changes in NAcc function may underlie increases in depression in adolescence following ELS. The current study examined the effects of ELS in 38 previously institutionalized children and adolescents in comparison to a group of 31 youths without a history of ELS. Consistent with previous research, the findings showed that depression was higher in adolescents than children with a history of ELS. Additionally, functional magnetic resonance imaging results showed atypical NAcc development, where the ELS group did not show a typical increase in NAcc reactivity during adolescence. Consequently, the ELS group showed NAcc hypoactivation during adolescence, and lower NAcc reactivity was correlated with higher depression scores. The results have important implications for understanding how ELS may influence increases in depression via neural development during the transition to adolescence and highlight the importance of identifying at-risk individuals in childhood, a potential critical period for depression-targeted intervention.

Maternal Buffering of Human Amygdala-Prefrontal Circuitry During Childhood but Not During Adolescence

Mature amygdala-prefrontal circuitry regulates affect in adulthood but shows protracted development. In altricial and semialtricial species, caregivers provide potent affect regulation when mature neurocircuitry is absent. The present investigation examined a potential mechanism through which caregivers provide regulatory influences in childhood. Children, but not adolescents, showed evidence of maternal buffering, such that maternal stimuli suppressed amygdala reactivity. In the absence of maternal stimuli, children exhibited immature amygdala-prefrontal connectivity. However, in the presence of maternal stimuli, children’s connectivity was more mature, resembling adolescents’ connectivity. Children showed improved affect-related regulation in the presence of their mothers. Individual differences emerged, with greater maternal influence on amygdala-prefrontal circuitry associated with stronger mother-child relationships and maternal modulation of behavioral regulation. These findings suggest a neural mechanism through which caregivers modulate children’s regulatory behavior by inducing more mature connectivity and buffering against heightened reactivity. Maternal buffering in childhood, but not adolescence, suggests that childhood may be a sensitive period for amygdala-prefrontal development.

A negativity bias for ambiguous facial-expression valence during childhood: converging evidence from behavior and facial corrugator muscle responses.

Interpretations of facial expressions with ambiguous valence, such as surprised (which can be perceived as having positive or negative valence), reveal individual differences in positivity-negativity biases. Negative interpretations are first and fast, but this initial negativity default can be overridden by regulatory control processes that result in positive interpretations. We tested the initial negativity hypothesis by examining positivity-negativity biases during development. We hypothesized that during childhood, the default negativity mode would be more evident than in adulthood and, as a group, children would show a negativity bias when processing ambiguous facial expressions. We examined ratings of two ambiguous expressions, surprised and neutral expressions, from childhood through adolescence and recorded facial corrugator muscle activity, a physiological index of negative appraisals. Surprised faces were rated as conveying clear negative affect by younger participants as indexed by fast RTs and negative ratings, and corrugator data showed a corresponding increase in activity to surprised faces. By adolescence, positive ratings of surprised faces became more frequent and RTs slowed, suggesting that surprised faces were perceived as having more ambiguous meaning. Accordingly, corrugator activity also decreased during adolescence. Neutral faces also produced negative ratings by children, but were also rated as conveying negative affect by older participants. Accordingly, neutral faces also elicited high corrugator activity that was similar to that elicited by negative expressions. These data show that early in life, ambiguous facial expressions are perceived as conveying negative meaning, adding support for an initial-negativity hypothesis.

Normative development of ventral striatal resting state connectivity in humans

Incentives play a crucial role in guiding behavior throughout our lives, but perhaps no more so than during the early years of life. The ventral striatum is a critical piece of an incentive-based learning circuit, sharing robust anatomical connections with subcortical (e.g., amygdala, hippocampus) and cortical structures (e.g., medial prefrontal cortex (mPFC), insula) that collectively support incentive valuation and learning. Resting-state functional connectivity (rsFC) is a powerful method that provides insight into the development of the functional architecture of these connections involved in incentive-based learning. We employed a seed-based correlation approach to investigate ventral striatal rsFC in a cross-sectional sample of typically developing individuals between the ages of 4.5 and 23-years old (n=66). Ventral striatal rsFC with the mPFC showed regionally specific linear age-related changes in connectivity that were associated with age-related increases in circulating testosterone levels. Further, ventral striatal connectivity with the posterior hippocampus and posterior insula demonstrated quadratic age-related changes characterized by negative connectivity in adolescence. Finally, across this age range, the ventral striatum demonstrated positive coupling with the amygdala beginning during childhood and remaining consistently positive across age. In sum, our findings suggest that normative ventral striatal rsFC development is dynamic and characterized by early establishment of connectivity with medial prefrontal and limbic structures supporting incentive-based learning, as well as substantial functional reorganization with later developing regions during transitions into and out of adolescence.

Exploration-exploitation strategy is dependent on early experience.

Traditional conceptualizations of early adversity characterize behavioral outcomes as maladaptive. However, conditional adaptation theory proposes that differing behavioral phenotypes following early experience are appropriate for the expected environment (e.g., behaviors likely to result in the best outcome based on environmental expectations). In the present study, youth with (n = 46) and without (n = 91) a history of previous institutionalization completed a laboratory-based experimental paradigm in which exploration-exploitation strategy was examined, a phenotype relevant to environmental expectations. Previous institutionalization was associated with decreased exploration and increased exploitation. A strategy favoring exploration resulted in greater success in the generous task condition whereas a strategy favoring exploitation produced greater success in the restricted task condition. These results suggest that exploration-exploitation strategy may be influenced by early experience, and the resulting success of strategy choice is context dependent and in line with expectations of the future environment based on early experience.

Previous Institutionalization Is Followed by Broader Amygdala-Hippocampal-PFC Network Connectivity during Aversive Learning in Human Development

Early institutional care can be profoundly stressful for the human infant, and, as such, can lead to significant alterations in brain development. In animal models, similar variants of early adversity have been shown to modify amygdala–hippocampal–prefrontal cortex development and associated aversive learning. The current study examined this rearing aberration in human development. Eighty-nine children and adolescents who were either previously institutionalized (PI youth; N = 46; 33 females and 13 males; age range, 7–16 years) or were raised by their biological parents from birth (N = 43; 22 females and 21 males; age range, 7–16 years) completed an aversive-learning paradigm while undergoing functional neuroimaging, wherein visual cues were paired with either an aversive sound (CS+) or no sound (CS−). For the PI youth, better aversive learning was associated with higher concurrent trait anxiety. Both groups showed robust learning and amygdala activation for CS+ versus CS− trials. However, PI youth also exhibited broader recruitment of several regions and increased hippocampal connectivity with prefrontal cortex. Stronger connectivity between the hippocampus and ventromedial PFC predicted significant improvements in future anxiety (measured 2 years later), and this was particularly true within the PI group. These results suggest that for humans as well as for other species, early adversity alters the neurobiology of aversive learning by engaging a broader prefrontal–subcortical circuit than same-aged peers. These differences are interpreted as ontogenetic adaptations and potential sources of resilience. SIGNIFICANCE STATEMENT Prior institutionalization is a significant form of early adversity. While nonhuman animal research suggests that early adversity alters aversive learning and associated neurocircuitry, no prior work has examined this in humans. Here, we show that youth who experienced prior institutionalization, but not comparison youth, recruit the hippocampus during aversive learning. Among youth who experienced prior institutionalization, individual differences in aversive learning were associated with worse current anxiety. However, connectivity between the hippocampus and prefrontal cortex prospectively predicted significant improvements in anxiety 2 years following scanning for previously institutionalized youth. Among youth who experienced prior institutionalization, age-atypical engagement of a distributed set of brain regions during aversive learning may serve a protective function.

Early Experience Shapes Amygdala Sensitivity to Race: An International Adoption Design

In the current study, we investigated how complete infant deprivation to out-group race impacts behavioral and neural sensitivity to race. Although monkey models have successfully achieved complete face deprivation in early life, this is typically impossible in human studies. We overcame this barrier by examining youths with exclusively homogenous racial experience in early postnatal development. These were youths raised in orphanage care in either East Asia or Eastern Europe as infants and later adopted by American families. The use of international adoption bolsters confidence of infant exposure to race (e.g., to solely Asian faces or European faces). Participants completed an emotional matching task during functional MRI. Our findings show that deprivation to other-race faces in infancy disrupts recognition of emotion and results in heightened amygdala response to out-group faces. Greater early deprivation (i.e., later age of adoption) is associated with greater biases to race. These data demonstrate how early social deprivation to race shapes amygdala function later in life and provides support that early postnatal development may represent a sensitive period for race perception.