Eva H. Telzer

Amygdala and Ventrolateral Prefrontal Cortex Activation to Masked Angry Faces in Children and Adolescents with Generalized Anxiety Disorder

CONTEXT Vigilance for threat is a key feature of generalized anxiety disorder (GAD). The amygdala and the ventrolateral prefrontal cortex constitute a neural circuit that is responsible for detection of threats. Disturbed interactions between these structures may underlie pediatric anxiety. To date, no study has selectively examined responses to briefly presented threats in GAD or in pediatric anxiety. OBJECTIVE To investigate amygdala and ventrolateral prefrontal cortex activation during processing of briefly presented threats in pediatric GAD. DESIGN Case-control study. SETTING Government clinical research institute. PARTICIPANTS Youth volunteers, 17 with GAD and 12 without a psychiatric diagnosis. MAIN OUTCOME MEASURES We used functional magnetic resonance imaging to measure blood oxygenation level-dependent signal. During imaging, subjects performed an attention-orienting task with rapidly presented (17 milliseconds) masked emotional (angry or happy) and neutral faces. RESULTS When viewing masked angry faces, youth with GAD relative to comparison subjects showed greater right amygdala activation that positively correlated with anxiety disorder severity. Moreover, in a functional connectivity (psychophysiological interaction) analysis, the right amygdala and the right ventrolateral prefrontal cortex showed strong negative coupling specifically to masked angry faces. This negative coupling tended to be weaker in youth with GAD than in comparison subjects. CONCLUSIONS Youth with GAD have hyperactivation of the amygdala to briefly presented masked threats. The presence of threat-related negative connectivity between the right ventrolateral prefrontal cortex and the amygdala suggests that the prefrontal cortex modulates the amygdala response to threat. In pediatric GAD, amygdala hyperresponse occurs in the absence of a compensatory increase in modulation by the ventrolateral prefrontal cortex.

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.

Expanding the Acculturation Gap-Distress Model: An Integrative Review of Research.

The acculturation gap-distress model purports that immigrant children acculturate to their new culture at a quicker pace than their parents, leading to family conflict and youth maladjustment. This article reviews literature on the acculturation gap-distress model, showing that acculturation gaps function in unique ways depending on many social and contextual variables. In contrast to the original model, which only discusses 1 type of acculturation gap, there are at least 4 types of acculturation gaps: (1) the child is more acculturated than the parent in the host culture, (2) the child is less acculturated than the parent in the host culture, (3) the child is more acculturated than the parent in the native culture, and (4) the child is less acculturated than the parent in the native culture. A review of research indicates that each of these types of gaps function in unique ways.

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.

A Preliminary Study of Daily Interpersonal Stress and C-Reactive Protein Levels Among Adolescents From Latin American and European Backgrounds

Objective: To examine the association between the experience of daily interpersonal stress and levels of C-reactive protein (CRP), an inflammatory marker that is a key indicator of cardiovascular risk, during the teenage years. Methods: A total of 69 adolescents (Mage= 17.78 years) completed daily diary checklists each night for 14 days in which they reported their experience of negative interpersonal interactions in the domains of family, peers, and school (e.g., conflict with family and friends, peer harassment, punishment by parents and teachers). Blood samples were obtained an average of 8.63 months later and assayed for circulating levels of CRP, using enzyme-linked immunosorbent assay. Measures of body mass index (BMI), socioeconomic status (SES), substance use, stressful life events, rejection sensitivity, and psychological distress were obtained. Results: A greater frequency of daily interpersonal stress was associated with higher levels of CRP, even after controlling for BMI, SES, substance use, life events, rejection sensitivity, psychological distress, and frequency of daily interpersonal stress 2 years earlier. Conclusions: Experiencing a high frequency of interpersonal stressors that are typical of adolescent life is associated with higher levels of inflammation even among a normative, healthy sample of adolescents. Additional work should focus on other daily experiences during the adolescent period and their implications for elevated risk for later cardiovascular disease. BMI = body mass index; CRP = C-reactive protein; CVD = cardiovascular disease.

Time spent with friends in adolescence relates to less neural sensitivity to later peer rejection

Involvement with friends carries many advantages for adolescents, including protection from the detrimental effects of being rejected by peers. However, little is known about the mechanisms through which friendships may serve their protective role at this age, or the potential benefit of these friendships as adolescents transition to adulthood. As such, this investigation tested whether friend involvement during adolescence related to less neural sensitivity to social threats during young adulthood. Twenty-one adolescents reported the amount of time they spent with friends outside of school using a daily diary. Two years later they underwent an fMRI scan, during which they were ostensibly excluded from an online ball-tossing game by two same-age peers. Findings from region of interest and whole brain analyses revealed that spending more time with friends during adolescence related to less activity in the dorsal anterior cingulate cortex and anterior insula--regions previously linked with negative affect and pain processing--during an experience of peer rejection 2 years later. These findings are consistent with the notion that positive relationships during adolescence may relate to individuals being less sensitive to negative social experiences later on.

The effects of poor quality sleep on brain function and risk taking in adolescence.

Insufficient sleep and poor quality sleep are pervasive during adolescence and relate to impairments in cognitive control and increased risk taking. However, the neurobiology underlying the association between sleep and adolescent behavior remains elusive. In the current study, we examine how poor sleep quality relates to cognitive control and reward related brain function during risk taking. Forty-six adolescents participated in a functional magnetic imaging (fMRI) scan during which they completed a cognitive control and risk taking task. Behaviorally, adolescents who reported poorer sleep also exhibited greater risk-taking. This association was paralleled by less recruitment of the dorsolateral prefrontal cortex (DLPFC) during cognitive control, greater insula activation during reward processing, and reduced functional coupling between the DLPFC and affective regions including the insula and ventral striatum during reward processing. Collectively, these results suggest that poor sleep may exaggerate the normative imbalance between affective and cognitive control systems, leading to greater risk-taking in adolescents.

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.