Summary We all experience a host of common life stressors such as the death of a family member, medical illness, and financial uncertainty. While most of us are resilient to such stressors, continuing to function normally, for a subset of individuals, experiencing these stressors increases the likelihood of developing treatment-resistant, chronic psychological problems, including depression and anxiety. It is thus paramount to identify predictive markers of risk, particularly those reflecting fundamental biological processes that can be targets for intervention and prevention. Using data from a longitudinal study of 340 healthy young adults, we demonstrate that individual differences in threat-related amygdala reactivity predict psychological vulnerability to life stress occurring as much as 1 to 4 years later. These results highlight a readily assayed biomarker, threat-related amygdala reactivity, which predicts psychological vulnerability to commonly experienced stressors and represents a discrete target for intervention and prevention.

The uncinate fasciculus is a major white matter tract that provides a crucial link between areas of the human brain that underlie emotion processing and regulation. Specifically, the uncinate fasciculus is the major direct fiber tract that connects the prefrontal cortex and the amygdala. The aim of the present study was to use a multi-modal imaging approach in order to simultaneously examine the relation between structural connectivity of the uncinate fasciculus and functional activation of the amygdala in a youth sample (children and adolescents). Participants were 9 to 19 years old and underwent diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI). Results indicate that greater structural connectivity of the uncinate fasciculus predicts reduced amygdala activation to sad and happy faces. This effect is moderated by age, with younger participants exhibiting a stronger relation. Further, decreased amygdala activation to sad faces predicts lower internalizing symptoms. These results provide important insights into brain structure-function relationships during adolescence, and suggest that greater structural connectivity of the uncinate fasciculus may facilitate regulation of the amygdala, particularly during early adolescence. These findings also have implications for understanding the relation between brain structure, function, and the development of emotion regulation difficulties, such as internalizing symptoms.

Objective Though heightened amygdala reactivity is observed in patients with major depression, two critical gaps in our knowledge remain. First, it is unclear whether heightened amygdala reactivity is a premorbid vulnerability or consequence of the disorder. Second, it is unknown how and when this neural phenotype develops. The objective of this study was to address these gaps by evaluating developmental change in threat-related amygdala reactivity in adolescents at high or low risk for depression based on family history, before the onset of disorder. Method Adolescents (initially aged 11–15 years) completed an fMRI paradigm that elicited threat-related amygdala reactivity at baseline and again 2 years later. After quality control, data from 232 adolescents at Wave 1 and 197 adolescents at Wave 2 were available. Longitudinal data (meeting quality control at both waves) were available for 157 of these participants. Change in amygdala reactivity was assessed as a function of family history of depression and stressful life event severity. Results Threat-related amygdala reactivity increased with age in those with a positive family history regardless of the severity of life stress reported, and in adolescents with a negative family history when they reported relatively severe life stress. Critically, these changes in amygdala reactivity with age occurred in the absence of clinical disorder or increases in depressive symptoms. Conclusions These results suggest that heightened amygdala reactivity emerges during adolescence prior to the development of depression as a function of familial risk or, in the absence of familial risk, stressful life events.

Objective Amygdala habituation, the rapid decrease in amygdala responsiveness to repeated presentation of stimuli, is fundamental to the nervous system. Habituation is important for maintaining adaptive levels of arousal to predictable social stimuli and reduced habituation is associated with heightened anxiety. Input from the ventromedial prefrontal cortex (vmPFC) regulates amygdala activity. Although previous research demonstrated abnormal amygdala function in youth with autism spectrum disorders (ASD), no study had examined amygdala habituation in a young sample or whether habituation related to amygdala connectivity with the vmPFC. Method Data were analyzed from 32 children and adolescents with ASD and 56 typically developing controls who underwent functional magnetic resonance imaging (fMRI) scanning while performing a gender identification task for faces that were fearful, happy, sad, or neutral. Habituation was tested by comparing amygdala activation to faces during the first half versus the second half of the session. VmPFC–amygdala connectivity was examined through psychophysiological interaction analysis. Results Youth with ASD had decreased amygdala habituation to sad and neutral faces relative to controls. Moreover, reduced amygdala habituation correlated with autism severity as measured by the Social Responsiveness Scale. There was a group difference in vmPFC–amygdala connectivity while viewing sad faces, and connectivity predicted amygdala habituation to sad faces within controls. Conclusions Sustained amygdala activation to faces suggests that repeated faces are processed differently in individuals with ASD, which could contribute to social impairments. Abnormal modulation of the amygdala by the vmPFC may play a role in reduced habituation.