Johnna R. Swartz

A Neural Biomarker of Psychological Vulnerability to Future Life Stress

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.

Developmental change in amygdala reactivity during adolescence: effects of family history of depression and stressful life events.

OBJECTIVE Although 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 a consequence of the disorder. Second, it is unknown how and when this neural phenotype develops. The authors sought 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 onset of disorder. METHOD At baseline and again 2 years later, adolescents (initially 11-15 years of age) participated in a functional MRI paradigm that elicited threat-related amygdala reactivity. After quality control, data were available for 232 adolescents at wave 1 and 197 adolescents at wave 2; 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 severity of stressful life events. RESULTS Threat-related amygdala reactivity increased with age in participants with a positive family history regardless of the severity of life stress reported, and it increased in adolescents with a negative family history who reported relatively severe life stress. 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.

An epigenetic mechanism links socioeconomic status to changes in depression-related brain function in high-risk adolescents

Identifying biological mechanisms through which the experience of adversity emerges as individual risk for mental illness is an important step toward developing strategies for personalized treatment and, ultimately, prevention. Preclinical studies have identified epigenetic modification of gene expression as one such mechanism. Recent clinical studies have suggested that epigenetic modification, particularly methylation of gene regulatory regions, also acts to shape human brain function associated with risk for mental illness. However, it is not yet clear whether differential gene methylation as a function of adversity contributes to the emergence of individual risk for mental illness. Using prospective longitudinal epigenetic, neuroimaging and behavioral data from 132 adolescents, we demonstrate that changes in gene methylation associated with lower socioeconomic status (SES) predict changes in risk-related brain function. Specifically, we find that lower SES during adolescence is associated with an increase in methylation of the proximal promoter of the serotonin transporter gene, which predicts greater increases in threat-related amygdala reactivity. We subsequently demonstrate that greater increases in amygdala reactivity moderate the association between a positive family history for depression and the later manifestation of depressive symptoms. These initial results suggest a specific biological mechanism through which adversity contributes to altered brain function, which in turn moderates the emergence of general liability as individual risk for mental illness. If replicated, this prospective pathway may represent a novel target biomarker for intervention and prevention among high-risk individuals.

A Common Polymorphism in a Williams Syndrome Gene Predicts Amygdala Reactivity and Extraversion in Healthy Adults

BACKGROUND Williams syndrome (WS), a genetic disorder resulting from hemizygous microdeletion of chromosome 7q11.23, has emerged as a model for identifying the genetic architecture of socioemotional behavior. Common polymorphisms in GTF2I, which is found within the WS microdeletion, have been associated with reduced social anxiety in the general population. Identifying neural phenotypes affected by these polymorphisms would help advance our understanding not only of this specific genetic association but also of the broader neurogenetic mechanisms of variability in socioemotional behavior. METHODS Through an ongoing parent protocol, the Duke Neurogenetics Study, we measured threat-related amygdala reactivity to fearful and angry facial expressions using functional magnetic resonance imaging, assessed trait personality using the Revised NEO Personality Inventory, and imputed GTF2I rs13227433 from saliva-derived DNA using custom Illumina arrays. Participants included 808 non-Hispanic Caucasian, African American, and Asian university students. RESULTS The GTF2I rs13227433 AA genotype, previously associated with lower social anxiety, predicted decreased threat-related amygdala reactivity. An indirect effect of GTF2I genotype on the warmth facet of extraversion was mediated by decreased threat-related amygdala reactivity in women but not men. CONCLUSIONS A common polymorphism in the WS gene GTF2I associated with reduced social anxiety predicts decreased threat-related amygdala reactivity, which mediates an association between genotype and increased warmth in women. These results are consistent with reduced threat-related amygdala reactivity in WS and suggest that common variation in GTF2I contributes to broader variability in socioemotional brain function and behavior, with implications for understanding the neurogenetic bases of WS as well as social anxiety.

Thinking and Feeling Individual Differences in Habitual Emotion Regulation and Stress-Related Mood Are Associated With Prefrontal Executive Control

Calculating math problems from memory may seem unrelated to everyday processing of emotions, but they have more in common than one might think. Prior research highlights the importance of the dorsolateral prefrontal cortex (dlPFC) in executive control, intentional emotion regulation, and experience of dysfunctional mood and anxiety. Although it has been hypothesized that emotion regulation may be related to “cold” (i.e., not emotion-related) executive control, this assertion has not been tested. We address this gap by providing evidence that greater dlPFC activity during cold executive control is associated with increased use of cognitive reappraisal to regulate emotions in everyday life. We then demonstrate that in the presence of increased life stress, increased dlPFC activity is associated with lower mood and anxiety symptoms and clinical diagnoses. Collectively, our results encourage ongoing efforts to understand prefrontal executive control as a possible intervention target for improving emotion regulation in mood and anxiety disorders.

A Functional Interleukin-18 Haplotype Predicts Depression and Anxiety through Increased Threat-Related Amygdala Reactivity in Women but Not Men

Common functional polymorphisms in the gene encoding interleukin-18 (IL18), a cytokine belonging to the IL-1 superfamily that can induce synthesis of several other cytokines, have been associated with major depressive episodes following the experience of stressful life events. The neural mechanisms underlying these associations remain unexamined. Here we use an imaging genetics strategy to examine the effects of risk-related IL18 haplotypes comprising rs187238 and rs1946518 on threat-related amygdala reactivity and, through an indirect effect, stress-related symptoms of depression and anxiety in 448 non-Hispanic Caucasian university students. Analyses indicated that women but not men possessing an IL18 haplotype comprising both risk-related alleles evidenced increased threat-related left centromedial amygdala reactivity relative to other haplotype groups. Moreover, in women only, increased threat-related left centromedial amygdala reactivity predicted increased symptoms of depression and anxiety in individuals also reporting higher levels of life stress. Path analyses revealed a significant indirect effect of IL18 risk haplotype on symptoms of depression and anxiety through increased threat-related amygdala reactivity. These results suggest that a common functional IL18 haplotype associated with heightened proinflammatory responses confers susceptibility to stress-related depression and anxiety through effects on threat-related amygdala function, a risk pathway specific to women. If replicated, these patterns can inform the search for personalized interventions targeting neurobiological pathways of risk associated with inflammation.

Threat-related amygdala activity is associated with peripheral CRP concentrations in men but not women

Increased levels of peripheral inflammatory markers, including C-Reactive Protein (CRP), are associated with increased risk for depression, anxiety, and suicidality. The brain mechanisms that may underlie the association between peripheral inflammation and internalizing problems remain to be determined. The present study examines associations between peripheral CRP concentrations and threat-related amygdala activity, a neural biomarker of depression and anxiety risk, in a sample of 172 young adult undergraduate students. Participants underwent functional MRI scanning while performing an emotional face matching task to obtain a measure of threat-related amygdala activity to angry and fearful faces; CRP concentrations were assayed from dried blood spots. Results indicated a significant interaction between CRP and sex: in men, but not women, higher CRP was associated with higher threat-related amygdala activity. These results add to the literature finding associations between systemic levels of inflammation and brain function and suggest that threat-related amygdala activity may serve as a potential pathway through which heightened chronic inflammation may increase risk for mood and anxiety problems.

Amygdala reactivity predicts adolescent antisocial behavior but not callous-unemotional traits

Highlights • Greater amygdala reactivity to angry faces predicted youth antisocial behavior.• Callous-unemotional traits were not related to amygdala reactivity.• Findings were similar across sex, ethnicity, and pubertal stage.

Peering into the brain to predict behavior: Peer-reported, but not self-reported, conscientiousness links threat-related amygdala activity to future problem drinking

Abstract Personality traits such as conscientiousness as self‐reported by individuals can help predict a range of outcomes, from job performance to longevity. Asking others to rate the personality of their acquaintances often provides even better predictive power than using self‐report. Here, we examine whether peer‐reported personality can provide a better link between brain function, namely threat‐related amygdala activity, and future health‐related behavior, namely problem drinking, than self‐reported personality. Using data from a sample of 377 young adult university students who were rated on five personality traits by peers, we find that higher threat‐related amygdala activity to fearful facial expressions is associated with higher peer‐reported, but not self‐reported, conscientiousness. Moreover, higher peer‐reported, but not self‐reported, conscientiousness predicts lower future problem drinking more than one year later, an effect specific to men. Remarkably, relatively higher amygdala activity has an indirect effect on future drinking behavior in men, linked by peer‐reported conscientiousness to lower future problem drinking. Our results provide initial evidence that the perceived conscientiousness of an individual by their peers uniquely reflects variability in a core neural mechanism supporting threat responsiveness. These novel patterns further suggest that incorporating peer‐reported measures of personality into individual differences research can reveal novel predictive pathways of risk and protection for problem behaviors. HighlightsNeural correlates of self‐ and peer‐reported personality are examined.Higher amygdala activity is associated with peer‐reported conscientiousness.Peer‐reported conscientiousness predicts lower future problem drinking in men.Peer report may reveal novel associations between brain, personality, and behavior.