Cumulative lifetime stressor exposure impairs stimulus-response but not contextual learning.

Greater exposure to stressors over the life course is believed to promote striatum-dependent over hippocampus-dependent learning and memory processes under stressful conditions. However, little research in this context has actually assessed lifetime stressor exposure and, moreover, it remains unknown whether greater cumulative lifetime stressor exposure exerts comparable effects on striatum-dependent learning and hippocampus-dependent learning in non-stressful contexts. To investigate this issue, we used the Stress and Adversity Inventory for Adults (Adult STRAIN) and Multicued Search Task to investigate the relation between cumulative lifetime stressor exposure and striatum-dependent stimulus-response learning and hippocampus-dependent contextual learning under non-stressful conditions among healthcare professionals (N = 205; 157 females, 48 males; Age: M = 34.23, SD 9.3, range 20-59 years). Individuals with moderate, but not low, cumulative lifetime stressor exposure exhibited impaired learning for stimulus-response associations. In contrast, learning for context associations was unrelated to participants' lifetime stressor exposure profiles. These results thus provide first evidence that cumulative lifetime stressor exposure may have negative consequences on human striatum-dependent stimulus-response learning under non-stressful environmental conditions.

Cumulative lifetime stressor exposure and health in elite athletes: the moderating role of perfectionism.

Although greater lifetime stressor exposure has been associated with physical and mental health issues in the general population, relatively little is known about how lifetime stressors impact the physical and mental health of elite athletes or the factors moderating this association. Given that many elite athletes show signs of perfectionism, and that this trait has been linked with ill-health, it is possible that perfectionism may moderate the lifetime stressor-health relationship. To test this possibility, we examined how cumulative lifetime stressor exposure was associated with general mental and physical health complaints in elite athletes, and the extent to which these associations were moderated by perfectionism. Participants were 110 elite athletes (64 female; M age = 29.98 years, SD = 10.54) who completed assessments of lifetime stressor exposure, physical health, psychological distress, and perfectionism. As hypothesised, hierarchical regression analyses revealed that experiencing more severe lifetime stressors was related to poorer physical and mental health. Furthermore, self-oriented perfectionism moderated the association between lifetime stressor count and severity and physical health, but not mental health. Overall, these data demonstrate stressor-specific effects among elite athletes and highlight the potential importance of assessing lifetime stressor exposure and perfectionistic tendencies in order to improve athlete health and well-being.

Lifetime stressor exposure is associated with greater rewarding effects of stress-related eating.

Acute stressors tend to shift preferences toward comfort foods, yet they do not ubiquitously increase the amount of food consumed. Moreover, although many individuals eat more under stress, others eat less or show no change. Although the precise mechanisms explaining this variability in stress-related eating are unknown, they may be driven by individual differences in the rewarding effects of comfort eating, which are enhanced by greater lifetime stressor exposure. To investigate this possibility, we examined whether differences in lifetime stressor exposure predicted reductions in negative affect following snacking (i.e., negative reinforcement) and if this effect was specific to stress-related snacking or snacking in general. Participants were 26 women (23% non-White) between 20 and 45 years old (M = 31), with a mean body mass index of 26, who completed three laboratory visits. Participants completed an assessment of lifetime stressor exposure (i.e., STRAIN) on the first visit and, on two subsequent laboratory visits in counterbalanced order, were given snacks after an acute social stress task (i.e., TSST) or rest period. Greater lifetime stressor exposure was related to greater post-ingestive decreases in negative affect following the acute social stressor but not following the rest period. If stress-related eating is more comforting for women with greater lifetime stressors and contributes to a stronger stress-eating association, then this may inform obesity-related clinical treatments that target behaviors and cognitions related to reward-based learning.

Impact of lifetime stressor exposure on neuroenergetics in schizophrenia spectrum disorders.

N-acetylasparate and lactate are two prominent brain metabolites closely related to mitochondrial functioning. Prior research revealing lower levels of NAA and higher levels of lactate in the cerebral cortex of patients with schizophrenia suggest possible abnormalities in the energy supply pathway necessary for brain function. Given that stress and adversity are a strong risk factor for a variety of mental health problems, including psychotic disorders, we investigated the hypothesis that stress contributes to abnormal neuroenergetics in patients with schizophrenia. To test this hypothesis, we used the Stress and Adversity Inventory (STRAIN) to comprehensively assess the lifetime stressor exposure profiles of 35 patients with schizophrenia spectrum disorders and 33 healthy controls who were also assessed with proton magnetic resonance spectroscopy at the anterior cingulate cortex using 3 Tesla scanner. Consistent with the hypothesis, greater lifetime stressor exposure was significantly associated with lower levels of N-acetylasparate (ß = -0.36, p = .005) and higher levels of lactate (ß = 0.43, p = .001). Moreover, these results were driven by patients, as these associations were significant for the patient but not control group. Though preliminary, these findings suggest a possible role for stress processes in the pathophysiology of abnormal neuroenergetics in schizophrenia.

The Stress Phenotyping Framework: A multidisciplinary biobehavioral approach for assessing and therapeutically targeting maladaptive stress physiology.

Although dysregulated stress biology is becoming increasingly recognized as a key driver of lifelong disparities in chronic disease, we presently have no validated biomarkers of toxic stress physiology; no biological, behavioral, or cognitive treatments specifically focused on normalizing toxic stress processes; and no agreed-upon guidelines for treating stress in the clinic or evaluating the efficacy of interventions that seek to reduce toxic stress and improve human functioning. We address these critical issues by (a) systematically describing key systems and mechanisms that are dysregulated by stress; (b) summarizing indicators, biomarkers, and instruments for assessing stress response systems; and (c) highlighting therapeutic approaches that can be used to normalize stress-related biopsychosocial functioning. We also present a novel multidisciplinary Stress Phenotyping Framework that can bring stress researchers and clinicians one step closer to realizing the goal of using precision medicine-based approaches to prevent and treat stress-associated health problems.

Human immune and metabolic biomarker levels, and stress-biomarker associations, differ by season: Implications for biomedical health research.

Although seasonal changes in physiology are well documented, little is known about how human immune and metabolic markers vary across seasons, and no studies have examined how stress → health biomarker associations differ across the year. To investigate these issues, we analyzed data from 2118 participants of the Midlife in the United States (MIDUS) study to determine whether there were differences in (a) levels of 19 immune and metabolic markers, and (b) the association between perceived stress and each biomarker across the year. Results of component-wide boosted generalized additive models revealed seasonal patterning for most biomarkers, with immune proteins generally peaking when days were shorter. Moreover, whereas levels of hemoglobin A1C rose from late fall to spring, triglycerides were elevated in the summer and fall, and high-density lipoprotein decreased steadily from January to December. Urinary cortisol and cortisone exhibited opposite patterns, peaking at the beginning and end of the year, respectively. Most critically, we found that the effects of perceived stress on 18 of the 19 health biomarkers assessed varied by month of measurement. In some cases, these differences involved the magnitude of the stress → biomarker association but, in other cases, it was the direction of the effect that changed. Studies that do not account for month of biomarker assessment may thus yield misleading or unreproducible results.

Caregiver Report of Children's Exposure to Adverse Life Events: Concordance Between Questionnaire and Interview Approaches.

Assessment practices for measuring adverse life events (ALEs) are often characterized by considerable variability, which is associated with inconsistency and reproducibility issues when conducting research on children with ALE exposure. One aspect of assessment variability for caregiver report of children's ALE history that has received minimal attention is assessment format. To address this issue, the current study evaluated concordance between two main ALE assessment formats: interviews and questionnaires. This involved examining overall endorsement of ALEs and concordance among multiple characteristics of ALE exposure, including type, polyvictimization, frequency, severity, and age of onset. Fifty-eight caregivers (Mage = 33.72; 60% Black; 55% below the federal poverty line) of preschool and school-age children were administered an ALE assessment in both a questionnaire and interview format across two sessions. The sum scores and concordance rates between format responses were compared based on ALE type, polyvictimization, frequency, severity, and age of onset of exposure. Results indicated that most total or sum scores were similar between formats, with the exception of ALE severity scores. However, there was most often low-to-moderate concordance across the 50 types of ALEs examined in the current study, suggesting that a different constellation of events comprised each sum or total score. This was also the case across all characteristics of the ALEs and most notably for the severity of ALE. Based on these findings, the format of assessment may be associated with inconsistent reporting of children's ALE exposure across multiple characteristics of ALE. Researchers may need to utilize multiple types of ALE assessments when relying on caregiver report of a child's ALEs.

Bullying fosters interpersonal distrust and degrades adolescent mental health as predicted by Social Safety Theory.

Social Safety Theory predicts that socially threatening experiences such as bullying degrade mental health partly by fostering the belief that others cannot be trusted. Here we tested this prediction by examining how peer bullying in childhood impacted adolescent mental health, and whether this effect was mediated by interpersonal distrust and several other commonly studied mediators-namely diet, sleep and physical activity-in 10,000 youth drawn from the UK's Millennium Cohort Study. Youth bullied in childhood developed more internalizing, externalizing and total mental health problems in late adolescence, and this effect was partially mediated by interpersonal distrust during middle adolescence. Indeed, adolescents who developed greater distrust were approximately 3.5 times more likely to subsequently experience clinically significant mental health problems than those who developed less distrust. Individual and school-based interventions aimed at reducing the negative impact of bullying on mental health may thus benefit from bolstering youths' sense of trust in others.

Sex Differences in Stress Susceptibility as a Key Mechanism Underlying Depression Risk.

PURPOSE OF REVIEW: Although females are at relatively greater risk for a variety of disorders, including depression, the biological mechanisms underlying this striking health disparity remain unclear. To address this issue, we highlight sex differences in stress susceptibility as a key mechanism potentially driving this effect and describe the interacting inflammatory, hormonal, epigenomic, and social-environmental mechanisms involved. RECENT FINDINGS: Using the Social Signal Transduction Theory of Depression as a theoretical framework, women's elevated risk for depression may stem from a tight link between life stress, inflammation, and depression in women. Further, research finds hormonal contraceptive use alters cortisol and inflammatory reactivity to acute stress in ways that may increase depression risk in females. Finally, beyond established epigenetic mechanisms, mothers may transfer risk for depression to their female offspring through stressful family environments, which influence stress generation and stress-related gene expression. Together, these findings provide initial, biologically plausible clues that may help explain the relatively greater risk for depression in females vs. males. Looking forward, much more research is needed to address the longstanding underrepresentation of females in biomedical research on the biology of stress and depression.

Characterizing the hierarchical depression phenotype in sexually diverse individuals.

INTRODUCTION: Sexual diverse individuals are at high risk for internalizing psychopathologies, such as depression. Understanding how symptom profiles of heterogeneous psychiatric disorders such as depression differ for sexually diverse vs. heterosexual individuals is thus critical to advance precision psychiatry and maximize our ability to effectively treat members of this population. Research has failed to consider the possibility of hierarchical phenotypes, wherein sexual orientation status may be uniquely and simultaneously associated with both depression broadly and with individual symptoms. METHOD: To address these issues, we conducted a moderated nonlinear factor analysis in Wave IV of the Add Health study, using sexual diversity status as a predictor of (a) latent depression, (b) factor loadings, and (c) individual symptoms, with and without controlling for race. RESULTS: Sexual diversity status was positively and simultaneously associated with latent depression, concentration difficulties, and happiness. DISCUSSION: These findings suggest that sexually diverse populations not only face greater depression, broadly defined, but are disproportionately more likely to experience concentration difficulties and be happier compared to heterosexual counterparts. Methodologically, these models indicate that the CES-D is scalar noninvariant as a function of sexual diversity status (i.e., identical scores on the CES-D may represent different manifestations of depression for sexually diverse and heterosexual participants). Studies examining disparities in depression across heterosexual and sexually diverse samples should thus consider depression broadly as well as specific symptoms. Further, it is critical to examine whether these relations function via different mechanisms.

The Psychoneuroimmunological Model of Moral Distress and Health in Healthcare Workers: Toward Individual and System-Level Solutions.

Healthcare is presently experiencing a global workforce crisis, marked by the inability of hospitals to retain qualified healthcare workers. Indeed, poor working conditions and staff shortages have contributed to structural collapse and placed a heavy toll on healthcare workers' (HCWs) well-being, with many suffering from stress, exhaustion, demoralization, and burnout. An additional factor driving qualified HCWs away is the repeated experience of moral distress, or the inability to act according to internally held moral values and perceived ethical obligations due to internal and external constraints. Despite general awareness of this crisis, we currently lack an organized understanding of how stress leads to poor health, wellbeing, and performance in healthcare workers. To address this critical issue, we first review the literature on moral distress, stress, and health in HCWs. Second, we summarize the biobehavioral pathways linking occupational and interpersonal stressors to health in this population, focusing on neuroendocrine, immune, genetic, and epigenetic processes. Third, we propose a novel Psychoneuroimmunological Model of Moral Distress and Health in HCWs based on this literature. Finally, we discuss evidence-based individual- and system-level interventions for preventing stress and promoting resilience at work. Throughout this review, we underscore that stress levels in HCWs are a major public health concern, and that a combination of system-level and individual-level interventions are necessary to address preventable health care harm and foster resilience in this population, including new health policies, mental health initiatives, and additional translational research.

Multi-omics in stress and health research: study designs that will drive the field forward.

Despite decades of stress research, there still exist substantial gaps in our understanding of how social, environmental, and biological factors interact and combine with developmental stressor exposures, cognitive appraisals of stressors, and psychosocial coping processes to shape individuals' stress reactivity, health, and disease risk. Relatively new biological profiling approaches, called multi-omics, are helping address these issues by enabling researchers to quantify thousands of molecules from a single blood or tissue sample, thus providing a panoramic snapshot of the molecular processes occurring in an organism from a systems perspective. In this review, we summarize two types of research designs for which multi-omics approaches are best suited, and describe how these approaches can help advance our understanding of stress processes and the development, prevention, and treatment of stress-related pathologies. We first discuss incorporating multi-omics approaches into theory-rich, intensive longitudinal study designs to characterize, in high-resolution, the transition to stress-related multisystem dysfunction and disease throughout development. Next, we discuss how multi-omics approaches should be incorporated into intervention research to better understand the transition from stress-related dysfunction back to health, which can help inform novel precision medicine approaches to managing stress and fostering biopsychosocial resilience. Throughout, we provide concrete recommendations for types of studies that will help advance stress research, and translate multi-omics data into better health and health care.

Brain network connectivity during peer evaluation in adolescent females: Associations with age, pubertal hormones, timing, and status.

Despite copious data linking brain function with changes to social behavior and mental health, little is known about how puberty relates to brain functioning. We investigated the specificity of brain network connectivity associations with pubertal indices and age to inform neurodevelopmental models of adolescence. We examined how brain network connectivity during a peer evaluation fMRI task related to pubertal hormones (dehydroepiandrosterone and testosterone), pubertal timing and status, and age. Participants were 99 adolescents assigned female at birth aged 9-15 (M = 12.38, SD = 1.81) enriched for the presence of internalizing symptoms. Multivariate analysis revealed that within Salience, between Frontoparietal - Reward and Cinguloopercular - Reward network connectivity were associated with all measures of pubertal development and age. Specifically, Salience connectivity linked with age, pubertal hormones, and status, but not timing. In contrast, Frontoparietal - Reward connectivity was only associated with hormones. Finally, Cinguloopercular - Reward connectivity related to age and pubertal status, but not hormones or timing. These results provide evidence that the salience processing underlying peer evaluation is jointly influenced by various indices of puberty and age, while coordination between cognitive control and reward circuitry is related to pubertal hormones, pubertal status, and age in unique ways.

Rural-urban disparities in psychosocial functioning in epithelial ovarian cancer patients.

OBJECTIVE: Although rural residence has been related to health disparities in cancer patients, little is known about how rural residence impacts mental health and quality of life (QOL) in ovarian cancer patients over time. This prospective longitudinal study investigated mental health and QOL of ovarian cancer patients in the first-year post-diagnosis. METHOD: Women with suspected ovarian cancer completed psychosocial surveys pre-surgery, at 6 months and one-year; clinical data were obtained from medical records. Histologically confirmed high grade epithelial ovarian cancer patients were eligible. Rural/urban residence was categorized from patient counties using the USDA Rural-Urban Continuum Codes. Linear mixed effects models examined differences in psychosocial measures over time, adjusting for covariates. RESULTS: Although disparities were not observed at study entry for any psychosocial variable (all p-values >0.22), urban patients showed greater improvement in total distress over the year following diagnosis than rural patients (p = 0.025) and were significantly less distressed at one year (p = 0.03). Urban patients had a more consistent QOL improvement than their rural counterparts (p = 0.006). There were no differences in the course of depressive symptoms over the year (p = 0.17). Social support of urban patients at 12 months was significantly higher than that of rural patients (p = 0.04). CONCLUSION: Rural patients reported less improvement in psychological functioning in the year following diagnosis than their urban counterparts. Clinicians should be aware of rurality as a potential risk factor for ongoing distress. Future studies should examine causes of these health disparities and potential long-term inequities and develop interventions to address these issues.

Toward a dynamic immunopsychiatry.

In this article, we briefly clarify several points regarding immunopsychiatry. In particular, we argue that higher density data and a greater focus on temporal dynamics are both important, and that studies incorporating these features have the potential to greatly advance the field. We also respond to recent comments made on our original article on this topic (Moriarity and Slavich, 2023), including the contention that our perspective on immunopsychiatry is reductionistic. To the contrary, we believe that strong immunopsychiatry studies are highly integrative and include data from multiple major levels of analysis to form a more complete picture of how processes that are relevant for mental health and behavior emerge and dynamically change over time in relation to one another.

Lifetime adversity predicts depression, anxiety, and cognitive impairment in a nationally representative sample of older adults in the United States.

OBJECTIVE: Although life stress and adversity are well-known risk factors for mental health problems and cognitive impairment among older adults, limited research has comprehensively examined the impact of both childhood and adulthood adversity on psychiatric and cognitive impairment symptoms over a prolonged period. To address this issue, we investigated how lifetime adversity exposure is related to symptoms of depression, anxiety, and cognitive impairment in a nationally representative, longitudinal sample of older adults in the United States. METHOD: We analyzed data from the Health and Retirement Study (1992-2016). The sample included 3496 individuals (59.9% female), aged ≥64 years old (Mage = 76.0 ± 7.6 years in 2016). We used the individual-level panel data and ordinary least squares regressions to estimate associations between childhood and adulthood adversities, and later-life depression, anxiety, and cognitive impairment. RESULTS: Many participants experienced a significant early life (38%) or adulthood (79%) stressor. Moreover, experiencing one childhood adversity (vs. none) was associated with a 17.4% increased risk of adulthood adversity. Finally, as hypothesized, childhood adversity exposure was related to experiencing more depression and anxiety symptoms in later life, whereas adulthood stressor exposure predicted more cognitive impairment as well as more depression and anxiety symptoms. DISCUSSION: These findings demonstrate significant associations between lifetime adversity and symptoms of depression, anxiety, and cognitive impairment in older adults. Screening for lifetime stressors may thus help healthcare professionals and policymakers identify individuals who could potentially benefit from interventions designed to reduce stress and enhance resilience.

Neural Correlates of the p Factor in Adolescence: Cognitive Control With and Without Enhanced Positive Affective Demands.

BACKGROUND: Recent research has aimed to characterize processes underlying general liability toward psychopathology, termed the p factor. Given previous research linking the p factor with difficulties in both executive functioning and affective regulation, the present study investigated nonaffective and positive affective inhibition in the context of a sustained attention/inhibition paradigm in adolescents exhibiting mild to severe psychopathology. METHODS: Functional magnetic resonance imaging data were collected during an integrated reward conditioning and go/no-go task in 138 adolescents assigned female at birth. We modeled the p factor using hierarchical confirmatory factor analysis. Positive affective inhibition was measured by examining responses to no-go stimuli with a history of reward conditioning. We examined associations between p factor scores and neural function and behavioral performance. RESULTS: Consistent with nonaffective executive function as a primary risk factor, p factor scores were associated with worse behavioral performance and hypoactivation in the left superior frontal gyrus and middle frontal gyrus during response initiation (go trials). The p factor scores were additionally associated with increased error-related signaling in the temporal cortex during incorrect no-go trials. CONCLUSIONS: During adolescence, a period characterized by heightened risk for emergent psychopathology, we observed unique associations between p factor scores and neural and behavioral indices of response initiation, which relies primarily on sustained attention. These findings suggest that shared variation in mental disorder categories is characterized in part by sustained attention deficits. While we did not find evidence that the p factor was associated with inhibition in this study, this observation is consistent with our hypothesis that the p factor would be related to nonaffective control processes.

The biology of hope: Inflammatory and neuroendocrine profiles in ovarian cancer patients.

INTRODUCTION: Although the concept of hope is highly relevant for cancer patients, little is known about its association with cancer-relevant biomarkers. Here we examined how hope was related to diurnal cortisol and interleukin-6 (IL-6), a pro-inflammatory cytokine previously associated with tumor biology and survival in ovarian cancer. Secondly, we examined whether hope and hopelessness are distinctly associated with these biomarkers. METHOD: Participants were 292 high-grade ovarian cancer patients who completed surveys and provided saliva samples 4x/daily for 3 days pre-surgery to assess diurnal cortisol. Blood (pre-surgery) and ascites were assessed for IL-6. Hope and hopelessness were assessed using standardized survey items from established scales (Center for Epidemiological Studies Depression Scale; Profile of Mood States, Functional Assessment of Cancer Therapy). Two hopeless items were z-scored and combined into a composite for analysis. Regression models related these variables to nocturnal cortisol, cortisol slope, plasma and ascites IL-6, adjusting for cancer stage, BMI, age, and depression. RESULTS: Greater hope was significantly related to a steeper cortisol slope, ß = -0.193, p = 0.046, and lower night cortisol, ß = -0.227, p = 0.018, plasma IL-6, ß = -0.142, p = 0.033, and ascites IL-6, ß = -0.290, p = 0.002. Secondary analyses including both hope and hopelessness showed similar patterns, with distinct relationships of hope with significantly lower nocturnal cortisol ß = -0.233,p = 0.017 and ascites IL-6, ß = -0.282,p = 0.003, and between hopelessness and a flatter cortisol slope, ß = 0.211, p = 0.031. CONCLUSIONS: These data suggest a biological signature of hope associated with less inflammation and more normalized diurnal cortisol in ovarian cancer. These findings have potential clinical utility but need replication with more diverse samples and validated assessments of hope.

A qualitative exploration of how lifetime stressor exposure influences sport performers' health, well-being, and performance.

BACKGROUND AND OBJECTIVES: Recent research has shown that lifetime stressor exposure can negatively impact sport performers. However, this work has predominantly relied on quantitative methods, which has provided limited information regarding how stressors occurring over the life course affect health, well-being, and performance. This study aimed to explore how relatively high levels of lifetime (non-sport and sport-specific) stressor exposure influenced sport performers' health, well-being, and performance. METHODS AND DESIGN: To identify participants who had experienced high lifetime (non-sport and sport-specific) stressors, we used criterion-based purposeful sampling from a prior study. Subsequently, semi-structured interviews, complemented by timelining, were conducted with 22 sport performers (17 female; Mage = 25.89, SD = 10.20). RESULTS: We used reflexive thematic analysis to develop three overarching themes that illustrate how high lifetime (non-sport and sport-specific) stressor exposure influences sport performers' health, well-being, and performance. These were: psychological (e.g., maladaptive coping strategies), social (e.g., difficulties in building relationships), and behavioral (e.g., risky behaviors) factors. CONCLUSIONS: These findings can help practitioners identify sport performers at risk of developing stress-related health, well-being, and performance problems, and may aid the development of effective interventions.

Heightened neural activity and functional connectivity responses to social rejection in female adolescents at risk for depression: Testing the Social Signal Transduction Theory of Depression.

BACKGROUND: Although social rejection is among the strongest proximal precipitants of major depressive disorder (MDD), little is known about the underlying neurobiological mechanisms and whether neural sensitivity to social rejection may help explain differences in MDD risk. To address this issue, we tested whether neural responses to social threat differed in female adolescents at high vs. low maternal risk for MDD. METHOD: Female adolescents with (high-risk; n = 22, Mage = 14.68) and without (low-risk; n = 30, Mage = 15.07) a maternal history of depression were experimentally exposed to negative and neutral social evaluation while undergoing an fMRI scan. Neural responses were assessed by event-related activity and functional connectivity, as well as multivoxel pattern analysis. Activity and functional connectivity analyses focused on a priori-selected regions of interest implicated in self-referential processing and emotion regulation. RESULTS: Compared to low-risk female adolescents, high-risk female adolescents exhibited greater increases in self-reported depression and social disconnection following social evaluation. Moreover, compared to low-risk female adolescents, high-risk female adolescents exhibited greater amygdala responses to negative social evaluation and a differential pattern of functional connectivity in brain regions related to emotion regulation, self-referential processing, and negative affect. Additionally, these markers of neural threat reactivity were related to depressive symptoms. LIMITATIONS: A cross-sectional study design and relatively small, Western sample. CONCLUSIONS: These results suggest that exaggerated neural reactivity to social threat-and an atypical pattern of related functional connectivity-is evident in individuals with a preclinical risk factor for depression. Targeting such responding may thus be a fruitful strategy for preventing depression in at-risk youth.