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BackgroundAlthough 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.MethodFemale 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.ResultsCompared 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.LimitationsA cross-sectional study design and relatively small, Western sample.ConclusionsThese 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.

The ability to maintain functional independence throughout the lifespan may be diminished among medically compromised and chronically stressed populations. People living with HIV are more likely to demonstrate functional impairment and report greater exposure to lifetime and chronic stressors than their seronegative counterparts. It is well-known that exposure to stressors and adversity is associated with functional impairment outcomes. However, to our knowledge, no studies have examined how protective factors such as psychological grit mitigate the negative effects of lifetime and chronic stressor exposure on functional impairment, and how this association differs by HIV-status. To address this issue, we studied associations between lifetime and chronic stressor exposure, grit, and functional impairment in 176 African American and non-Hispanic White HIV-seropositive (n = 100) and HIV-seronegative (n = 76) adults, aged 24-85 (M = 57.28, SD = 9.02). As hypothesised, HIV-seropositive status and lower grit, but not lifetime stressor exposure, were independently associated with more functional impairment. Moreover, there was a significant three-way interaction between HIV-status, grit, and lifetime stressor exposure, b = 0.07, p = 0.025, 95% CI [0.009, 0.135]. Specifically, lifetime stressor exposure was related to more functional impairment for HIV-seronegative-but not HIV-seropositive-adults who reported low levels of grit. These findings suggest that the protective effects of grit may differ across populations at risk for functional impairment.

BackgroundAlthough maternal stressor exposure has been associated with shorter telomere length (TL) in offspring, this literature is based largely on White samples. Furthermore, timing of maternal stressors has rarely been examined. Here, we examined how maternal stressors occurring during adolescence, pregnancy, and across the lifespan related to child TL in Black and White mothers.MethodMothers (112 Black; 110 White; Mage = 39) and their youngest offspring (n = 222; Mage = 8) were part of a larger prospective cohort study, wherein mothers reported their stressors during adolescence (assessed twice during adolescence for the past year), pregnancy (assessed in midlife for most recent pregnancy), and across their lifespan (assessed in midlife). Mother and child provided saliva for TL measurement. Multiple linear regression models examined the interaction of maternal stressor exposure and race in relation to child TL, controlling for maternal TL and child gender and age. Race-stratified analyses were also conducted.ResultsNeither maternal adolescence nor lifespan stressors interacted with race in relation to child TL. In contrast, greater maternal pregnancy stressors were associated with shorter child TL, but this effect was present for children of White but not Black mothers. Moreover, this effect was significant for financial but not social pregnancy stressors. Race-stratified models revealed that greater financial pregnancy stressors predicted shorter telomeres in offspring of White, but not Black mothers.ConclusionsRace and maternal stressors interact and are related to biological aging across generations, but these effects are specific to certain races, stressors, and exposure time periods.

The long-term value of immunopsychiatry will be based on its ability to translate basic science into effective clinical interventions. In this article, we discuss a key obstacle to achieving this important translational goal-namely, the preponderance of studies that are cross-sectional, or that have months-to-years long follow-up periods. Immunopsychiatric processes such as stress, inflammation, and depression symptoms are inherently dynamic and fluctuate over hours, days, and weeks. This fact suggests that higher-density data collection with only days between measurements is necessary to capture-with adequate resolution-the actual dynamics of these systems, determine optimal time lags with which to observe associations between variables of interest, and maximize the translational potential of these data. To illustrate these points, we use pilot data from our own intensive longitudinal immunopsychiatric study. We then conclude by making several recommendations for future research. By learning how to better use existing data for dynamically informative studies as well as collecting intensive longitudinal data, we believe immunopsychiatry will be much better positioned to advance our causal understanding of the interplay between the immune system and health.

Adolescents' suicidal behavior frequently is preceded by interpersonal stress, but not all who experience distress attempt to end their lives. Recent theories have posited individual differences in stress-related inflammatory reactivity may be associated with psychopathology risk; this study examined inflammatory reactivity as a moderator of the prospective association between interpersonal stress and adolescents' suicidal behavior. Participants included 157 at-risk adolescent females (ages 12 to 16 years) and assessed individual differences in proinflammatory cytokine responses to a brief laboratory-based social stressor, both interpersonal and non-interpersonal life events, and suicidal behavior over an 18-month follow-up period. Measuring levels of the key proinflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) before and after an experimentally-induced social stressor, results revealed that blunted cytokine reactivity heightened the effect of high interpersonal stress exposure on risk for suicidal behaviors over the subsequent 9 months. Significant effects were not revealed for non-interpersonally themed stress. Finding highlight the urgent need for more research examining inflammation reactivity among adolescents.

PurposeThe purpose of the current study, The National Institute of Child Health and Human Development (NICHD) Study of Health in Early and Adult Life (SHINE), was to build on the landmark Study of Early Child Care and Youth Development (SECCYD), a longitudinal birth cohort initiated in 1991, by conducting a health-focused follow-up of the now adult participants. This effort has produced an invaluable resource for the pursuit of life course research examining links between early life risk and resilience factors and adulthood health and disease risk.ParticipantsOf the 927 NICHD SECCYD participants available for recruitment in the current study, 705 (76.1%) participated in the study. Participants were between 26 and 31 years and living in diverse geographic locations throughout the USA.Findings to dateIn descriptive analyses, the sample exhibited risk on health status indicators, especially related to obesity, hypertension and diabetes. Of particular concern, the prevalence of hypertension (29.4%) and diabetes (25.8%) exceeded national estimates in similar-age individuals. Health behaviour indicators generally tracked with the parameters of poor health status, showing a pattern of poor diet, low activity and disrupted sleep. The juxtaposition of the sample's relatively young age (mean=28.6 years) and high educational status (55.6% college educated or greater) with its poor health status is noteworthy, suggesting a dissociation between health and factors that are typically health protective. This is consistent with observed population health trends, which show a worsening of cardiometabolic health status in younger generations of Americans.Future plansThe current study, SHINE, lays the groundwork for future analyses in which the uniquely robust measures collected as a part of the original NICHD SECCYD will be leveraged to pinpoint specific early life risk and resilience factors as well as the correlates and potential mechanisms accounting for variability in health and disease risk indicators in young adulthood.

The motivation to socially connect with peers increases during adolescence in parallel with changes in neurodevelopment. These changes in social motivation create opportunities for experiences that can impact risk for psychopathology, but the specific motivational presentations that confer greater psychopathology risk are not fully understood. To address this issue, we used a latent profile analysis to identify the multidimensional presentations of self-reported social goals in a sample of 220 girls (9-15 years old, M = 11.81, SD = 1.81) that was enriched for internalizing symptoms, and tested the association between social goal profiles and psychopathology. Associations between social goals and brain network connectivity were also examined in a subsample of 138 youth. Preregistered analyses revealed four unique profiles of social goal presentations in these girls. Greater psychopathology was associated with heightened social goals such that higher clinical symptoms were related to a greater desire to attain social competence, avoid negative feedback and gain positive feedback from peers. The profiles endorsing these excessive social goals were characterized by denser connections among social-affective and cognitive control brain regions. These findings thus provide preliminary support for adolescent-onset changes in motivating factors supporting social engagement that may contribute to risk for psychopathology in vulnerable girls.

Classic theories of stress and health are largely based on assumptions regarding how different psychosocial stressors influence biological processes that, in turn, affect human health and behavior. Although theoretically rich, this work has yielded little consensus and led to numerous conceptual, measurement, and reproducibility issues. Social Safety Theory aims to address these issues by using the primary goal and regulatory logic of the human brain and immune system as the basis for specifying the social-environmental situations to which these systems should respond most strongly to maximize reproductive success and survival. This analysis gave rise to the integrated, multi-level formulation described herein, which transforms thinking about stress biology and provides a biologically based, evolutionary account for how and why experiences of social safety and social threat are strongly related to health, well-being, aging, and longevity. In doing so, the theory advances a testable framework for investigating the biopsychosocial roots of health disparities as well as how health-relevant biopsychosocial processes crystalize over time and how perceptions of the social environment interact with childhood microbial environment, birth cohort, culture, air pollution, genetics, sleep, diet, personality, and self-harm to affect health. The theory also highlights several interventions for reducing social threat and promoting resilience.

Although race/ethnicity is associated with substantial differences in risk for depression and other diseases of aging in the United States, the processes underlying these health disparities remain poorly understood. We addressed this issue by examining how levels of a robust marker of inflammatory activity, C-reactive protein (CRP), and depression symptoms varied across racial/ethnic groups. Additionally, we tested whether the inflammation-depression association differed across groups. Data were drawn from the Chicago Community Adult Health Survey, an epidemiological survey examining biopsychosocial factors affecting health and well-being. Participants were 3105 Chicago community adults, of which 610 provided blood samples and were included in analyses. C-reactive protein was assayed from blood samples, and depression symptoms were assessed using the 11-item Center for Epidemiologic Studies-Depression scale. Race/ethnicity was self-reported and consisted of Black, Hispanic, White, and other racial/ethnic groups. Results revealed that these racial/ethnic groups differed in terms of both their CRP and depression levels. Specifically, Black Americans exhibited higher levels of CRP as compared to White and other race/ethnicity Americans. Moreover, Black Americans exhibited more depression symptoms than Hispanic Americans. Finally, we found that inflammatory levels were strongly related to depression symptoms but only for Black Americans, with CRP alone accounting for 8% of the variance in depression symptoms in this subgroup. These data thus point to a biological process that may help to explain disparities in mental health outcomes across race/ethnicity in the United States. At the same time, additional research is needed to understand the social and structural factors driving these effects.

Many of life's most impactful experiences involve either social safety (e.g., acceptance, affiliation, belonging, inclusion) or social threat (e.g., conflict, isolation, rejection, exclusion). According to Social Safety Theory, these experiences greatly impact human health and behavior because a fundamental goal of the brain and immune system is to keep the body biologically safe. To achieve this crucial goal, social threats likely gained the ability to activate anticipatory neural-immune responses that would have historically benefited reproduction and survival; the presence of social safety, in turn, likely dampened these responses. Viewing positive and negative social experiences through this lens affords a biologically based evolutionary account for why certain stressors are particularly impactful. It also provides an integrated, multi-level framework for investigating the biopsychosocial roots of psychopathology, health disparities, aging, longevity, and interpersonal cognition and behavior. Ultimately, this work has the potential to inform new strategies for reducing disease risk and promoting resilience.

Psychiatry stands to benefit from brief non-pharmacological treatments that effectively reduce depressive symptoms. To address this need, we conducted a single-blind randomized clinical trial assessing how a 6-day immersive psychosocial training program, followed by 10-min daily psychosocial exercises for 30 days, improves depressive symptoms. Forty-five adults were block-randomized by depression score to two arms: (a) the immersive psychosocial training program and 10-min daily exercise group (36 days total; total n = 23; depressed at baseline n = 14); or (b) a gratitude journaling control group (36 days total; total n = 22; depressed at baseline n = 13). The self-report PHQ-9 was used to assess depression levels in both groups at three time points: baseline, study week one, and study week six. Depression severity improved over time, with a significantly greater reduction in the psychosocial training program group (-82.7%) vs. the control group (-23%), p = 0.02 for baseline vs. week six. The effect size for this reduction in depression symptoms was large for the intervention group (d = -1.3; 95% CI, -2.07, -0.45; p

Prior research has struggled to differentiate cortisol stress response patterns reflective of well-regulated versus dysregulated hypothalamic-pituitary-adrenal (HPA) axis function among adolescents. Here, we show how exploring profiles of joint HPA-inflammatory stress responsivity, and linking those profiles to pubertal development and peer stress exposure may aid such distinction. Adolescent girls (N = 157, Mage  = 14.72 years, SD = 1.38) at risk for psychopathology completed assessments of salivary cortisol and pro-inflammatory cytokines (i.e., tumor necrosis factor-α, interleukin-1β, and interleukin-6) prior to and following the Trier Social Stress Test. Adolescents, a close friend, and a caregiver completed questionnaire measures of peer stress and pubertal status. Multitrajectory modeling of adolescents' cortisol and cytokine levels revealed three profiles: low cortisol response-stably low cytokine (n = 75), high cortisol response-stably moderate cytokine (n = 47), and low cortisol response-stably high cytokine (n = 35). Relative to low cortisol response-stably low cytokine, adolescents exhibiting the high cortisol response-stably moderate cytokine profile were more advanced in their pubertal development, but presented with similarly low levels of peer stress exposure. Despite showing cortisol responses that were indistinguishable from low cortisol response-stably low cytokine, adolescents exhibiting the low cortisol response-stably high cytokine profile were more pubertally advanced, but also more likely to have experienced chronic peer strain (self-report) and relational peer victimization (close friend-report). These findings thus illustrate the potential value of taking a multisystem approach to studying adolescent stress responsivity and underscore the importance of considering developmental and social factors when interpreting cortisol stress response patterns. Ultimately, such work may help inform developmental models of neuroendocrine dysregulation and related risk for psychopathology.

ObjectiveAlthough exposure to abuse in early life predicts earlier pubertal timing, especially for girls, it is unclear if this association generalizes to nonabuse stressors. In addition, the impact of race on the stress-maturation association remains unknown. To address these issues, we examined whether race moderates the effects of early adversity on pubertal timing and tempo using a longitudinal study design.MethodsIn a cohort of 9- and 10-year-old Black and White girls, pubertal (areolar and pubic hair) maturation was assessed annually for 7 years. In adulthood, 368 participants (186 Black, 182 White) reported on abuse and nonabuse stressors they experienced from ages 0 to 12 years.ResultsEarly life abuse was associated with earlier pubertal timing, as indexed by younger age at menarche (b = -0.22, p = .005, 95% confidence interval [CI] = -0.39 to -0.06) and greater pubic hair development (b = 0.11, p = .003, 95% CI = 0.04 to 0.18), in addition to slower pubertal tempo, as indexed by slower rate of pubic hair (b = -0.03, p < .001, 95% CI = -0.05 to -0.01) and areolar (b = -0.02, p = .02, 95% CI = -0.03 to -0.003) development. These associations were not found for nonabuse adversity. Black girls with early life abuse had greater pubic hair development (b = 0.23, p < .001, 95% CI = 0.12 to 0.35) and were slower in pubic hair tempo (b = -0.07, p < .001, 95% CI = -0.09 to -0.04) than their White counterparts.ConclusionsScreening for early life abuse may help address health disparities related to earlier pubertal timing.

ObjectiveExposure to stressors in daily life and dysregulated stress responses are associated with increased risk for a variety of chronic mental and physical health problems, including anxiety disorders, depression, asthma, heart disease, certain cancers, and autoimmune and neurodegenerative disorders. Despite this fact, stress exposure and responses are rarely assessed in the primary care setting and infrequently targeted for disease prevention or treatment.MethodIn this narrative review, we describe the primary reasons for this striking disjoint between the centrality of stress for promoting disease and how rarely it is assessed by summarizing the main conceptual, measurement, practical, and reimbursement issues that have made stress difficult to routinely measure in primary care. The following issues will be reviewed: a) assessment of stress in primary care, b) biobehavioral pathways linking stress and illness, c) the value of stress measurements for improving outcomes in primary care, d) barriers to measuring and managing stress, and e) key research questions relevant to stress assessment and intervention in primary care.ResultsOn the basis of our synthesis, we suggest several approaches that can be pursued to advance this work, including feasibility and acceptability studies, cost-benefit studies, and clinical improvement studies.ConclusionsAlthough stress is recognized as a key contributor to chronic disease risk and mortality, additional research is needed to determine how and when instruments for assessing life stress might be useful in the primary care setting, and how stress-related data could be integrated into disease prevention and treatment strategies to reduce chronic disease burden and improve human health and well-being.

There is increasing appreciation that certain biological processes may not be equally related to all psychiatric symptoms in a given diagnostic category. Research on the biological phenotyping of psychopathology has begun examining the etiological and treatment implications of identified biotypes; however, little attention has been paid to a critical methodological implication of these results: measurement noninvariance. Measurement invariance is the ability of an instrument to measure the same construct, the same way, across different people, or across different time points for the same individual. If what a measure quantifies differs across different people (e.g., those with or without a particular biotype) or time points, then it is invalid to directly compare means on that measure. Using a running example of inflammatory phenotypes of depression, we first describe the biological phenotyping of psychopathology. Second, we discuss three types of measurement invariance. Third, we demonstrate how differential biology-symptom associations invariably creates measurement noninvariance using a theoretical example and simulated data (for which code is provided). We also show how this issue can lead to false conclusions about the broader diagnostic construct. Finally, we provide several suggestions for addressing these important issues to help advance the field of biological psychiatry.

The present study investigated the contribution of health risk factors (using the Charlson Comorbidity Index [CCI]) on cognitive outcomes in a sample of 380 HIV-positive (HIV+; n = 221) and HIV-seronegative (HIV-; n = 159) African American and European American adults aged 50+.Participants were recruited from HIV clinics and community advertisements. HIV status was confirmed by serological testing. Self-report and chart history review was used to gather information about medical ssscomorbidities. The Charlson Comorbidity Index (CCI) was used to create a comorbidity score. Participants were administered a brief cognitive test battery.As expected, health risks were greater among those with HIV. There was a HIV × Race interaction on CCI scores, such that in the HIV + group, European Americans had significantly higher CCI scores (M = 3.74; SD = 2.1) than African American HIV + participants (M = 2.70; SD = 1.9). However, in the HIV - group, African Americans had significantly higher CCI scores (M = 2.20; SD = 1.1) than HIV - European American participants (M = 1.80; SD = 1.2). Also, consistent with hypotheses, across the entire sample CCI score was significantly associated with global cognition (β = -.24, p = .02).Study results underscore the importance of considering HIV serostatus in studies examining racial disparities in health, and how multiple medical risks relate to cognitive outcomes. Neuropsychologists evaluating patients living with HIV should consider how the presence of multiple medical comorbidities may contribute to the course of cognitive decline as people age.

Depression is a common, often recurrent disorder that causes substantial disease burden worldwide, and this is especially true for women following the pubertal transition. According to the Social Signal Transduction Theory of Depression, stressors involving social stress and rejection, which frequently precipitate major depressive episodes, induce depressive symptoms in vulnerable individuals in part by altering the activity and connectivity of stress-related neural pathways, and by upregulating components of the immune system involved in inflammation. To test this theory, we recruited adolescent females at high and low risk for depression and assessed their psychological, neural, inflammatory, and genomic responses to a brief (10 minute) social stress task, in addition to trait psychological and microbial factors affecting these responses. We then followed these adolescents longitudinally to investigate how their multi-level stress responses at baseline were related to their biological aging at baseline, and psychosocial and clinical functioning over one year. In this protocol paper, we describe the theoretical motivations for conducting this study as well as the sample, study design, procedures, and measures. Ultimately, our aim is to elucidate how social adversity influences the brain and immune system to cause depression, one of the most common and costly of all disorders.

Depression is a common, often recurrent disorder that causes substantial disease burden worldwide, and this is especially true for women following the pubertal transition. According to the Social Signal Transduction Theory of Depression, stressors involving social stress and rejection, which frequently precipitate major depressive episodes, induce depressive symptoms in vulnerable individuals in part by altering the activity and connectivity of stress-related neural pathways, and by upregulating components of the immune system involved in inflammation. To test this theory, we recruited adolescent females at high and low risk for depression and assessed their psychological, neural, inflammatory, and genomic responses to a brief (10 minute) social stress task, in addition to trait psychological and microbial factors affecting these responses. We then followed these adolescents longitudinally to investigate how their multi-level stress responses at baseline were related to their biological aging at baseline, and psychosocial and clinical functioning over one year. In this protocol paper, we describe the theoretical motivations for conducting this study as well as the sample, study design, procedures, and measures. Ultimately, our aim is to elucidate how social adversity influences the brain and immune system to cause depression, one of the most common and costly of all disorders.

Hierarchies naturally emerge in social species, and judgments of status in these hierarchies have consequences for social relationships and health. Although judgments of social status are shaped by appearance, the physical cues that inform judgments of status remain unclear. The transition to college presents an opportunity to examine judgments of social status in a newly developing social hierarchy. We examined whether appearances-as measured by raters' judgments of photographs and videos-provide information about undergraduate students' social status at their university and in society in Study 1. Exploratory analyses investigated whether associations differed by participants' sex. Eighty-one first-year undergraduate students (Mage  =  18.20, SD  =  0.50; 64.2% female) provided photographs and videos and reported their social status relative to university peers and relative to other people in society. As hypothesized, when participants were judged to be more attractive and dominant they were also judged to have higher status. These associations were replicated in two additional samples of raters who evaluated smiling and neutral photographs from the Chicago Faces Database in Study 2. Multilevel models also revealed that college students with higher self-reported university social status were judged to have higher status, attractiveness, and dominance, although judgments were not related to self-reported society social status. Findings highlight that there is agreement between self-reports of university status and observer-perceptions of status based solely on photographs and videos, and suggest that appearance may shape newly developing social hierarchies, such as those that emerge during the transition to college.

Although stress is a strong risk factor for poor health, especially for women, it remains unclear how stress affects the key neurohormones cortisol and oxytocin, which influence stress-related risk and resilience. Whereas cortisol mediates energy mobilization during stress, oxytocin has anti-inflammatory, anxiolytic, and analgesic effects that support social connection and survival across the lifespan. However, how these neurohormones interrelate and are associated with cognitive control of emotional information during stress remains unclear. To address these issues, we recruited 37 college-aged women (Mage = 19.19, SD = 1.58) and randomly assigned each to a one-hour experimental session consisting of either an acute stress (emotionally stressful video) or control (non-stressful video) condition in a cross-sectional manner across the semester. Salivary cortisol and oxytocin samples were collected at baseline and after the video, at which point participants also completed measures assessing affect and an emotional Stroop task. As hypothesized, the emotional stressor induced negative emotions that were associated with significant elevations in cortisol and faster Stroop reaction times. Moreover, higher baseline oxytocin predicted greater positive affect after the stressor and also better cognitive accuracy on the Stroop. Analyses examining the naturalistic stress effects revealed that basal oxytocin levels rose steeply three weeks before the semester's end, followed by rising cortisol levels one week later, with both neurohormones remaining elevated through the very stressful final exam period. Considered together, these data suggest that women's collective experiences of stress may be potentially buffered by a synchronous oxytocin surge that enhances cognitive accuracy and reduces stress "when the going gets tough".

BackgroundDepression rates increase markedly for girls across the adolescent transition, but the social-environmental and biological processes underlying this phenomenon remain unclear. To address this issue, we tested a key hypothesis from Social Signal Transduction Theory of Depression, which posits that individuals who mount stronger inflammatory responses to social stress should exhibit greater increases in depressive symptoms following interpersonal life stress exposure than those who mount weaker inflammatory responses to such stress.MethodParticipants were 116 adolescent girls (Mage  = 14.71) at risk for psychopathology, defined as having a history of mental health concerns (e.g., psychiatric treatment, significant symptoms) over the past 2 years. At baseline, we characterized their inflammatory reactivity to social stress by quantifying their salivary proinflammatory cytokine responses to a laboratory-based social stressor. Then, 9 months later, we assessed the interpersonal and noninterpersonal stressful life events that they experienced over the prior 9 months using an interview-based measure of life stress.ResultsAs hypothesized, greater interpersonal life stress exposure was associated with significant increases in depression over time, but only for girls exhibiting stronger salivary tumor necrosis factor-α and interleukin-1β reactivity to social stress. In contrast, noninterpersonal stress exposure was unrelated to changes in depression longitudinally, both alone and when combined with youths' cytokine reactivity scores.DiscussionThese results are consistent with Social Signal Transduction Theory of Depression and suggest that heightened inflammatory reactivity to social stress may increase adolescents' risk for depression. Consequently, it may be possible to reduce depression risk by modifying inflammatory responses to social stress.

Social Signal Transduction Theory of Depression is a biologically plausible, multi-level theory that describes neural, physiologic, molecular, and genomic mechanisms that link experiences of social-environmental adversity with internal biological processes that drive depression pathogenesis, maintenance, and recurrence. Central to this theory is the hypothesis that interpersonal stressors involving social threat (e.g., social conflict, evaluation, rejection, isolation, and exclusion) upregulate inflammatory processes that can induce several depressive symptoms, including sad mood, anhedonia, fatigue, psychomotor retardation, and social-behavioral withdrawal. The original article describing this formulation (Psychol Bull 140:774-815, 2014) addressed critical questions involving depression onset and recurrence, as well as why depression is strongly predicted by early life stress and comorbid with anxiety disorders and certain physical disease conditions, such as asthma, rheumatoid arthritis, chronic pain, and cardiovascular disease. Here, we extend the theory to help explain sex differences in depression prevalence, which is a defining feature of this disorder. Central to this extension is research demonstrating that ovarian hormone fluctuations modulate women's susceptibility to stress, brain structure and function, and inflammatory activity and reactivity. These effects are evident at multiple levels and are highly context-dependent, varying as a function of several factors including sex, age, reproductive state, endogenous versus exogenous hormones, and hormone administration mode and dose. Together, these effects help explain why women are at greater risk for developing inflammation-related depressed mood and other neuropsychiatric, neurodevelopmental, and neurodegenerative disorders during the reproductive years, especially for those already at heightened risk for depression or in the midst of a hormonal transition period.

Precision health relies on the ability to assess disease risk at an individual level, detect early preclinical conditions and initiate preventive strategies. Recent technological advances in omics and wearable monitoring enable deep molecular and physiological profiling and may provide important tools for precision health. We explored the ability of deep longitudinal profiling to make health-related discoveries, identify clinically relevant molecular pathways and affect behavior in a prospective longitudinal cohort (n = 109) enriched for risk of type 2 diabetes mellitus. The cohort underwent integrative personalized omics profiling from samples collected quarterly for up to 8 years (median, 2.8 years) using clinical measures and emerging technologies including genome, immunome, transcriptome, proteome, metabolome, microbiome and wearable monitoring. We discovered more than 67 clinically actionable health discoveries and identified multiple molecular pathways associated with metabolic, cardiovascular and oncologic pathophysiology. We developed prediction models for insulin resistance by using omics measurements, illustrating their potential to replace burdensome tests. Finally, study participation led the majority of participants to implement diet and exercise changes. Altogether, we conclude that deep longitudinal profiling can lead to actionable health discoveries and provide relevant information for precision health.

This study examined associations between multiple types of interpersonal and noninterpersonal stressors and the subsequent occurrence of suicide ideation and attempts among female adolescents. Adolescents ages 12 to 18 years old (n = 160) at elevated risk for suicidal thoughts and behaviors were followed for 18 months, divided into two 9-month epochs for data analysis (Periods 1 and 2). Exposure to acute relational victimization, targeted rejection, nonspecified interpersonal, and noninterpersonal life stressors over the first 9-month epoch (Period 1) was assessed using semistructured interviews and an independent life stress rating team. Participants also completed phone-based semistructured interviews of suicidal thoughts and behaviors. Preliminary analyses showed significant prospective associations between acute targeted rejection and nonspecified interpersonal stress during Period 1 and suicide ideation during Period 2, as well as relational victimization and noninterpersonal stress during Period 1 and suicide attempts during Period 2. However, in logistic regression analyses that adjusted for prior suicidality and depressive symptoms, relational victimization during Period 1 (but not targeted rejection, nonspecified interpersonal or noninterpersonal events) was associated with increased odds of suicide attempt during Period 2. Therefore, acute relational victimization exposure is associated with heightened risk for suicidal behaviors in female adolescents. Future studies should examine potential mediators and moderators of this association, and these stressors should be considered for inclusion in clinical screening tools.

Although prior research has examined how early adversity and chronic stress exposure relate to hypothalamic-pituitary-adrenal (HPA) axis responses to acute stress, to date, no studies have examined how stressors occurring over the entire lifespan predict such responses. To address this issue, we recruited 61 healthy young adults and measured their exposure to 55 different types of acute life events and chronic difficulties occurring over the lifespan. In addition, we characterized differences in participants' HPA axis responses to acute stress by measuring their salivary cortisol and DHEA responses to the Trier Social Stress Test for Groups. Greater cumulative stress exposure was associated with a blunted cortisol response, but a heightened DHEA response, to the acute stressor. Moreover, it was participants' exposure to these stressors (i.e., lifetime count), not their perceived severity, which predicted their cortisol and DHEA responses to acute stress. Furthermore, differential effects were observed by stress exposure domain. Notably, only adulthood and marital/partner stressors significantly predicted cortisol responses to acute stress, whereas stress was more uniformly associated with DHEA responses to the acute stressor. These results thus reveal how cumulative stress exposure is associated with HPA axis responsivity to acute stress, while highlighting the fact that different stressors may have substantially different associations with these biological outcomes.

Although substantial research has examined the effects of stress on cognition, much of this research has focused on acute stress (e.g. manipulated in the laboratory) or chronic stress (e.g. persistent interpersonal or financial difficulties). In contrast, the effects of recent life stress on cognition have been relatively understudied. To address this issue, we examined how recent life stress is associated with long-term, working memory, and self-reported memory in a sample of 142 healthy young adults who were assessed at two time points over a two-week period. Recent life stress was measured using the newly-developed Stress and Adversity Inventory for Daily Stress (Daily STRAIN), which assesses the frequency of relatively common stressful life events and difficulties over the preceding two weeks. To assess memory performance, participants completed both long-term and working memory tasks. Participants also provided self-reports of memory problems. As hypothesized, greater recent life stress exposure was associated with worse performance on measures of long-term and working memory, as well as more self-reported memory problems. These associations were largely robust while controlling for possible confounds, including participants' age, sex, and negative affect. The findings indicate that recent life stress exposure is broadly associated with worse memory. Future studies should thus consider assessing recent life stress as a potential predictor, moderator, or covariate of memory performance.

PURPOSE:Long-term survival of women with advanced-stage ovarian cancer is relatively rare. Little is known about quality of life (QOL) and survivorship concerns of these women. Here, we describe QOL of women with advanced-stage ovarian cancer surviving for 8.5 years or longer and compare women with 0-1 recurrence to those with multiple recurrences. METHODS:Participants (n=56) recruited from 5 academic medical centers and the Ovarian Cancer Research Fund Alliance completed surveys regarding QOL (FACT-O), mood (CESD), social support (SPS), physical activity (IPAQ-SF), diet, and clinical characteristics. Median survival was 14.0 years (range 8.8-33.3). RESULTS:QOL and psychological adjustment of long-term survivors was relatively good, with mean FACT-G scores (multiple recurrences: 80.81±13.95; 0-1 recurrence: 89.05 ±10.80) above norms for healthy community samples (80.1±18.1). Survivors with multiple recurrences reported more compromised QOL in domains of physical and emotional well-being (p

PURPOSE:Long-term survival of women with advanced-stage ovarian cancer is relatively rare. Little is known about quality of life (QOL) and survivorship concerns of these women. Here, we describe QOL of women with advanced-stage ovarian cancer surviving for 8.5 years or longer and compare women with 0-1 recurrence to those with multiple recurrences. METHODS:Participants (n=56) recruited from 5 academic medical centers and the Ovarian Cancer Research Fund Alliance completed surveys regarding QOL (FACT-O), mood (CESD), social support (SPS), physical activity (IPAQ-SF), diet, and clinical characteristics. Median survival was 14.0 years (range 8.8-33.3). RESULTS:QOL and psychological adjustment of long-term survivors was relatively good, with mean FACT-G scores (multiple recurrences: 80.81±13.95; 0-1 recurrence: 89.05 ±10.80) above norms for healthy community samples (80.1±18.1). Survivors with multiple recurrences reported more compromised QOL in domains of physical and emotional well-being (p

BackgroundPsychological stress is a well-known risk factor for poor health, and recent research has suggested that the emotion-focused coping process of forgiveness may help mitigate these effects. To date, however, no studies have examined how levels of forgiveness, stress, and health fluctuate and interrelate over time.PurposeWe addressed this issue by examining how forgiveness, stress, and mental and physical health symptoms change and relate to one another over 5 weeks. We hypothesized that increases in state levels of forgiveness would be associated with decreases in perceptions of stress, which would in turn be related to decreases in mental and physical health symptoms. A reverse effects model was also tested.MethodsWe recruited a large, community-based sample of 332 young, middle-aged, and older adults (16-79 years old; M age = 27.9). Each week for 5 weeks, participants reported on their levels of state forgiveness, perceived stress, and mental and physical health symptoms.ResultsLevels of forgiveness, stress, and mental and physical health symptoms each showed significant change and individual variability in change over time. As hypothesized, increases in forgiveness were associated with decreases in stress, which were in turn related to decreases in mental (but not physical) health symptoms (i.e., forgiveness → stress → health). The reverse effects model (i.e., health → stress → forgiveness) provided a relatively poorer fit.ConclusionsThis study is the first to provide prospective, longitudinal evidence showing that greater forgiveness is associated with less stress and, in turn, better mental health. Strategies for cultivating forgiveness may thus have beneficial effects on stress and health.

Social stratification has important implications for health and well-being, with individuals lower in standing in a hierarchy experiencing worse outcomes than those higher up the social ladder. Separate lines of past research suggest that alterations in inflammatory processes and neural responses to threat may link lower social status with poorer outcomes. This study was designed to bridge these literatures to investigate the neurocognitive mechanisms linking subjective social status and inflammation. Thirty-one participants reported their subjective social status, and underwent a functional magnetic resonance imaging scan while they were socially evaluated. Participants also provided blood samples before and after the stressor, which were analysed for changes in inflammation. Results showed that lower subjective social status was associated with greater increases in inflammation. Neuroimaging data revealed lower subjective social status was associated with greater neural activity in the dorsomedial prefrontal cortex (DMPFC) in response to negative feedback. Finally, results indicated that activation in the DMPFC in response to negative feedback mediated the relation between social status and increases in inflammatory activity. This study provides the first evidence of a neurocognitive pathway linking subjective social status and inflammation, thus furthering our understanding of how social hierarchies shape neural and physiological responses to social interactions.

Stress is strongly associated with several mental and physical health problems that involve inflammation, including asthma, cardiovascular disease, certain types of cancer, and depression. It has been hypothesized that better cognitive control of emotional information may lead to reduced inflammatory reactivity to stress and thus better health, but to date no studies have examined whether differences in cognitive control predict pro-inflammatory cytokine responses to stress. To address this issue, we conducted a laboratory-based experimental study in which we randomly assigned healthy young-adult females to either an acute emotional stress (emotionally evocative video) or no-stress (control video) condition. Salivary levels of the key pro-inflammatory cytokines IL-1β, IL-6, and IL-8 were measured before and after the experimental manipulation, and following the last cytokine sample, we assessed participants' cognitive control of emotional information using an emotional Stroop task. We also assessed participants' cortisol levels before and after the manipulation to verify that documented effects were specific to cytokines and not simply due to increased nonwater salivary output. As hypothesized, the emotional stressor triggered significant increases in IL-1β, IL-6, and IL-8. Moreover, even in fully adjusted models, better cognitive control following the emotional (but not control) video predicted less pronounced cytokine responses to that stressor. In contrast, no effects were observed for cortisol. These data thus indicate that better cognitive control specifically following an emotional stressor is uniquely associated with less pronounced pro-inflammatory cytokine reactivity to such stress. These findings may therefore help explain why superior cognitive control portends better health over the lifespan.

The dorsal anterior cingulate cortex (dACC) is recruited when a person is socially rejected or negatively evaluated. However, it remains to be fully understood how this region responds to repeated exposure to personally-relevant social evaluation, in both healthy populations and those vulnerable to Major Depressive Disorder (MDD), as well as how responding in these regions is associated with subsequent clinical functioning. To address this gap in the literature, we recruited 17 young women with past history of MDD (previously depressed) and 31 healthy controls and exposed them to a social evaluative session in a neuroimaging environment. In two bouts, participants received an equal amount of positive, negative, and neutral feedback from a confederate. All participants reported increases in feelings of social evaluation in response to the evaluative task. However, compared to healthy controls, previously depressed participants tended to show greater increases in depressed mood following the task. At the neural level, in response to negative (vs. positive) feedback, no main effect of group or evaluation periods was observed. However, a significant interaction between group and evaluation periods was found. Specifically, over the two bouts of evaluation, activity in the dACC decreased among healthy participants while it increased among previously depressed individuals. Interestingly and unexpectedly, in the previously depressed group specifically, this increased activity in dACC over time was associated with lower levels of depressive symptoms at baseline and at 6-months following the evaluation session (controlling for baseline levels). Thus, the subset of previously depressed participants who showed increases in the recruitment of the dACC over time in response to the negative evaluation seemed to fair better emotionally. These findings suggest that examining how the dACC responds to repeated bouts of negative evaluation reveals a new dimension to the role of the dACC in processing exclusion and contributing to mental health outcomes in a population vulnerable to MDD. Further, investigation of the dynamics of the dACC response to negative social evaluation is warranted.

This study examined the utility of a lifetime cumulative adversities and trauma model in predicting the severity of mental health symptoms of depression, anxiety, and posttraumatic stress disorder. We also tested whether ethnicity and gender moderate the effects of this stress exposure construct on mental health using multigroup structural equation modeling. A sample of 500 low-socioeconomic status African American and Latino men and women with histories of adversities and trauma were recruited and assessed with a standard battery of self-report measures of stress and mental health. Multiple-group structural equation models indicated good overall model fit. As hypothesized, experiences of discrimination, childhood family adversities, childhood sexual abuse, other childhood trauma, and chronic stresses all loaded on the latent cumulative burden of adversities and trauma construct (CBAT). The CBAT stress exposure index in turn predicted the mental health status latent variable. Although there were several significant univariate ethnic and gender differences, and ethnic and gender differences were observed on several paths, there were no significant ethnic differences in the final model fit of the data. These findings highlight the deleterious consequences of cumulative stress and trauma for mental health and underscore a need to assess these constructs in selecting appropriate clinical interventions for reducing mental health disparities and improving human health.

IntroductionHypothalamic-pituitary-adrenal (HPA) deregulation is commonly observed in cancer patients, but its clinical significance is not well understood. We prospectively examined the association between HPA activity, tumor-associated inflammation, and survival in ovarian cancer patients prior to treatment.Materials and methodsParticipants were 113 women with ovarian cancer who provided salivary cortisol for three days prior to treatment for calculation of cortisol slope, variability, and night cortisol. Cox proportional hazard regression analyses were used to examine associations between cortisol and survival in models adjusting for disease stage, tumor grade, cytoreduction and age. On a subsample of 41 patients with advanced disease ascites fluid was assayed for levels of interleukin-6 (IL-6) and correlated with cortisol variables.ResultsEach cortisol measure was associated with decreased survival time, adjusting for covariates (all p36, all p

Psychological stress is implicated in the etiology of many common chronic diseases and mental health disorders. Recent research suggests that inflammation may be a key biological mediator linking stress and health. Nevertheless, the neurocognitive pathways underlying stress-related increases in inflammatory activity are largely unknown. The present study thus examined associations between neural and inflammatory responses to an acute laboratory-based social stressor. Healthy female participants (n=31) were exposed to a brief episode of stress while they underwent an fMRI scan. Blood samples were taken before and after the stressor, and plasma was assayed for markers of inflammatory activity. Exposure to the stressor was associated with significant increases in feelings of social evaluation and rejection, and with increases in levels of inflammation. Analyses linking the neural and inflammatory data revealed that heightened neural activity in the amygdala in response to the stressor was associated with greater increases in inflammation. Functional connectivity analyses indicated that individuals who showed stronger coupling between the amygdala and the dorsomedial prefrontal cortex (DMPFC) also showed a heightened inflammatory response to the stressor. Interestingly, activity in a different set of neural regions was related to increases in feelings of social rejection. These data show that greater amygdala activity in response to a stressor, as well as tighter coupling between the amygdala and the DMPFC, are associated with greater increases in inflammatory activity. Results from this study begin to identify neural mechanisms that might link stress with increased risk for inflammation-related disorders such as cardiovascular disease and depression.

Major life stressors, especially those involving interpersonal stress and social rejection, are among the strongest proximal risk factors for depression. In this review, we propose a biologically plausible, multilevel theory that describes neural, physiologic, molecular, and genomic mechanisms that link experiences of social-environmental stress with internal biological processes that drive depression pathogenesis. Central to this social signal transduction theory of depression is the hypothesis that experiences of social threat and adversity up-regulate components of the immune system involved in inflammation. The key mediators of this response, called proinflammatory cytokines, can in turn elicit profound changes in behavior, which include the initiation of depressive symptoms such as sad mood, anhedonia, fatigue, psychomotor retardation, and social-behavioral withdrawal. This highly conserved biological response to adversity is critical for survival during times of actual physical threat or injury. However, this response can also be activated by modern-day social, symbolic, or imagined threats, leading to an increasingly proinflammatory phenotype that may be a key phenomenon driving depression pathogenesis and recurrence, as well as the overlap of depression with several somatic conditions including asthma, rheumatoid arthritis, chronic pain, metabolic syndrome, cardiovascular disease, obesity, and neurodegeneration. Insights from this theory may thus shed light on several important questions including how depression develops, why it frequently recurs, why it is strongly predicted by early life stress, and why it often co-occurs with symptoms of anxiety and with certain physical disease conditions. This work may also suggest new opportunities for preventing and treating depression by targeting inflammation.

Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is believed to play a role in the pathophysiology of depression. To investigate mechanisms that may underlie this effect, we examined several indices of HPA axis function - specifically, diurnal cortisol slope, cortisol awakening response, and suppression of cortisol release following dexamethasone administration - in 26 pre-menopausal depressed women and 23 never depressed women who were matched for age and body mass index. Salivary cortisol samples were collected at waking, 30 min after waking, and at bedtime over three consecutive days. On the third day, immediately after the bedtime sample, participants ingested a 0.5mg dexamethasone tablet; they then collected cortisol samples at waking and 30 min after waking the following morning. As predicted, depressed women exhibited flatter diurnal cortisol rhythms and more impaired suppression of cortisol following dexamethasone administration than non-depressed women over the three sampling days. In addition, flatter diurnal cortisol slopes were associated with reduced cortisol response to dexamethasone treatment, both for all women and for depressed women when considered separately. Finally, greater self-reported depression severity was associated with flatter diurnal cortisol slopes and with less dexamethasone-related cortisol suppression for depressed women. Depression in women thus appears to be characterized by altered HPA axis functioning, as indexed by flatter diurnal cortisol slopes and an associated impaired sensitivity of cortisol to dexamethasone. Given that altered HPA axis functioning has been implicated in several somatic conditions, the present findings may be relevant for understanding the pathophysiology of both depression and depression-related physical disease.