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.

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.

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.

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.

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.

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.

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.

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.

Threat exposure moderates associations between neural and physiological indices of emotion reactivity in adolescent females.

Early life adversity (ELA) characterized by threat (e.g., abuse, witnessing violence) impacts neural and physiologic systems involved in emotion reactivity; however, research on how threat exposure impacts the interplay between these systems is limited. This study investigates ELA characterized by threat as a potential moderator of the association between (a) neural activity during a negative image processing fMRI task and (b) cortisol production following a modified Trier Social Stress Test (TSST). The sample is comprised of 117 young adolescent females (Mage = 11.90 years, SD = 1.69) at elevated risk for internalizing problems. Whole-brain analyses revealed a positive association between cortisol production and increased right lateral orbitofrontal cortex activity during the emotion reactivity task. In moderation models, threat exposure interacted with bilateral amygdala activation (b = -3.34, p = 0.021) and bilateral hippocampal activation (b = -4.14, p = 0.047) to predict cortisol response to the TSST. Specifically, participants with low, but not high, levels of threat exposure demonstrated a positive association between cortisol production and neural activity in these regions, while no significant association emerged for participants with high threat exposure. Findings contribute to the growing field of research connecting physiological and neural emotion processing and response systems, suggesting that dimensions of ELA may uniquely disrupt associations between neural activation and cortisol production.

Hormonal contraceptive use is associated with differences in women's inflammatory and psychological reactivity to an acute social stressor.

Women using hormonal contraceptives (HCs) exhibit numerous signs of chronic inflammation, including elevated C-reactive protein levels and greater risk of developing mood and autoimmune disorders. However, users and non-users of HCs often have similar circulating proinflammatory cytokine levels, making the mechanism of association unclear. One possible explanation for this paradox is that HC users exhibit differences in their inflammatory responses to psychosocial stress that, over time, could contribute to chronic inflammation and its pathologies. Here, we tested this possibility by examining women's glucocorticoid, inflammatory, and psychological responses to the Trier Social Stress Test (TSST) in 67 naturally cycling (NC) and 60 oral HC-using women (Mage = 19.31, SDage = 1.95). As hypothesized, HC users and NC women exhibited different glucocorticoid and proinflammatory cytokine responses to the TSST. For NC women, TSST-induced increases in glucocorticoids were uncommon, and increases in glucocorticoids were accompanied by elevations in IL-6. In contrast, for women using HCs, increases in glucocorticoids in response to the TSST were common, and increases in glucocorticoids were accompanied by increases in TNF-α. HC users and NC women also differed in their psychological responses to the TSST, with HC users reporting elevated stress levels compared to NC women. Together, these results suggest that HC use impacts women's glucocorticoid, inflammatory, and psychological responses to psychosocial stress, potentially contributing to observed differences in these women's mental and physical health.

Stress-related cellular pathophysiology as a crosstalk risk factor for neurocognitive and psychiatric disorders.

In this narrative review, we examine biological processes linking psychological stress and cognition, with a focus on how psychological stress can activate multiple neurobiological mechanisms that drive cognitive decline and behavioral change. First, we describe the general neurobiology of the stress response to define neurocognitive stress reactivity. Second, we review aspects of epigenetic regulation, synaptic transmission, sex hormones, photoperiodic plasticity, and psychoneuroimmunological processes that can contribute to cognitive decline and neuropsychiatric conditions. Third, we explain mechanistic processes linking the stress response and neuropathology. Fourth, we discuss molecular nuances such as an interplay between kinases and proteins, as well as differential role of sex hormones, that can increase vulnerability to cognitive and emotional dysregulation following stress. Finally, we explicate several testable hypotheses for stress, neurocognitive, and neuropsychiatric research. Together, this work highlights how stress processes alter neurophysiology on multiple levels to increase individuals' risk for neurocognitive and psychiatric disorders, and points toward novel therapeutic targets for mitigating these effects. The resulting models can thus advance dementia and mental health research, and translational neuroscience, with an eye toward clinical application in cognitive and behavioral neurology, and psychiatry.

The effect of adverse childhood experience training, screening, and response in primary care: a systematic review.

Background: Adverse childhood experiences (ACEs) can have harmful, long-term health effects. Although primary care providers (PCPs) could help mitigate these effects, no studies have reviewed the impacts of ACE training, screening, and response in primary care. Methods: This systematic review searched four electronic databases (PubMed, Web of Science, APA PsycInfo, CINAHL) for peer-reviewed articles on ACE training, screening, and/or response in primary care published between Jan 1, 1998, and May 31, 2023. Searches were limited to primary research articles in the primary care setting that reported provider-related outcomes (knowledge, confidence, screening behavior, clinical care) and/or patient-related outcomes (satisfaction, referral engagement, health outcomes). Summary data were extracted from published reports. Findings: Of 6532 records, 58 met inclusion criteria. Fifty-two reported provider-related outcomes; 21 reported patient-related outcomes. 50 included pediatric populations, 12 included adults. A majority discussed screening interventions (n = 40). Equal numbers (n = 25) discussed training and clinical response interventions. Strength of evidence (SOE) was generally low, especially for adult studies. This was due to reliance on observational evidence, small samples, and self-report measures for heterogeneous outcomes. Exceptions with moderate SOE included the effect of training interventions on provider confidence/self-efficacy and the effect of screening interventions on screening uptake and patient satisfaction. Interpretation: Primary care represents a potentially strategic setting for addressing ACEs, but evidence on patient- and provider-related outcomes remains scarce. Funding: The California Department of Health Care Services and the Office of the California Surgeon General.

Neural Markers of Emotion Reactivity and Regulation Before and After a Targeted Social Rejection: Differences Among Girls With and Without Suicidal Ideation and Behavior Histories.

BACKGROUND: Suicidal thoughts and behaviors (STBs) are common among adolescent girls and increase risk for suicide death. Emotion regulation difficulties are linked with STBs, particularly in response to targeted social rejection. However, neural correlates of this link have not been investigated and may identify novel targets for interventions. Here, we examined neural correlates of emotion regulation before and after an experimentally delivered targeted social rejection in adolescent girls with STBs and girls without STBs (i.e., control participants). METHODS: Girls (N = 138; age range, 9-15 years; mean [SD] age = 11.6 [1.79] years) completed a functional neuroimaging emotion regulation task. In the middle of the task, participants were socially rejected by an unfamiliar confederate whom the participants had elected to meet. Participants also completed a multimethod STB assessment. RESULTS: Before rejection, girls with a history of STBs, compared with control participants, showed greater activation in the right superior frontal gyrus when passively viewing negative stimuli, and girls with suicidal behavior (SB) versus those without SB showed less activation in the right frontal pole during emotion regulation attempts. Following the rejection, girls with STBs, compared with control participants, showed greater activation in the right inferior frontal gyrus during emotion regulation. CONCLUSIONS: Before social rejection, girls with SB versus without SB may not activate brain regions implicated in emotion regulation, suggesting a vulnerability to poor regulation at their baseline emotional state. After social rejection, girls with any history of STBs showed altered activation in a brain region strongly associated with inhibition and emotion regulation success, possibly reflecting increased effort at inhibiting emotional responses during regulation following stress exposure.

Parents' Adverse and Positive Childhood Experiences and Offspring Involvement With the Criminal Legal System.

Importance: Intergenerational cycles of adversity likely increase one's risk of criminal legal system involvement, yet associations with potential contributors, such as parents' adverse childhood experiences (ACEs) and positive childhood experiences (PCEs), have not been explored. Objective: To investigate the association of parents' ACEs and PCEs with their adult children's involvement in US legal systems, from arrest to conviction. Design, Setting, and Participants: The study team analyzed data from the Panel Study of Income Dynamics (PSID), a nationally representative cohort study of families in the US. PSID-2013 survey data were merged with the 2014 PSID Childhood Retrospective Circumstances Study (CRCS), collected May 2014 to January 2015, which asked adults aged 18 to 97 years to retrospectively report on their childhood experiences. Parents and their adult children were linked in the data set. Data were analyzed from October 2022 to September 2023. Main Outcomes and Measures: The child arrest outcome was regressed on parents' ACE and PCE scores using logistic regression models. In addition, multinomial logistic regression models were used to assess the associations of parents' ACE and PCE scores with the number of times their child was arrested and convicted. Results: Of 12 985 eligible individuals, 8072 completed the CRCS. Among CRCS participants, there were 1854 eligible parent-child dyads (ie, parents and their adult children) that formed the analytic sample. The mean (SD) age of offspring at the time of CRCS completion was 38.5 (10.9) years, and 1076 offspring (51.3%) were female. Having 4 or more parental ACEs was associated with 1.91-fold (95% CI, 1.14-3.22) higher adjusted odds of arrest before age 26 and 3.22-fold (95% CI, 1.62-6.40) higher adjusted odds of conviction before age 26 years, compared with children of parents without ACEs. These associations persisted after controlling for parental PCEs. Conclusions and Relevance: In this nationally representative study, children of parents with higher ACEs were at greater risk of arrest during adolescence and young adulthood, even after controlling for parents' PCEs. Addressing and preventing childhood adversity through multigenerational life course approaches may help disrupt intergenerational pathways to the criminal legal system.

Cumulative lifetime acute stressor exposure interacts with reward responsiveness to predict longitudinal increases in depression severity in adolescence.

BACKGROUND: Life stress and blunted reward processing each have been associated with the onset and maintenance of major depressive disorder. However, much of this work has been cross-sectional, conducted in separate lines of inquiry, and focused on recent life stressor exposure, despite the fact that theories of depression posit that stressors can have cumulative effects over the lifespan. To address these limitations, we investigated whether acute and chronic stressors occurring over the lifespan interacted with blunted reward processing to predict increases in depression over time in healthy youth. METHOD: Participants were 245 adolescent girls aged 8-14 years old (Mage = 12.4, s.d. = 1.8) who were evaluated at baseline and two years later. The reward positivity (RewP), an event-related potential measure of reward responsiveness, was assessed at baseline using the doors task. Cumulative lifetime exposure to acute and chronic stressors was assessed two years later using the Stress and Adversity Inventory for Adolescents (Adolescent STRAIN). Finally, depressive symptoms were assessed at both baseline and follow-up using the Children's Depression Inventory. RESULTS: As hypothesized, greater lifetime acute stressor exposure predicted increases in depressive symptoms over two years, but only for youth exhibiting a blunted RewP. This interaction, however, was not found for chronic stressors. CONCLUSIONS: Lifetime acute stressor exposure may be particularly depressogenic for youth exhibiting a blunted RewP. Conversely, a robust RewP may be protective in the presence of greater acute lifetime stressor exposure.

Multi-omics approaches in psychoneuroimmunology and health research: Conceptual considerations and methodological recommendations.

The field of psychoneuroimmunology (PNI) has grown substantially in both relevance and prominence over the past 40 years. Notwithstanding its impressive trajectory, a majority of PNI studies are still based on a relatively small number of analytes. To advance this work, we suggest that PNI, and health research in general, can benefit greatly from adopting a multi-omics approach, which involves integrating data across multiple biological levels (e.g., the genome, proteome, transcriptome, metabolome, lipidome, and microbiome/metagenome) to more comprehensively profile biological functions and relate these profiles to clinical and behavioral outcomes. To assist investigators in this endeavor, we provide an overview of multi-omics research, highlight recent landmark multi-omics studies investigating human health and disease risk, and discuss how multi-omics can be applied to better elucidate links between psychological, nervous system, and immune system activity. In doing so, we describe how to design high-quality multi-omics studies, decide which biological samples (e.g., blood, stool, urine, saliva, solid tissue) are most relevant, incorporate behavioral and wearable sensing data into multi-omics research, and understand key data quality, integration, analysis, and interpretation issues. PNI researchers are addressing some of the most interesting and important questions at the intersection of psychology, neuroscience, and immunology. Applying a multi-omics approach to this work will greatly expand the horizon of what is possible in PNI and has the potential to revolutionize our understanding of mind-body medicine.

Wearable technologies for health research: Opportunities, limitations, and practical and conceptual considerations.

One of the most notable limitations of laboratory-based health research is its inability to continuously monitor health-relevant physiological processes as individuals go about their daily lives. As a result, we have generated large amounts of data with unknown generalizability to real-world situations and also created a schism between where data are collected (i.e., in the lab) and where we need to intervene to prevent disease (i.e., in the field). Devices using noninvasive wearable technology are changing all of this, however, with their ability to provide high-frequency assessments of peoples' ever-changing physiological states in daily life in a manner that is relatively noninvasive, affordable, and scalable. Here, we discuss critical points that every researcher should keep in mind when using these wearables in research, spanning device and metric decisions, hardware and software selection, and data quality and sampling rate issues, using research on stress and health as an example throughout. We also address usability and participant acceptability issues, and how wearable "digital biomarker" and behavioral data can be integrated to enhance basic science and intervention studies. Finally, we summarize 10 key questions that should be addressed to make every wearable study as strong as possible. Collectively, keeping these points in mind can improve our ability to study the psychobiology of human health, and to intervene, precisely where it matters most: in peoples' daily lives.