State and trait predictors of cognitive responses to acute stress and uncertainty.

Stress occurs when conditions burden or exceed an individual's adaptive resources. Military personnel are often tasked with maintaining peak performance under such stressful conditions. Importantly, the effects of stress are nuanced and may vary as a function of individual traits and states. Recent interdisciplinary research has sought to model and identify such relationships. In two previously reported efforts, Soldiers first completed a comprehensive battery of trait assessments across four general domains thought to be predictive of performance: cognitive, health, physical, and social-emotional, and then completed the Decision-Making under Uncertainty and Stress (DeMUS) virtual reality task that probed spatial cognition, memory, and decision-making under stress and variable uncertainty. The present analysis explores whether cognitive, health, physical, and social-emotional trait assessments, as well as physiological state measures, predict or modulate DeMUS performance outcomes under stress. Multiple regression analyses examined the effect of each trait predictor and stress responsiveness on quantitative task performance outcomes. Results revealed that one measure of state stress reactivity, salivary cortisol, predicted lower recognition memory sensitivity. Further, trait measures of healthy eating, agility, flexibility, cognitive updating, and positive emotion predicted enhanced spatial orienting and decision-making performance and confidence. Together, the results suggest that select individual states and traits may predict cognition under stress. Future research should expand to ecologically relevant military stressors during training and operations.

Patterns of experience, expression, and physiology of stress relate to depressive symptoms and self-injurious thoughts and behaviors in adolescents: a person-centered approach.

BACKGROUND: Preliminary evidence shows that discordance in stress experience, expression, and physiology (EEP) in adolescents is linked to depression, suicidal ideation (SI), non-suicidal self-injury (NSSI), and brain functioning. This study employs person-centered analysis to probe the relationship between stress responses, psychopathology, and neural patterns in female adolescents who are oversampled for engagement in NSSI. METHODS: Adolescent females (N = 109, ages 12-17) underwent a social stress test from which self-report measures of stress experience, observer ratings of stress expression, and physiological metrics of stress (via salivary cortisol) were obtained. Multi-trajectory modeling was employed to identify concordant and discordant stress EEP groups. Depressive symptoms, SI and attempt, NSSI engagement, frontal and limbic activation to emotional stimuli, and resting state fronto-limbic connectivity were examined in the EEP groups derived from the multi-trajectory models. RESULTS: Four groups were identified, three of which demonstrated relatively concordant EEP and one which demonstrated discordant EEP (High Experience-High Expression-Low Physiology). Further, replicating past research, the High Experience-High Expression-Low Physiology discordant group exhibited higher depressive symptoms, SI, suicide attempt, and NSSI episodes (only for sensitivity analyses based on past year) relative to other EEP groups. No significant group differences in brain functioning emerged. CONCLUSION: Results indicate that within-person, multi-level patterns in stress responding capture risk for dysfunction including depression and self-injurious thoughts and behaviors. Further interrogating of system-level stress functioning may better inform assessment and intervention efforts.

Profiles of autonomic stress responsivity in a sample of justice-involved youth: Associations with childhood trauma exposure and emotional and behavioral functioning.

A limited number of studies have begun to investigate how the coordinated actions of distinct physiological systems may be related to the development of psychopathology. However, the form taken by these patterns of coordination as well as their antecedents and developmental implications remain to be clarified. The Adaptive Calibration Model (ACM) proposes four prototypical patterns of physiological stress responsivity and corresponding behavioral patterns, which are further tied to varying levels of childhood adversity. The current study is among the first to investigate whether patterns of sympathetic and parasympathetic stress responsivity predicted by the ACM generalize to a sample of justice-involved youth with disproportionately high rates of childhood trauma exposure. Psychophysiological and self-report data were collected from 822 justice-involved youth (182 girls) ages 12-19 years. Latent profile analyses yielded five profiles of physiological responsivity that largely corresponded to the patterns proposed by the ACM. Further, these profiles demonstrated predicted associations with self-reported emotionality and adjustment. Trauma exposure was associated with a lower likelihood of membership in one of the profiles showing blunted physiological responsivity. Our discussion highlights ways in which insights from the ACM may inform understanding about linkages between physiology and adjustment.

Autonomic nervous system functioning in early childhood: Responses to cognitive and negatively valenced emotional challenges.

Although autonomic nervous system (ANS) functioning is "context-dependent," few studies examined children's normative sympathetic and parasympathetic autonomic responses to distinct challenges in early childhood years. Examining children's ANS responsivity to distinct challenges is important for understanding normative autonomic responses toward everyday life stressors and identifying paradigms that effectively elicit a "stress response." We examined children's (N = 278) sympathetic (preejection period [PEP]) and parasympathetic (respiratory sinus arrhythmia [RSA]) responses to cognitive (i.e., problem-solving and cognitive control) and negatively valenced emotional (i.e., blocked goal and unfairness) challenges in preschool, kindergarten, and grade 1. Children, on average, demonstrated parasympathetic inhibition (RSA withdrawal) in response to all challenges but the magnitude of these responses depended on the task. Children showed sympathetic activation (PEP shortening) toward the problem-solving task at each assessment and there was no sample-level change in the magnitude of this response over time. Children showed greater sympathetic responsivity toward the cognitive control task over time, with evidence for a sympathetic activation response only in grade 1. Children experienced sympathetic inhibition (PEP lengthening) toward the unfairness tasks but did not experience significant sympathetic responsivity toward the blocked goal tasks. Parasympathetic responsivity to most challenges were modestly stable but there was no stability in sympathetic responsivity across time.

Sex-dependent effects of MC4R genotype on HPA axis tone: implications for stress-associated cardiometabolic disease.

The melanocortin-4 receptor (MC4R) facilitates hypothalamic-pituitary-adrenocortical (HPA) axis responses to acute stress in male rodents and is a well known to regulator of energy balance. Mutations in the MC4R is the most common monogenic cause of obesity in humans and has been associated with sex-specific effects, but whether stress regulation by the MC4R is sex-dependent, and whether the MC4R facilitates HPA responses to chronic stress, is unknown. We hypothesized that MC4R-signaling contributes to HPA axis dysregulation and metabolic pathophysiology following chronic stress exposure. We measured changes in energy balance, HPA axis tone, and vascular remodeling during chronic variable stress (CVS) in male and female rats with MC4R loss-of-function. Rats were placed into three groups (n = 9-18/genotype/sex) and half of each group was subjected to CVS for 30 days or were non-stressed littermate controls. All rats underwent an acute restraint stress challenge on Day 30. Rats were euthanized on Day 31, adrenals collected for weight, and descending aortas fixed for morphological indices of vascular pathophysiology. We observed a marked interaction between Mc4r genotype and sex for basal HPA axis tone and acute stress responsivity. MC4R loss-of-function blunted both endpoints in males but exaggerated them in females. Contrary to our hypothesis, Mc4r genotype had no effect on either HPA axis responses or metabolic responses to chronic stress. Heightened stress reactivity of females with MC4R mutations suggests a possible mechanism for the sex-dependent effects associated with this mutation in humans and highlights how stress may differentially regulate metabolism in males and females. Lay summary The hypothalamic melanocortin system is an important regulator of energy balance and stress responses. Here, we report a sex-difference in the stress reactivity of rats with a mutation in this system. Our findings highlight how stress may regulate metabolism differently in males and females and may provide insight into sex-differences associated with this mutation in humans.

Blood lead levels and hypothalamic-pituitary-adrenal function in middle-aged individuals.

Experimental and epidemiological studies suggested that exposure to lead (Pb) may influence the hypothalamic-pituitary-adrenal (HPA) axis. However, previous studies have yielded mixed results. We evaluated changes in basal salivary cortisol levels and acute cortisol responsivity to psychological stress in relation with blood Pb levels (BPb), in Caucasian individuals 50-67 years of age. Data were collected through the Study of Genetics, Stress and Cognitive Development (2004-2006). Diurnal basal and stress-reactive salivary cortisol levels were collected and BPb levels were determined using inductively coupled plasma mass spectroscopy. A total of 65 participants were included in the current study. General linear mixed models were used to assess the association between BPb level and change in cortisol secretion over time, for diurnal basal pattern and stress-reactive pattern, respectively. The geometric mean BPb was 2.70µg/dL (± 1.44) and two exposure groups were created based on the median value of 2.48µg/dL. No difference in geometric mean of salivary cortisol (µg/dL) at awakening was observed between High and Low BPb groups (0.23 (± 0.11) vs 0.20 (± 0.11), p = 0.36). The overall pattern of change in both diurnal basal (from the awakening to bedtime) and reactive salivary cortisol (during the stress induction protocol) did not differ between groups. In these middle-aged and older adults, we concluded that Pb exposure, within the range observed in the current study, was associated with neither diurnal nor stress-reactive cortisol secretion. Further investigation with larger datasets are needed to confirm our observations.

Ghrelin levels after a cold pressor stress test in obese women with binge eating disorder.

OBJECTIVE: Ghrelin, a peptide hormone secreted mainly by the stomach, increases appetite and food intake. Surprisingly, ghrelin levels are lower in obese individuals with binge eating disorder (BED) than in obese non-BED individuals. Acute psychological stress has been shown to raise ghrelin levels in animals and humans. Our aim was to assess ghrelin levels after a cold pressor test (CPT) in women with BED. We also examined the relationship between the cortisol stress response and changes in ghrelin levels. METHODS: Twenty-one obese (mean [standard deviation] body mass index = 34.9 [5.8] kg/m(2)) women (10 non-BED, 11 BED) underwent the CPT, hand submerged in ice water for 2 minutes. Blood samples were drawn for 70 minutes and assayed for ghrelin and cortisol. RESULTS: There were no differences between the groups in ghrelin levels at baseline (-10 minutes). Ghrelin rose significantly after the CPT (F = 2.4, p = .024) peaking at 19 minutes before declining (F = 17.9, p < .001), but there were no differences between the BED and non-BED groups. Area under the curve for ghrelin was not related to ratings of pain, stress, hunger, or desire to eat after CPT. In addition, there were no observed relationships between the area under the curves for ghrelin or cortisol after stress. CONCLUSIONS: Although there were no differences between BED groups, there was a significant rise in ghrelin in obese humans after a stressor, consistent with other recent reports suggesting a stress-related role for ghrelin.

Effects of social isolation and galactic cosmic radiation on fine motor skills and behavioral performance.

Future NASA missions will require astronauts to travel farther and spend longer durations in space than ever before. This will also expose astronauts to longer periods of several physical and psychological challenges, including exposure to space radiation (SR) and periods of social isolation (SI), which could have unknown negative effects on physical and mental health. Each also has the potential to negatively impact sleep which can reduce the ability to cope with stressful experiences and lead to sensorimotor, neurocognitive, and physical deficits. The effects of SI and SR on gross motor performance has been shown to vary, and depend on, individual differences in stress resilience and vulnerability based on our established animal model in which stress produces different effects on sleep. In this study, the impact that SI and SR, either alone or together, had on fine motor skill performance (bilateral tactile adhesive removal task (BTAR)) was assessed in male rats. We also examined emotional, exploratory, and other off-task behavioral responses during testing and assessed whether sensorimotor performance and emotion varied with individual differences in resilience and vulnerability. BTAR task performance was differentially impacted by SI and SR, and were further influenced by the stress resilience/vulnerability phenotype of the rats. These findings further demonstrate that identifying individual responses to stressors that can impact sensorimotor ability and behavior necessary to perform mission-related tasks will be of particular importance for astronauts and future missions. Should similar effects occur in humans, there may be considerable inter-individual variability in the impact that inflight stressors have on astronauts and their ability to perform mission-related tasks.

Non-invasive, real-time stress measurement: Vocalization compared with thermal imaging in kittens of the domestic cat in response to social separation.

Finding tools to assess the stress response which can be easily applied, are non-invasive, reliable and measured in real time is still a relevant topic in many areas of biology. Vocal characteristics and temperature of certain body areas have been suggested to reflect HPA axis and ANS activation. We hypothesized that changes in vocalizations and peripheral body temperature will show the magnitude of the stress response, and that the change in these will covary. Our aim was to measure the change in vocal characteristics and eye and nasal temperature of kittens (n = 43 from nine litters of seven mixed-breed mothers) during a potentially stressful event and to test how these correlated. We found change in several vocal and thermal parameters during a short social separation. Our findings indicate that arousal due to ANS activation in kittens of the domestic cat resulted in an increasing number of vocalisations of longer duration and higher intensity, and in lower and a wider range in fundamental frequency. Calls also became less tonal with more jitter. Change in temperature was generally negative in the lacrimal caruncle as well as in the rhinarium, but with great variance across individuals. Change in eye temperature positively correlated with the intensity of the calls and the change in nose temperature positively correlated with the change in call length. The results suggest the continued difficulty in interpreting both physiological and behavioural data to assess an individual´s stress response.

The relationship between stress responding in family context and stress sensitivity with sleep dysfunction in individuals at clinical high-risk for psychosis.

Stress and sleep have been implicated in the etiology of psychosis, and literature suggests they are closely related. Two distinct domains of stress associated with sleep dysfunction in the general population are responsivity to environmental stressors and stress sensitivity. However, to date, no research has examined relationships between these stress domains and sleep dysfunction in individuals at clinical high-risk (CHR) for psychosis. A total of 57 CHR (mean age = 18.89, SD = 1.82) and 61 healthy control (HC; mean age = 18.34, SD = 2.41) adolescents and young adults completed a measure of emerging stress intolerance. A subset of participants (CHR = 50, HC = 49) completed a measure indexing responsivity to family stressors - an integral context for this developmental stage overlapping with the psychosis-risk period. Sleep efficiency, continuity, and duration were objectively assessed by actigraphy (CHR = 38, HC = 36). Partial correlations with age and sex as covariates were conducted in both groups separately to examine relationships between stress and sleep. Results indicated that automatic maladaptive responsivity to family stressors was associated with disrupted sleep in the CHR but not HC group. Specifically, greater involuntary engagement was associated with poorer sleep efficiency (r = -.42) but not sleep continuity (r = 0.31) and duration (r = .-19). Interestingly, both adaptative and maladaptive voluntary responses to stressors (engagement and disengagement coping) were not associated with sleep. Finally, impaired stress tolerance was associated with sleep efficiency (r = -0.47), continuity (r = 0.37), and duration (r = -0.43). Taken together, findings provided important groundwork for understanding the role of the relationship between involuntary maladaptive responsivity to family stressors and stress sensitivity with sleep in psychosis etiology.

Bipolar disorder: An evolutionary psychoneuroimmunological approach.

Bipolar disorder is a mental health disorder characterized by extreme shifts in mood, high suicide rate, sleep problems, and dysfunction of psychological traits like self-esteem (feeling inferior when depressed and superior when manic). Bipolar disorder is rare among populations that have not adopted contemporary Western lifestyles, which supports the hypothesis that bipolar disorder results from a mismatch between Homo sapiens's evolutionary and current environments. Recent studies have connected bipolar disorder with low-grade inflammation, the malfunctioning of the internal clock, and the resulting sleep disturbances. Stress is often a triggering factor for mania and sleep problems, but stress also causes low-grade inflammation. Since inflammation desynchronizes the internal clock, chronic stress and inflammation are the primary biological mechanisms behind bipolar disorder. Chronic stress and inflammation are driven by contemporary Western lifestyles, including stressful social environments, unhealthy dietary patterns, limited physical activity, and obesity. The treatment of bipolar disorder should focus on reducing stress, stress sensitivity, and inflammation by lifestyle changes rather than just temporarily alleviating symptoms with psychopharmacological interventions.

Cortisol Responses to Naturally Occurring Psychosocial Stressors Across the Psychosis Spectrum: A Systematic Review and Meta-Analysis.

BACKGROUND: Individuals with established psychosis and those at high-risk for the disorder have been found to show abnormalities within the hypothalamic-pituitary-adrenal (HPA) axis, including elevations in basal and diurnal cortisol, but a blunted cortisol awakening response. However, the extent to which these features are associated with psychosocial stressors encountered in the natural environment (which are known to be more commonly experienced by these groups, and more distressing) is currently unclear. We therefore conducted a systematic review and meta-analysis to investigate the concordance between naturally-occurring psychosocial stressors and cortisol levels in these populations. METHODS: PubMed, PsycINFO, and EMBASE were searched up to November 2019 to identify studies examining the concordance between psychosocial stressors and cortisol in healthy controls and individuals on the psychosis spectrum (patients with established psychosis and/or high-risk individuals). An overall meta-analysis (including data for all stressor-cortisol pairings) was performed to determine the degree of concordance irrespective of group status, with meta-regression employed to test whether the degree of concordance differed in established psychosis and high-risk groups compared to controls. Planned stratified analyses were then performed to examine group differences (where established psychosis and high-risk groups were combined) within individual stressor-cortisol pairings. RESULTS: Eighteen studies (16 datasets) were eligible for inclusion. The overall model, comprising 134 effect sizes, showed that stressors and cortisol measures were only weakly correlated [r=0.05 (95% CI: -0.00 to 0.10), p=0.059] and that neither established psychosis status (r=0.01, p=0.838) nor high-risk status (r=0.02, p=0.477) had a significant effect of the strength of correlation. In stratified analyses, significant differences between healthy controls and psychosis spectrum groups were observed for only one of the six stressor-cortisol pairings examined, where life event exposure and diurnal cortisol were positively correlated in controls [r=0.25 (95% CI: 0.01 to 0.46)], but negatively correlated in the psychosis spectrum group [r=-0.28 (95% CI: -0.49 to -0.04)]. CONCLUSIONS: Overall, we observed poor concordance between naturally-occurring psychosocial stressors and cortisol irrespective of stressor type, cortisol measure, or group status. We consider a range of methodological factors that may have obscured the ability to detect "true" associations and provide recommendations for future studies in this field.

Eating Disorders: An Evolutionary Psychoneuroimmunological Approach.

Eating disorders are evolutionarily novel conditions. They lead to some of the highest mortality rates of all psychiatric disorders. Several evolutionary hypotheses have been proposed for eating disorders, but only the intrasexual competition hypothesis is extensively supported by evidence. We present the mismatch hypothesis as a necessary extension to the current theoretical framework of eating disorders. This hypothesis explains the evolutionarily novel adaptive metaproblem that has arisen when mating motives conflict with the large-scale and easy availability of hyper-rewarding but obesogenic foods. This situation is exacerbated particularly in those contemporary environments that are characterized by sedentary lifestyles, ever-present junk foods, caloric surplus and the ubiquity of social comparisons that take place via social media. Our psychoneuroimmunological model connects ultimate-level causation with proximate mechanisms by showing how the adaptive metaproblem between mating motives and food rewards leads to chronic stress and, further, to disordered eating. Chronic stress causes neuroinflammation, which increases susceptibility to OCD-like behaviors that typically co-occur with eating disorders. Chronic stress upregulates the serotonergic system and causes dysphoric mood in anorexia nervosa patients. Dieting, however, reduces serotonin levels and dysphoric mood, leading to a vicious serotonergic-homeostatic stress/starvation cycle whereby cortisol and neuroinflammation increase through stringent dieting. Our psychoneuroimmunological model indicates that between-individual and within-individual variation in eating disorders partially arises from (co)variation in gut microbiota and stress responsivity, which influence neuroinflammation and the serotonergic system. We review the advances that have been made in recent years in understanding how to best treat eating disorders, outlining directions for future clinical research. Current evidence indicates that eating disorder treatments should aim to reduce the chronic stress, neuroinflammation, stress responsivity and gut dysbiosis that fuel the disorders. Connecting ultimate causes with proximate mechanisms and treating biopsychosocial causes rather than manifest symptoms is expected to bring more effective and sophisticated long-term interventions for the millions of people who suffer from eating disorders.

Maternal anxiety and depressive disorders prior to, during and after pregnancy and infant interaction behaviors during the Face-to-Face Still Face Paradigm at 4 months postpartum: A prospective-longitudinal study.

BACKGROUND: Few studies prospectively examined the role of maternal anxiety and depressive disorders for early infant psychosocial stress responsivity. AIMS: To investigate the role of lifetime maternal anxiety and depressive disorders for various early infant interaction behaviors during the Face-to-Face Still Face Paradigm (FFSFP) at 4 months postpartum. STUDY DESIGN/SUBJECTS: Prospective-longitudinal study among n = 251 mothers (and their infants) from early pregnancy until 4 months postpartum. PREDICTOR: Cumulated lifetime diagnoses of maternal anxiety and depressive disorders, repeatedly assessed with the CIDI-V from early pregnancy until 4 months postpartum. OUTCOME MEASURES: Infant positive and negative facial expressions and vocalizations, distancing behavior, self- and object-touch, observed during the FFSFP at 4 months postpartum. RESULTS: As indicated by fractional logit models, higher proportions of object-touch were seen among infants of mothers with anxiety only (still face: 7.8%) and comorbid anxiety and depression (still face: 7.9%; reunion: 2.9%) vs. no anxiety and no depression. Higher proportion changes in object-touch were found among infants of mothers with anxiety only (play to still face: 6.4%) and comorbid anxiety and depression (play to still face: 7.2%; play to reunion: 2.7%) vs. no anxiety and no depression. Higher proportion changes in distancing behavior were seen among infants of mothers with comorbid anxiety and depression (still face to reunion: 1.1%; play to reunion: 1.3%) vs. no anxiety and no depression. CONCLUSIONS: Particularly mothers with anxiety only and comorbid anxiety and depression and their infants might profit from targeted early interventions to foster favorable interaction behaviors in early infancy and thereafter.

Approaches to modeling the development of physiological stress responsivity.

Influential biopsychosocial theories have proposed that some developmental periods in the lifespan are potential pivot points or opportunities for recalibration of stress response systems. To date, however, there have been few longitudinal studies of physiological stress responsivity and no studies comparing change in physiological stress responsivity across developmental periods. Our goals were to (a) address conceptual and methodological issues in studying the development of physiological stress responsivity within and between individuals, and (b) provide an exemplar for evaluating development of responsivity to stress in the parasympathetic nervous system, comparing respiratory sinus arrhythmia (RSA) responsivity from middle to late childhood with middle to late adolescence. We propose the use of latent growth modeling of stress responsivity that includes time-varying covariates to account for conceptual and methodological issues in the measurement of physiological stress responsivity. Such models allow researchers to address key aspects of developmental sensitivity including within-individual variability, mean level change over time, and between-individual variability over time. In an empirical example, we found significant between-individual variability over time in RSA responsivity to stress during middle to late childhood but not during middle to late adolescence, suggesting that childhood may be a period of greater developmental sensitivity at the between-individual level.

Early life stress, air pollution, inflammation, and disease: An integrative review and immunologic model of social-environmental adversity and lifespan health.

Socially disadvantaged individuals are at greater risk for simultaneously being exposed to adverse social and environmental conditions. Although the mechanisms underlying joint effects remain unclear, one hypothesis is that toxic social and environmental exposures have synergistic effects on inflammatory processes that underlie the development of chronic diseases, including cardiovascular disease, diabetes, depression, and certain types of cancer. In the present review, we examine how exposure to two risk factors that commonly occur with social disadvantage-early life stress and air pollution-affect health. Specifically, we identify neuroimmunologic pathways that could link early life stress, inflammation, air pollution, and poor health, and use this information to propose an integrated, multi-level model that describes how these factors may interact and cause health disparity across individuals based on social disadvantage. This model highlights the importance of interdisciplinary research considering multiple exposures across domains and the potential for synergistic, cross-domain effects on health, and may help identify factors that could potentially be targeted to reduce disease risk and improve lifespan health.

Hair cortisol concentrations in war-affected adolescents: A prospective intervention trial.

Temporal examinations of the biological signature of stress or trauma in war-affected populations are seldom undertaken. Moreover, few studies have examined whether stress biomarkers track biological sensitivity to brief interventions targeting the improvement of psychosocial wellbeing. Our study is the first to prospectively examine, in war-affected adolescents, the associations between hair cortisol concentrations (HCC) and self-reports of stress, insecurity, posttraumatic reactions, and lifetime trauma. We conducted a randomized controlled trial to test the impact of an 8-week intervention based on profound stress attunement. We collected data for a gender-balanced sample of 733 Syrian refugee (n = 411) and Jordanian non-refugee (n = 322) adolescents (12-18 years), at three time-points. We used growth mixture models to classify cortisol trajectories, and growth models to evaluate intervention impact on stress physiology. We observed three trajectories of HCC: hypersecretion, medium secretion, and hyposecretion (9.6%, 87.5% and 2.9% of the cohort, respectively). For every one percent increase in levels of insecurity, adolescents were 0.02 times more likely to have a trajectory of hypersecretion (95% CI: 1.00, 1.03, p = 0.01). For each additional symptom of posttraumatic stress reported, they were 0.07 times less likely to show hyposecretion (95% CI: 0.89, 0.98, p = 0.01). Indeed, stronger posttraumatic stress reactions were associated with a pattern of within-individual cortisol dysregulation and medium secretion. Overall, HCC decreased by a third in response to the intervention (95% CI: -0.19, -0.03, p = 0.01). While the intervention decreased HCC for youth with hypersecretion and medium secretion, it increased HCC for youth with hyposecretion (95% CI: 0.22, 1.16, p = 0.004), relative to controls. This suggests a beneficial regularization of cortisol levels, corroborating self-reports of improved psychosocial wellbeing. We did not find evidence to suggest that gender, resilience, or posttraumatic stress disorder influenced the strength or direction of responses to the intervention. This robust impact evaluation exemplifies the utility of biomarkers for tracking physiological changes in response to interventions over time. It enhances the understanding of trajectories of endocrine response in adverse environments and patterns of stress responsivity to ecological improvement.

Altered cytokine profile, pain sensitivity, and stress responsivity in mice with co-disruption of the developmental genes Neuregulin-1×DISC1.

The complex genetic origins of many human disorders suggest that epistatic (gene×gene) interactions may contribute to a significant proportion of their heritability estimates and phenotypic heterogeneity. Simultaneous disruption of the developmental genes and schizophrenia risk factors Neuregulin-1 (NRG1) and Disrupted-in-schizophrenia 1 (DISC1) in mice has been shown to produce disease-relevant and domain-specific phenotypic profiles different from that observed following disruption of either gene alone. In the current study, anxiety and stress responsivity phenotypes in male and female mutant mice with simultaneous disruption of DISC1 and NRG1 were examined. NRG1×DISC1 mutant mice were generated and adult mice from each genotype were assessed for pain sensitivity (hot plate and tail flick tests), anxiety (light-dark box), and stress-induced hypothermia. Serum samples were assayed to measure circulating levels of pro-inflammatory cytokines. Mice with the NRG1 mutation, irrespective of DISC1 mutation, spent significantly more time in the light chamber, displayed increased core body temperature following acute stress, and decreased pain sensitivity. Basal serum levels of cytokines IL8, IL1ß and IL10 were decreased in NRG1 mutants. Mutation of DISC1, in the absence of epistatic interaction with NRG1, was associated with increased serum levels of IL1ß. Epistatic effects were evident for IL6, IL12 and TNFα. NRG1 mutation alters stress and pain responsivity, anxiety, and is associated with changes in basal cytokine levels. Epistasis resulting from synergistic NRG1 and DISC1 gene mutations altered pro-inflammatory cytokine levels relative to the effects of each of these genes individually, highlighting the importance of epistatic mechanisms in immune-related pathology.

Association of Variants of Arginine Vasopressin and Arginine Vasopressin Receptor 1A With Severe Acetaminophen Liver Injury.

BACKGROUND & AIMS: Acetaminophen-related acute liver injury and liver failure (ALF) result from ingestion of supratherapeutic quantities of this analgesic, frequently in association with other forms of substance abuse including alcohol, opioids, and cocaine. Thus, overdosing represents a unique high-risk behavior associated with other forms of drug use disorder. METHODS: We examined a series of 21 single nucleotide polymorphisms (SNPs) in 9 genes related to impulsivity and/or stress responsivity that may modify response to stress. Study subjects were 229 white patients admitted to tertiary care liver centers for ALF that was determined to be due to acetaminophen toxicity after careful review of historical and biochemical data. Identification of relevant SNPs used Sanger sequencing, TaqMan, or custom microarray. Association tests were carried out to compare genotype frequencies between patients and healthy white controls. RESULTS: The mean age was 37 years, and 75.6% were female, with similar numbers classified as intentional overdose or unintentional (without suicidal intent, occurring for a period of several days, usually due to pain). There was concomitant alcohol abuse in 30%, opioid use in 33.6%, and use of other drugs of abuse in 30.6%. The genotype frequencies of 2 SNPs were found to be significantly different between the cases and controls, specifically SNP rs2282018 in the arginine vasopressin gene (AVP, odds ratio 1.64) and SNP rs11174811 in the AVP receptor 1A gene (AVPR1A, odds ratio 1.89), both of which have been previously linked to a drug use disorder diagnosis. CONCLUSIONS: Patients who develop acetaminophen-related ALF have increased frequency of gene variants that may cause altered stress responsivity, which has been shown to be associated with other unrelated substance use disorders.