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BACKGROUND: Although bio-psycho-social health research is an ideal, samples adequate for complex modeling require biomarker specimens from hundreds of participants. Ecological sampling departs from laboratory study norms, with implications for analysis. OBJECTIVE: To inform ecological study designs, this article compares salivary cortisol levels and effect sizes of 'focal' psychiatric factors, such as trauma history, posttraumatic stress diagnosis, comorbidity, and chronic stress, and 'nuisance' factors, including endocrine disorders and medications and physiological factors such as gestational age and smoking. STUDY DESIGN: This is a descriptive analysis of ecologically collected cortisol specimens, assayed in an ongoing perinatal psychobiological study, addressing methodological considerations. RESULTS: Focal and nuisance factors are often interdependent with similar effect sizes. Careful specimen deletion decisions and model specification are needed to achieve the hoped-for external validity while maintaining internal validity. CONCLUSIONS: Results of multivariate models lend support to the validity and usefulness of an ecological approach to incorporating biomarkers in health research. [ABSTRACT FROM AUTHOR]

Purpose: Most youth experiencing anxiety/depression lack access to evidence-based mental health practices (EBPs). School-delivered care improves access, and various support can help school professionals (SPs; school social workers, counselors) deliver EBPs, like Cognitive Behavioral Therapy (CBT). Understanding implementation strategies' impact on downstream mental health outcomes is crucial to scaling up EBPs to address the treatment gap, but it has rarely been assessed., Methods: This paper compares implementation strategies' impact on change in student outcomes, collected as exploratory outcomes from a type III hybrid implementation-effectiveness trial. A clustered, sequential, multiple-assignment randomized trial design was used, which embedded four implementation supports that differentially sequence three implementation strategies, Replicating Effective Programs (REP), Coaching, and Facilitation. Prior to the first randomization, N = 169 SPs from 94 Michigan high schools each identified up to 10 students whom they believed could benefit from CBT and facilitated student survey completion. Changes in students' depression (Patient Health Questionnaire-9, modified for teens) and anxiety symptoms (Generalized Anxiety Disorder-7) over 10 months were compared across the four sequences of implementation support using a generalization of a marginal, weighted least squares approach developed for a clustered SMARTs., Results: Small, non-clinically significant reductions in symptoms over the study period were found. Pairwise comparisons found no significant differences in symptom change across the four implementation strategies. The difference in the estimated mean PHQ-9T/GAD-7 scores between the least and the most intensive strategies (REP vs. REP+Coaching+Facilitation) was 1.04 (95%CI = -0.95, 3.04) for depression and 0.82 (95%CI = -0.89, 2.52) for anxiety., Discussion: No difference in symptom change was found across the four implementation strategies. Multiple forms of implementation support may be useful for improving student mental health outcomes., Trial Registration: NCT03541317-Registered on 29 May 2018 on ClinicalTrials.gov PRS., Competing Interests: Declaration of competing interest The authors of this manuscript warrant that we have no actual or perceived conflicts of interest—financial or non-financial—in the procedures described in the enclosed manuscript. The views expressed are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs or other public entity. During completion of this manuscript, TRAILS was in the process of applying for non-profit corporation status (501c.3)., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In healthy individuals, the majority of cortisol secretion occurs within several hours surrounding morning awakening. A highly studied component of this secretory period is the cortisol awakening response (CAR), the rapid increase in cortisol levels across the first 30-45 min after morning awakening. This strong cortisol burst at the start of the active phase has been proposed to be functional in preparing the organism for the challenges of the upcoming day. Here, we review evidence on key regulatory and functional processes of the CAR and develop an integrative model of its functional role. Specifically, we propose that, in healthy individuals, the CAR is closely regulated by an intricate dual-control system, which draws upon key circadian, environmental and neurocognitive processes to best predict the daily need for cortisol-related action. Fine-tuned CAR expression, in turn, is then assumed to induce potent glucocorticoid action via rapid non-genomic and slower genomic pathways (e.g., affecting circadian clock gene expression) to support and modulate daily activity through relevant metabolic, immunological and neurocognitive systems. We propose that this concerted action is adaptive in mediating two main functions: a primary process to mobilize resources to meet activity-related demands and a secondary process to help the organism counterregulate adverse prior-day emotional experiences., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Schools are a promising access point for youth with mental health concerns, but school-based mental health professionals (SPs) often need ongoing support to provide high-fidelity cognitive behavioral therapy (CBT). Adherence and competence, two critical elements of fidelity, were examined in a cluster-randomized implementation trial. We evaluated CBT adherence and then triangulated CBT adherence with end-of-study competence. We then evaluated the effects of two implementation supports, Coaching and (for slower-responding schools) Facilitation, on adherence and competence. By the end of the 43-week study period, 27.8% of SPs met adherence criteria. Adherent SPs scored higher on the competence measure, the CBT Competence Scale ( t (116.2) = 3.71, p < .001). No significant difference in adherence was found among SPs at schools assigned to Coaching vs. not (Δ = 6.0%, p = .385), however SPs at schools randomized to Coaching scored significantly higher on two of the four competence subscales (Non-Behavioral and Behavioral skills). Among slower-responder schools, SPs at schools assigned to Facilitation were more likely to demonstrate adherence (Δ = 16.3%, p = .022), but there was no effect of Facilitation on competence. Approximately one quarter of SPs met adherence criteria in the trial; adequate delivery of exposure was a primary obstacle to reaching adherence. Facilitation may be especially suited to help SPs overcome barriers to delivery, whereas Coaching may be especially suited to help SPs improve CBT competence. Both are likely needed to build a mental health work force with the competence and ability to deliver EBPs in schools.

Background: Functional alterations of tripartite neural networks during cognitive control (i.e., frontoparietal network [FPN], cingulo-opercular network, and default mode network) occur in patients with obsessive-compulsive disorder (OCD) and may contribute to illness expression. However, the degree to which changes in these networks are elicited by gold standard treatment (e.g., exposure and response prevention [EX/RP]) remains unknown. Understanding how EX/RP modulates network connectivity in adolescent versus adult patients with OCD may aid the identification of developmentally sensitive treatment targets that enhance cognitive control., Methods: Data from a total of 169 adolescents (13-17 years) and adults (25-40 years; 57% female) were analyzed, including healthy control participants (n = 58) and patients with OCD (n = 111) who were randomized to either EX/RP or an active control therapy (stress management training). Participants performed a flanker task during functional magnetic resonance imaging pre- and posttreatment. To retain sensitivity to individual differences in connectivity, group iterative multiple model estimation was used to assess functional connectivity (i.e., density) within and between brain networks., Results: Significant increases in FPN density and decreases in FPN-default mode network density were observed from pre- to posttreatment in patients who received EX/RP. The opposite patterns of change occurred in patients who received stress management training. These treatment-related changes in network density did not differ across age group., Conclusions: Results suggest EX/RP-specific changes in task-based connectivity in patients with OCD. Given baseline differences between healthy control participants and patients by age group, these treatment-related changes may indicate restoration of healthy FPN and default mode network development across patients, providing targets for improving response to EX/RP., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Though exposure and response prevention (ERP) is a well-proven treatment for OCD across the lifespan, prior RCTs have not studied adolescent and adult patients with the same ERP protocol relative to an active comparator that controls for non-specific effects of treatment. This approach assesses differences in the effect of OCD-specific exposures in affected adolescents and adults and in response to ERP compared to a stress-management control therapy (SMT)., Methods: This assessor-blinded, parallel, 2-arm, randomized, ambulatory clinical superiority trial randomized adolescents (aged 12-18) and adults (24-46) with OCD (N = 126) to 12 weekly sessions of ERP or SMT. OCD severity was measured before, during and after treatment using the child or adult version of the Yale-Brown Obsessive Compulsive Scale (C/Y-BOCS), depending on participant age. We predicted that ERP would produce greater improvement in OCD symptoms than SMT and that there would be no significant post-treatment differences across age groups., Results: ERP (n = 63) produced significantly greater improvements on C/Y-BOCS scores at post-treatment than SMT (n = 63) (Effect size = -0.72, CI = -0.52 to -0.91, p < .001). ERP also produced more treatment responders (ERP = 86%, SMT = 32%; χ 2  = 46.37, p < .001) and remitters than SMT (ERP = 39%, SMT = 7%; χ 2  = 16.14, p < .001). Finally, there were no statistically significant post-treatment differences in C/Y-BOCS scores between adolescents and adults assigned to ERP., Conclusion: A single ERP protocol is superior to SMT in treating both adolescents and adults with OCD. OCD-specific therapy is necessary across the lifespan for optimal outcomes in this highly disabling disorder, though non-specific treatments like SMT are still all-too-commonly provided., Competing Interests: Declaration of competing interest Declarations of interest: none., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: Exposure-based therapy (EXP) and behavioral activation (BA) are empirically-supported behavioral intervention techniques that target avoidance and approach behavior to alleviate symptoms. Although EXP is an established treatment for generalized anxiety disorder (GAD), the effectiveness of BA for GAD has not been directly tested or compared with that of EXP. This study examined the efficacy of EXP and BA for adults with GAD., Method: In a randomized clinical trial (clinicaltrials.gov: NCT02807480) with partial blinding in Tulsa, OK, 102 adults with GAD were allocated to manualized, 10-session EXP or BA between April 2016-April 2021. Primary analyses were intention-to-treat and included the 94 (46 EXP, 48 BA) participants who started treatment. The GAD-7 self-report scale was the primary outcome measure., Results: Similar GAD-7 declines were observed at post-treatment for EXP ( d =-0.97 [95% CI -1.40 to -0.53]) and BA ( d =-1.14 [95% CI -1.57 to -0.70]), and were maintained through 6-month follow-up (EXP: d =-2.13, BA: d =-1.98). Compared to EXP, BA yielded more rapid declines in anxiety and depression scores during therapy ( d =0.75-0.77), as well as lower anxiety and depression scores ( d =0.13-0.14) and greater participant-rated improvement ( d =0.64) at post-treatment. Bayesian analyses indicated 74-99% probability of greater change in BA than EXP at post-treatment., Conclusions: BA and EXP are both effective in treating GAD, and BA may confer greater benefit during treatment. Future research is warranted to inform personalized treatment approaches., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests, Robin Aupperle reports financial support was provided by National Institute of Mental Health. Christopher Martell reports receiving royalties for four books on the topic of behavioral activation. Martin Paulus has received royalties for an article about methamphetamine published in UpToDate. The other authors have no conflicts of interest to declare.

Salivary cortisol stress biomarkers have been extensively used in epidemiological work to document links between stress and ill health. There has been little effort to ground field friendly cortisol measures in the hypothalamic-pituitary-adrenal (HPA) axis regulatory biology that is likely relevant to delineating mechanistic pathways leading from stress exposure to detrimental health outcomes. Here, we utilized a healthy convenience sample (n = 140) to examine normal linkages between extensively collected salivary cortisol measures and available laboratory probes of HPA axis regulatory biology. Participants provided 9 saliva samples per day over 6 days within a month, while engaging in usual activities, and also participated in 5 regulatory tests (adrenocorticoptripin stimulation, dexamethasone/corticotropin-releasing-hormone stimulation, metyrapone, dexamethasone suppression, and Trier Social Stress Test). Logistical regression was used to test specific predictions linking cortisol curve components to regulatory variables and to explore widely for non-predicted associations. We found support for 2 of 3 original hypotheses, showing associations (1) between cortisol diurnal decline and feedback sensitivity as measured by dexamethasone suppression, and (2) between morning cortisol levels and adrenal sensitivity. We did not find links between central drive (metyrapone test) and end of day salivary levels. We confirmed an a priori expectation of limited linkage between regulatory biology and diurnal salivary cortisol measures, beyond those predicted. These data support an emerging focus on measures related to diurnal decline in epidemiological stress work. They raise questions about the biological meaning of other curve components, including morning cortisol levels, and perhaps CAR (Cortisol Awakening Response). If morning cortisol dynamics are linked to stress, more work on adrenal sensitivity in stress adaptation and stress-health links may be warranted., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: Cortical-subcortical hyperconnectivity related to affective-behavioral integration and cortical network hypoconnectivity related to cognitive control have been demonstrated in obsessive-compulsive disorder (OCD); the study objective was to examine whether these connectivity patterns predict treatment response., Methods: Adolescents (ages 12-17) and adults (ages 24-45) were randomly assigned to 12 sessions of exposure and response prevention (ERP) or stress management therapy (SMT), an active control. Before treatment, resting-state connectivity of ventromedial prefrontal cortical (vmPFC), cingulo-opercular, frontoparietal, and subcortical regions was assessed with functional MRI. OCD severity was assessed with the Yale-Brown Obsessive Compulsive Scale before, during, and after treatment. Usable fMRI and longitudinal symptom data were obtained from 116 patients (68 female; 54 adolescents; 60 medicated)., Results: ERP produced greater decreases in symptom scores than SMT. ERP was selectively associated with less vmPFC-subcortical (caudate and thalamus) connectivity in both age groups and primarily in unmedicated participants. Greater symptom improvement with both ERP and SMT was associated with greater cognitive-control (cingulo-opercular and frontoparietal) and subcortical (putamen) connectivity across age groups. Developmental specificity was observed across ERP and SMT treatments, such that greater improvements with ERP than SMT were associated with greater frontoparietal-subcortical (nucleus accumbens) connectivity in adolescents but greater connectivity between frontoparietal regions in adults. Comparison of response-predictive connections revealed no significant differences compared with a matched healthy control group., Conclusions: The results suggest that less vmPFC-subcortical connectivity related to affect-influenced behavior may be important for ERP engagement, whereas greater cognitive-control and motor circuit connectivity may generally facilitate response to psychotherapy. Finally, neural predictors of treatment response may differ by age.

Background: We have previously reported activation in reward, salience and executive control regions during functional MRI (fMRI) using an approach-avoidance conflict (AAC) decision-making task with healthy adults. Further investigations into how anxiety and depressive disorders relate to differences in neural responses during AAC can inform their understanding and treatment. We tested the hypothesis that people with anxiety or depression have altered neural activation during AAC., Methods: We compared 118 treatment-seeking adults with anxiety or depression and 58 healthy adults using linear mixed-effects models to examine group-level differences in neural activation (fMRI) during AAC decision-making. Correlational analyses examined relationships between behavioural and neural measures., Results: Adults with anxiety or depression had greater striatal engagement when reacting to affective stimuli ( p = 0.008, d = 0.31) regardless of valence, and weaker striatal engagement during reward feedback ( p = 0.046, d = -0.27) regardless of the presence of monetary reward. They also had blunted amygdala activity during decision-making ( p = 0.023, d = -0.32) regardless of the presence of conflict. Across groups, approach behaviour during conflict decision-making was inversely correlated with striatal activation during affective stimuli ( p < 0.001, r = -0.28) and positively related to striatal activation during reward feedback ( p < 0.001, r = 0.27)., Limitations: Our transdiagnostic approach did not allow for comparisons between specific anxiety disorders, and our cross-sectional approach did not allow for causal inference., Conclusion: Anxiety and depression were associated with altered neural responses to AAC. Findings were consistent with the role of the striatum in action selection and reward responsivity, and they point toward striatal reactivity as a future treatment target. Blunting of amygdala activity in anxiety or depression may indicate a compensatory response to inhibit affective salience and maintain approach., Competing Interests: Competing interests: M. Paulus is an advisor to Spring Care, Inc., a behavioural health startup; has received royalties for an article about methamphetamine in UpToDate; and serves on the board of directors of the Anxiety and Depression Association of America. R. Aupperle has received payment for invited lectures at Harvard Medical School and the University of Michigan, and has participated in a data safety monitoring board at New York University Langone Health. No other competing interests declared., (© 2022 CMA Impact Inc. or its licensors.)

Background: Schools increasingly provide mental health services to students, but often lack access to implementation strategies to support school-based (and school professional [SP]) delivery of evidence-based practices. Given substantial heterogeneity in implementation barriers across schools, development of adaptive implementation strategies that guide which implementation strategies to provide to which schools and when may be necessary to support scale-up., Methods: A clustered, sequential, multiple-assignment randomized trial (SMART) of high schools across Michigan was used to inform the development of a school-level adaptive implementation strategy for supporting SP-delivered cognitive behavioral therapy (CBT). All schools were first provided with implementation support informed by Replicating Effective Programs (REP) and then were randomized to add in-person Coaching or not (phase 1). After 8 weeks, schools were assessed for response based on SP-reported frequency of CBT delivered to students and/or barriers reported. Responder schools continued with phase 1 implementation strategies. Slower-responder schools (not providing ≥ 3 CBT components to ≥10 students or >2 organizational barriers identified) were re-randomized to add Facilitation to current support or not (phase 2). The primary aim hypothesis was that SPs at schools receiving the REP + Coaching + Facilitation adaptive implementation strategy would deliver more CBT sessions than SPs at schools receiving REP alone. Secondary aims compared four implementation strategies (Coaching vs no Coaching × Facilitation vs no Facilitation) on CBT sessions delivered, including by type (group, brief and full individual). Analyses used a marginal, weighted least squares approach developed for clustered SMARTs., Results: SPs (n = 169) at 94 high schools entered the study. N = 83 schools (88%) were slower-responders after phase 1. Contrary to the primary aim hypothesis, there was no evidence of a significant difference in CBT sessions delivered between REP + Coaching + Facilitation and REP alone (111.4 vs. 121.1 average total CBT sessions; p = 0.63). In secondary analyses, the adaptive strategy that offered REP + Facilitation resulted in the highest average CBT delivery (154.1 sessions) and the non-adaptive strategy offering REP + Coaching the lowest (94.5 sessions)., Conclusions: The most effective strategy in terms of average SP-reported CBT delivery is the adaptive implementation strategy that (i) begins with REP, (ii) augments with Facilitation for slower-responder schools (schools where SPs identified organizational barriers or struggled to deliver CBT), and (iii) stays the course with REP for responder schools., Trial Registration: ClinicalTrials.gov, NCT03541317 , May 30, 2018., (© 2022. The Author(s).)

Objectives: Chronic stressors are associated with cardiometabolic health conditions and disparities. Mechanisms linking stressors and health remain poorly understood. Methods: Two cohort studies (Cardiac Rehabilitation And The Experience [CREATE] and Tracking Risk Identification for Adult Diabetes [TRIAD]) with harmonized variables were used to examine relationships between six types of chronic stressors in adulthood and Hypothalamic-Pituitary-Adrenal (HPA) axis dysregulation, as indicated by blunted diurnal cortisol slopes, which are stress-sensitive biomarkers implicated in cardiometabolic health (merged N = 213, mean age 61, 18% Black). A secondary aim was to explore whether these chronic stressors accounted for Black-White disparities in HPA axis regulation. Results: Some chronic stressors were linked to HPA axis dysregulation, with recent stressors most salient ( b = 0.00353, SE = 0.00133, p = .008). Black-White disparities in HPA axis regulation persisted after controlling for racial differences in chronic stressors, which reduced the disparity 11.46%. Discussion: Chronic stressors in adulthood may increase risk for HPA axis dysregulation and associated cardiometabolic health outcomes but may not be a key factor in racial disparities.

Psychosocial stress in childhood and adolescence is linked to stress system dysregulation, although few studies have examined the relative impacts of parental harshness and parental disengagement. This study prospectively tested whether parental harshness and disengagement show differential associations with overall cortisol output in adolescence. Associations between overall cortisol output and adolescent mental health problems were tested concurrently. Adolescents from the Fragile Families and Child Wellbeing Study (FFCWS) provided hair samples for cortisol assay at 15 years (N = 171). Caregivers reported on parental harshness and disengagement experiences at 1, 3, 5, 9, and 15 years, and adolescents reported at 15 years. Both parent and adolescent reported depressive and anxiety symptoms and antisocial behaviors at 15. Greater parental harshness from 1-15 years, and harshness reported at 15 years in particular, was associated with higher overall cortisol output at 15. Greater parental disengagement from 1-15 years, and disengagement at 1 year specifically, was associated with lower cortisol output. There were no significant associations between cortisol output and depressive symptoms, anxiety symptoms, or antisocial behaviors. These results suggest that the unique variances of parental harshness and disengagement may have opposing associations with cortisol output at 15 years, with unclear implications for adolescent mental health.

Glucocorticoids exert profound effects on the brain and behavior, but cortisol concentrations are rarely linked to subjectively reported emotional states in humans. This study examined whether the link between cortisol and subjective anxiety varied by childhood maltreatment history. To do this, 97 individuals (60.8% female) participated in a standardized stress task in the laboratory (Trier Social Stress Test, TSST) while providing serial ratings of their feelings of anxiety as well as cortisol samples in blood. These measurements were collected nine times across the laboratory visit, from immediately before the TSST to 65 minutes after stress initiation. We estimated the within-person association between cortisol concentrations and momentary feelings of anxiety for individuals with and without exposure to childhood maltreatment, measured via self-report on the Childhood Trauma Questionnaire (CTQ). Individuals exposed to maltreatment during childhood reported the greatest feelings of anxiety when cortisol concentrations were lowest. This pattern was exaggerated among female participants, those with posttraumatic stress disorder (PTSD), and those exposed to emotional neglect relative to other forms of maltreatment. Early life adversity, such as parental maltreatment, may alter the role of cortisol in affective experiences. This observation may provide preliminary, translational evidence of a novel pathway through which stress may lead to and maintain internalizing symptoms in humans. More studies accounting for the moderating role of childhood maltreatment in biobehavioral pathways are needed.

Objective: The authors sought to examine whether brain activity is associated with treatment response to cognitive-behavioral therapy (CBT) in adolescents and adults with obsessive-compulsive disorder (OCD), and whether any associations are treatment specific relative to an active control psychotherapy (stress management therapy; SMT)., Methods: Eighty-seven patients with OCD (age range 12-45 years; 57 female, 39 medicated) were randomly assigned to receive 12 weeks of CBT or SMT. Prior to treatment, functional MRI scans were conducted in patients performing an incentive flanker task, which probes brain activation to both cognitive control and reward processing. Voxelwise linear mixed-effects models examined whether baseline brain activation was differentially associated with change in scores on the Yale-Brown Obsessive Compulsive Scale (standard or Children's version) over the course of CBT or SMT treatment., Results: Within the CBT group, a better treatment response was significantly associated with greater pretreatment activation within the right temporal lobe and rostral anterior cingulate cortex during cognitive control and within the ventromedial prefrontal, orbitofrontal, lateral prefrontal, and amygdala regions during reward processing. In contrast, reduced pretreatment activation within a largely overlapping set of regions was significantly associated with a better treatment response to SMT., Conclusions: The study findings demonstrate that associations between brain activation and treatment response were treatment specific to CBT relative to a control psychotherapy and that these associations were stable from adolescence to mature adulthood. Such treatment-specific associations are important for the development of biomarkers to personalize treatment in OCD.

Background: Much work has documented hypothalamic pituitary adrenal (HPA) axis abnormalities in major depressive disorder (MDD), but inconsistencies leave this system's role in the illness unclear. Comparisons across studies are complicated by variation in co-morbidity (Posttraumatic Stress Disorder-PTSD, anxiety disorders), exposure to trauma, and timing of trauma (child vs. adult). Here, we examined the impact of these factors on HPA axis profiles in depression., Methods: We recruited 5 groups of participants: MDD (n = 14), comorbid MDD + PTSD following adulthood trauma (MDD + PTSD-Adult; n = 12), comorbid MDD + PTSD following childhood trauma (MDD + PTSD-Child; n = 18), comorbid MDD + social anxiety disorder (MDD + SAD; n = 12), and non-depressed control participants who were sex and age matched to patients (combined total n = 36). HPA axis function was assessed using three challenges: stress reactivity via the Trier Social Stress Test (TSST), feedback sensitivity via a dexamethasone suppression test (DST), and central drive via a metyrapone challenge (MET). We compared hormonal responses between patient groups and their respective non-depressed controls., Results: MDD + PTSD-Child showed low cortisol levels at baseline, and reduced adrenocorticotropic hormone (ACTH) levels at baseline and throughout the TSST. MDD-only, MDD + PTSD-Adult, and MDD + SAD did not differ from non-depressed controls in HPA axis responses to the TSST. Controlling for childhood trauma severity, the reduced baseline levels in MDD + PTSD-Child were no longer significant and significantly reduced baseline cortisol levels emerged for MDD + PTSD-Adult. No diagnostic group effects were detected with DST and MET. Childhood maltreatment subtypes were associated with unique HPA axis responses to TSST and MET., Conclusion: Comorbidity and trauma exposure, as well as their timing and type, contribute to inconsistencies in the depression literature and must be included in efforts to clarify the role of the HPA axis in MDD., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Psychological stressors such as violence victimization are known contributors to obesity. However, moderators and mediators of this association have not been studied, although they might offer pathways for intervention or prevention. Using a sample of African American young adults, this study tested: (1) the moderating effect of sex on the effect of violence victimization on trajectories of body mass index (BMI), and (2) the mediating effect of dehydroepiandrosterone (DHEA) on this association. This 13-year longitudinal study followed 73 male and 80 female African American young adults who lived in an urban area from 1999 to 2012 when the youth were 20-32 years old. The independent variable was violence victimization measured in 1999 and 2000. The dependent variable was BMI measured in 2002 and 2012. The mediator was DHEA measured in 2001 and 2002. Multilevel path analysis was used to test if males and females differed in violence victimization predicting change in BMI (Model I) and the mediating effect of DHEA change on the above association (Model II). The results of Model I suggested that the change in violence victimization from 1999 to 2000 predicted change in BMI from 2002 to 2012 for females, but not males. Based on Model II, the DHEA change from 2000 to 2001 for females fully mediated the association between violence victimization from 1999 to 2000 and increases in BMI from 2002 to 2012. Our findings suggest that violence victimization in urban areas contributes to the development of obesity among African American female young adults and change in DHEA mediates this link. Violence prevention may have important implications for obesity prevention of African American young women who live in unsafe urban areas. This study also suggests that DHEA may be involved in the violence victimization-obesity link for African American women.

Introduction: It has been hypothesized that people diagnosed with anxiety and obsessive-compulsive disorder (OCD) exhibit behavioral aberrations when faced with the potential for negative outcomes, but the specific cognitive aspects of decision-making that may be altered have not been systematically studied in clinical populations. Here, we studied decision-making in a clinical cohort using a task that allows for examination of the decision weights and values associated with different choice outcomes. Methods: Patients diagnosed with OCD ( n = 10), generalized anxiety disorder ( n = 15), social anxiety disorder ( n = 14), and healthy controls ( n = 20) were given a decision-making task and choices were modeled using a cumulative prospect theory framework. Results: We found OCD patients to have lower value discrimination than controls, as well as less optimal performance on the task, an effect that was mostly driven by trials with only positive outcomes. Discussion: Our results shed light on the cognitive processes that drive altered decision-making under risk in OCD. Specifically, they demonstrate that OCD patients have diminished sensitivity to positive outcomes, which might be associated with risk aversion and altered learning of gain. These findings also extend prior reports, suggesting that altered cognitive processing during decision-making is linked to altered perception of value, but not probability, in these patients.

Study Objectives: While anxiety rates are alarmingly high in short sleeping insomniacs, the relationship between insomnia and anxiety symptoms has not been extensively studied, especially in comparison to the relationship between insomnia and depressive symptoms. Using residency training as a naturalistic stress exposure, we prospectively assessed the role of sleep disturbance and duration on anxiety-risk in response to stress., Methods: Web-based survey data from 1336 first-year training physicians (interns) prior to and then quarterly across medical internship. Using mixed effects modeling, we examined how pre-internship sleep disturbance and internship sleep duration predicted symptoms of anxiety, using an established tool for quantifying symptom severity in generalized anxiety disorder (GAD)., Results: Pre-internship poor sleepers are at more than twice the odds of having short sleep (≤6 h) during internship as good sleepers (OR = 2.38, 95% CI = 1.61, 3.57). Poor sleepers were also at twice the odds for screening positive for probable GAD diagnosis (OR = 2.08, 95% CI = 1.26, 3.45). Notably, sleep onset insomnia strongly predicted anxiety development under stress (OR = 3.55, 95% CI = 1.49, 8.45). During internship, short sleep associated with concurrent anxiety symptoms (b = -0.26, 95% CI = -0.38, -0.14) and predicted future anxiety symptoms even more strongly (b = -0.39, 95% CI = -0.76, -0.03)., Conclusions: Poor sleepers, particularly those with sleep onset insomnia symptoms, are vulnerable to short sleep and GAD anxiety and worry during chronic stress., (Copyright © 2018. Published by Elsevier B.V.)

Chronic insomnia is highly prevalent and associated with significant morbidity (i.e., confers risk for multiple psychiatric and medical disorders, such as depression and hypertension). Therefore, it is essential to identify factors that perpetuate this disorder. One candidate factor in the neurobiology of chronic insomnia is hypothalamic-pituitary-adrenal-axis dysregulation, and in particular, alterations in circadian cortisol rhythmicity. Cortisol secretory patterns, however, fluctuate with both a circadian and an ultradian rhythm (i.e., pulses every 60-120 min). Ultradian cortisol pulses are thought to be involved in the maintenance of wakefulness during the day and their relative absence at night may allow for the consolidation of sleep and/or shorter nocturnal awakenings. It is possible that the wakefulness that occurs in chronic insomnia may be associated with the aberrant occurrence of cortisol pulses at night. While cortisol pulses naturally occur with transient awakenings, it may also be the case that cortisol pulsatility becomes a conditioned phenomenon that predisposes one to awaken and/or experience prolonged nocturnal awakenings. The current review summarizes the literature on cortisol rhythmicity in subjects with chronic insomnia, and proffers the suggestion that it may be abnormalities in the ultradian rather than circadian cortisol that is associated with the pathophysiology of insomnia., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Depressive and anxiety disorders affect 20-30% of school-age youth, most of whom do not receive adequate services, contributing to poor developmental and academic outcomes. Evidence-based practices (EBPs) such as cognitive behavioral therapy (CBT) can improve outcomes, but numerous barriers limit access among affected youth. Many youth try to access mental health services in schools, but school professionals (SPs: counselors, psychologists, social workers) are rarely trained adequately in CBT methods. Further, SPs face organizational barriers to providing CBT, such as lack of administrative support. Three promising implementation strategies to address barriers to school-based CBT delivery include (1) Replicating Effective Programs (REP), which deploys customized CBT packaging, didactic training in CBT, and technical assistance; (2) coaching, which extends training via live supervision to improve SP competence in CBT delivery; and (3) facilitation, which employs an organizational expert who mentors SPs in strategic thinking to promote self-efficacy in garnering administrative support. REP is a relatively low-intensity/low-cost strategy, whereas coaching and facilitation require additional resources. However, not all schools will require all three strategies. The primary aim of this study is to compare the effectiveness of a school-level adaptive implementation intervention involving REP, coaching, and facilitation versus REP alone on the frequency of CBT delivered to students by SPs and student mental health outcomes. Secondary and exploratory aims examine cost-effectiveness, moderators, and mechanisms of implementation strategies., Methods: Using a clustered, sequential multiple-assignment, randomized trial (SMART) design, ≥ 200 SPs from 100 schools across Michigan will be randomized initially to receive REP vs. REP+coaching. After 8 weeks, schools that do not meet a pre-specified implementation benchmark are re-randomized to continue with the initial strategy or to augment with facilitation., Discussion: EBPs need to be implemented successfully and efficiently in settings where individuals are most likely to seek care in order to gain large-scale impact on public health. Adaptive implementation interventions hold the promise of providing cost-effective implementation support. This is the first study to test an adaptive implementation of CBT for school-age youth, at a statewide level, delivered by school staff, taking an EBP to large populations with limited mental health care access., Trial Registration: NCT03541317 -Registered on 29 May 2018 on ClinicalTrials.gov PRS.

While biomarkers have been used to define pathophysiological types and to optimize treatment in many areas of medicine, in psychiatry such biomarkers remain elusive. Based on previously described abnormalities of hypothalamic-pituitary-adrenal (HPA) axis function in severe forms of depression, we hypothesized that the temporal trajectory of basal cortisol levels would vary among individuals with depression due to heterogeneity in pathophysiology, and that cortisol trajectories that reflect elevated or increasing HPA activity would predict better response to electroconvulsive therapy (ECT). To test that hypothesis, we sampled scalp hair from 39 subjects with treatment-resistant depression just before ECT. Cortisol trajectory over the 12 weeks preceding ECT was reconstructed from cortisol concentrations in sequential hair segments. Cortisol trajectories varied widely between individuals, and exploratory analyses of clinical features revealed associations with melancholia and global severity. ECT non-responders showed a decreasing trajectory (mean change -25%, 95%-CI = [-1%,-43%]) during the 8 weeks preceding ECT (group-by-time interaction, p = 0.004). The association between cortisol trajectory and subsequent ECT response was independent of clinical features. A classification algorithm showed that cortisol trajectory predicted ECT response with 80% accuracy, suggesting that this biomarker might be developed into a clinically useful test for ECT-responsive depression. In conclusion, cortisol trajectory mapped onto symptoms of melancholia and independently predicted response to ECT in this severely depressed sample. These findings deserve to be replicated in a larger sample. Cortisol trajectory holds promise as a reliable, noninvasive, inexpensive biomarker for psychiatric disorders., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Many psychiatric disorders are associated with cognitive dysfunction that is ineffectively treated by existing pharmacotherapies and which may contribute to poor real-world functioning. D-cycloserine (DCS) is a partial N-methyl-D-aspartate (NMDA) agonist that has attracted attention because of its cognitive enhancing properties, including in people with post-traumatic stress disorder (PTSD). Here, we examined the effect of DCS on reversal learning - a type of cognitive flexibility - following exposure to single prolonged stress (SPS), a rodent model of PTSD. Male Sprague Dawley rats (n = 64) were trained to press levers in an operant chamber, matched for performance and assigned to SPS or control (unstressed) groups. Following SPS, rats received three additional lever press sessions, followed by a side bias test on day three. One day later they learned a response discrimination rule (press left or right lever, opposite to side bias) and on a subsequent day were trained (and tested) for reversal to the opposite lever. DCS (15 mg/kg) or vehicle was administered 30 minutes prior to the reversal session. No between-group differences were found in acquisition or retrieval of the initial rule, but a significant drug x stress interaction on response discrimination reversal indicated that DCS had a greater beneficial effect on SPS rats' cognitive flexibility than it did on performance in controls. These findings add to a growing literature on the beneficial effects of DCS for treating a wide variety of deficits that develop following exposure to extreme stress and may have implications for the development of novel pharmacotherapies for PTSD., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Stress plays a causal role in depression onset, perhaps via alteration of hypothalamic-pituitary-adrenal (HPA) axis functioning. HPA axis hyperactivity has been reported in depression, though inconsistently, and the nature of this relationship remains unclear, partly because cortisol measurement over time has been challenging. Development of hair cortisol assessment, a method that captures cortisol over prolonged periods of time, creates new possibilities. In this study, hair cortisol was incorporated into a prospective and longitudinal study of medical internship, stress and symptoms of depression. This provided a rare opportunity to 1) prospectively assess hair cortisol responses to stress, and 2) examine whether stress-induced changes in hair cortisol predict depressive symptom development., Methods: Hair cortisol, depressive symptoms, and stress-relevant variables (work hours, sleep, perceived stress, mastery/control) were assessed in interns (n = 74; age 25-33) before and repeatedly throughout medical internship., Results: Hair cortisol sharply increased with stressor onset, decreased as internship continued, and rose again at year's end. Depressive symptoms rose significantly during internship, but were not predicted by cortisol levels. Hair cortisol also did not correlate with increased stressor demands (work hours, sleep) or stress perceptions (perceived stress, mastery/control); but these variables did predict depressive symptoms., Discussion: Hair cortisol and depressive responses increased with stress, but they were decoupled, following distinct trajectories that likely reflected different aspects of stress reactivity. While depressive symptoms correlated with stressor demands and stress perceptions, the longitudinal pattern of hair cortisol suggested that it responded to contextual features related to anticipation, novelty/familiarity, and social evaluative threat., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Social anxiety disorder (SAD) is characterized by exaggerated reactivity to social threat, often documented by biased attention to threatening information, and increased activation in brain regions involved in salience/threat processing. Attention training has been developed to ameliorate the attention bias documented in individuals with SAD, with mixed results. We investigated patterns of brain activation underlying acute attention modulation in 41 participants (29 with SAD and 12 health controls). We then investigated how brain activation changed over time in both groups in response to a 4-session attention training protocol (toward threat, away from threat, no-training control). Results revealed diminished pre-training deactivation in the insula in SAD participants during attention modulation. SAD participants also demonstrated an increase in insula deactivation over time, suggestive of an improvement in attention modulation of emotion, and this was associated with a decrease in symptom severity. Attention training did not, itself, lead to clinical improvement, though there was a trend level effect of training toward threat on increased insula deactivation over time. While deficits in attentional control and emotion modulation are documented in individuals with SAD, current attention training protocols are not robustly effective in ameliorating aberrant functioning. Pursuit of training protocols that have more robust impacts on the relevant neural circuitry may have some value., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: Interpersonal models of depression and anxiety have not examined the role of interpersonal goals in shaping relationships and symptoms. Striving to promote/protect desired self-images (self-image goals) may undermine relationships and increase symptoms, whereas striving to support others (compassionate goals) may be protective, but clinical relevance is unknown., Method: We tested effects of compassionate versus self-image goals on interpersonal functioning and symptoms in clinically depressed and/or anxious participants (N = 47) during 10 days of experience sampling, over a 6-week follow-up, and in a dyadic relationship., Results: Participants reported higher conflict and symptoms on days that they most pursued self-image goals, but noted higher perceived support and lower symptoms when pursuing compassionate goals. Goals prospectively predicted symptom changes 6 weeks later. Lastly, informant-rated interpersonal goals predicted relationship satisfaction of both patients and significant others., Conclusion: Results suggest the relevance of self-image and compassionate goals for the interpersonal maintenance of depression and anxiety., (© 2017 Wiley Periodicals, Inc.)

Objectives: The hypothalamic-pituitary-adrenal (HPA) axis is thought to mediate the effects of stress on illness. Research has identified a limited number of psychological variables that modulate human HPA responses to stressors (e.g. perceived control and social support). Prosocial goals can reduce subjective stress, but have not been carefully examined in experimental settings where pathways of impact on biological stress markers may be traced. Recent work demonstrated that coaching individuals to strive to help others reduced HPA responses to the Trier Social Stress Test (TSST) relative to other cognitive interventions. However, identification of mediational pathways, which were not examined in the original study, is necessary to determine whether the HPA buffering effects were due to helping motivations (compassionate goals; CGs) rather than via previously identified variables such as control or support., Methods: In this new analysis, we combined the original cortisol data with novel observer ratings of interpersonal behavior and psychological variables during the stress task, and conducted new, theory-driven analyses to determine psychological mediators for the intervention's effect on cortisol responses (N = 54; 21 females, 33 males; 486 cortisol samples)., Results: Control, support, and task ego-threat failed to account for the effects of the intervention. As hypothesized, self and observer-rated CGs, as well as observer-rated perceptions of participants' interpersonal behavior as morally desirable (but not as dominant or affiliative) were significant mediators of neuroendocrine responses., Conclusions: The findings suggest that stress-reduction interventions based on prosocial behavior should target particular motivational and interpersonal features.

The HPA axis plays a key role in mediating the effects of "stress" on health, but clarifying mechanisms requires an understanding of psycho-biological linkages. There has long been an implicit assumption that subjective emotional distress (e.g., fear) should activate the HPA axis. Although this assumption was challenged 25 years ago (Curtis, 1976), laboratory studies in humans are limited. In this study we sought to replicate Curtis' findings and extend it by investigating if presence or absence of stressor control shapes HPA axis reactivity in a phobic fear exposure model. We recruited 19-45-year-old specific phobia participants (n=32 spider/snake phobia; n=14 claustrophobia) and gradually exposed them to their feared object or situation while measuring hormonal (ACTH and cortisol) and subjective (emotional distress, perceived control) responses. Utilizing a dyadic yoked design, we compared HPA reactivity when the pace of exposure was controlled by participants to identical exposure given to matched participants in the absence of control. Results showed that phobic fear exposure generated intense emotional distress without a corresponding increase in HPA axis activity. Although our actual manipulation of control failed to impact HPA responses, perceived control during exposure was associated with lower cortisol, an effect that was moderated by actual availability of stressor control. Our findings replicate Curtis' findings and challenge the still common but unsupported assumption that HPA axis activity reflects subjective distress. These results also highlight the importance of both perceived and actual aspects of stressor control in understanding what is truly "stressful" to the HPA axis system., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Obsessive-compulsive disorder (OCD) is characterized by excessive absorption with internally-generated distressing thoughts and urges, with difficulty incorporating external information running counter to their fears and concerns. In the present study, we experimentally probed this core feature of OCD through the use of a novel attention switching task that investigates transitions between internally focused (IF) and externally focused (EF) attentional states. Eighteen OCD patients and 18 controls imagined positive and negative personal event scenarios (IF state) or performed a color-word Stroop task (EF state). The IF/EF states were followed by a target detection (TD) task requiring responses to external stimuli. Compared to controls, OCD patients made significantly more errors and showed reduced activation of superior and inferior occipital cortex, thalamus, and putamen during TD following negative IF, with the inferior occipital hypoactivation being significantly greater for TD following negative IF compared to TD following the other conditions. Patients showed stronger functional connectivity between the inferior occipital region and dorsomedial prefrontal cortex. These findings point to an OCD-related impairment in the visual processing of external stimuli specifically when they follow a period of negative internal focus, and suggest that future treatments may wish to target the transition between attentional states., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Childhood trauma (CT) is associated with long-lasting alterations of the hypothalamic-pituitary-adrenal (HPA) axis and elevated risk for stress exposure in adulthood. Although HPA alterations are present in the early aftermath of trauma, it remains unclear how initial HPA activity is associated with subsequent stress exposure and whether CT exposure influences the strength and direction of this association. The present study examined prospective associations between hair cortisol content (HCC) and stress exposure from baseline to 3-month follow-up in young adult women with recent (i.e. past 3 months) exposure to interpersonal violence (IPV; i.e. physical or sexual assault) and non-traumatized controls. History of significant CT abuse or neglect was determined based on clinical cutoffs for a self-report CT measure: 12 women had abuse or neglect and recent IPV exposure (CT + IPV); 7 women had abuse or neglect but no IPV exposure (CT); 15 women had no history of trauma (NTC). HCC was computed for 3 cm sections reflecting cortisol secretion during the 3 months preceding the baseline assessment. The interaction of cumulative trauma and HCC predicted stress exposure over 3-month follow-up, controlling for baseline stress exposure and depressive symptoms. Simple slopes analyses revealed that lower baseline HCC predicted greater stress exposure in the CT + IPV group compared to the CT group; HCC was not associated with stress exposure in the NTC group. The present findings highlight the potential utility of HCC as a predictor of stress exposure for women with a history of childhood abuse or neglect, particularly in the context of recent IPV. Lay summary Adults with a history of CT show long-lasting alterations in major stress response systems, including the HPA axis. They are also more likely to experience stressful life events in adulthood. However, it is not clear how altered HPA activity influences risk for stress exposure and whether CT affects their relationship. The results from this study show that lower HPA activity (measured with hair cortisol) predicted greater stress exposure in women with CT - particularly for women who also experienced recent incidents involving physical or sexual assault.

Psychosocial well-being requires effective regulation of emotional responding in context of threat or stress. Neuroimaging studies have focused on instructed, volitional regulation (e.g., reappraisal or distancing), largely ignoring implicit regulation that does not involve purposeful effort to alter emotional experience. These implicit processes may or may not involve the same neural pathways as explicit regulatory strategies. We examined the neurobiology of implicit emotional regulation processes and the impact of the stress hormone cortisol on these processes. Our study task employed composite pictures of faces and places to examine neural activity during implicit emotional processing (of emotional faces), while these responses were implicitly regulated by attention shift away from the emotionally evocative stimuli, and while subjects reflectively appraised their own emotional response to them. Subjects completed the task in an fMRI scanner after random assignment to receive placebo or hydrocortisone (HCT), an orally administered version of cortisol. Implicit emotional processing activated insula/IFG, dACC/dMPFC, midbrain and amygdala. With attention shifting, we saw diminished signal in emotion generating/response regions (e.g., amygdala) and increased activations in task specific attention regions like parahippocampus. With appraisal of emotions, we observed robust activations in medial prefrontal areas, where activation is also seen in instructed reappraisal studies. We observed no main effects of HCT administration on brain, but males and females showed opposing neural effects in prefrontal areas. The data suggest that different types of emotion regulation utilize overlapping circuits, but with some strategy specific activation. Further study of the dimorphic sex response to cortisol is needed.

Evidence suggests that sighs regulate stress and emotions, e.g. by facilitating relief. This study aimed to investigate sigh rates during relief. In addition, links between sighs, anxiety sensitivity and HPA-axis activity were explored. Healthy volunteers (N=29) were presented cues predicting the valence of subsequent stimuli. By sequencing cues that predicted pleasant or unpleasant stimuli with or without certainty, transitions to certain pleasantness (relief) or to certain unpleasantness (control) were created and compared to no transitions. Salivary cortisol, anxiety sensitivity and respiration were measured. Sigh frequency was significantly higher during relief than during control transitions and no transition states, and higher during control transitions than during no transition states. Sigh frequency increased with steeper cortisol declines for high anxiety sensitive persons. Results confirm a relationship between sighs and relief. In addition, results suggest that sigh frequency is importantly related to HPA-axis activity, particularly in high anxiety sensitive persons., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: No simple way to augment fear extinction has been established. Cortisol has shown to enhance memory extinction and preliminary evidence suggest that extinction learning maybe more successful in the morning when cortisol is high. The aim was to determine whether exposure sessions conducted earlier in the day are associated with superior therapeutic gains in extinction-based psychotherapy. We also examined the role of cortisol levels as a mediator between time of day and therapeutic gains., Method: Participants were 24 individuals meeting DSM-IV criteria for panic disorder with agoraphobia. Participants received 3 weekly in-vivo exposure sessions, yielding 72 total sessions for analysis of time of day effects. Session start times were evenly distributed across the day. The outcome measures were reductions in panic symptom severity (avoidance behaviors, threat misappraisal, perceived control, and panic disorder symptom severity)., Results: Sessions starting earlier in the day were associated with superior therapeutic gains by the next therapy session. Earlier sessions were also associated with higher pre-exposure cortisol levels, which in turn were related to greater clinical improvement by the next session. Cortisol thus was found to mediate the effect of time of day on subsequent outcome, providing a link between earlier exposure sessions and greater clinical improvement., Conclusion: The data suggest that early-day extinction-based therapy sessions yield better outcomes than later-day sessions, partly due to the enhancing effect of higher cortisol levels., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Individuals with posttraumatic stress disorder (PTSD) typically exhibit altered hypothalamic-pituitary-adrenal (HPA) function and sympathetic nervous system (SNS) activity. The goals of this study were to determine whether HPA and SNS alterations in the immediate aftermath of trauma predict subsequent PTSD symptom development and whether inconsistencies observed between studies can be explained by key demographic and methodological factors. This work informs secondary prevention of PTSD by identifying subgroups of trauma survivors at risk for PTSD. This meta-analysis (26 studies, N=5186 individuals) revealed that higher heart rate measured soon after trauma exposure was associated with higher PTSD symptoms subsequently (r=0.13). Neither cortisol (r=-0.07) nor blood pressure (diastolic: r=-0.01; systolic: r=0.02) were associated with PTSD symptoms which may be influenced by methodological limitations. Associations between risk markers (heart rate, cortisol, systolic blood pressure) and PTSD symptoms were in the positive direction for younger samples and negative direction for older samples. These findings extend developmental traumatology models of PTSD by revealing an age-related shift in the presentation of early risk markers. More work will be needed to identify risk markers and pathways to PTSD while addressing methodological limitations in order to shape and target preventive interventions., Competing Interests: The authors report no conflicts of interest., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Progress in clinical and affective neuroscience is redefining psychiatric illness as symptomatic expression of cellular/molecular dysfunctions in specific brain circuits. Post-traumatic stress disorder (PTSD) has been an exemplar of this progress, with improved understanding of neurobiological systems subserving fear learning, salience detection, and emotion regulation explaining much of its phenomenology and neurobiology. However, many features remain unexplained and a parsimonious model that more fully accounts for symptoms and the core neurobiology remains elusive. Contextual processing is a key modulatory function of hippocampal-prefrontal-thalamic circuitry, allowing organisms to disambiguate cues and derive situation-specific meaning from the world. We propose that dysregulation within this context-processing circuit is at the core of PTSD pathophysiology, accounting for much of its phenomenology and most of its biological findings. Understanding core mechanisms like this, and their underlying neural circuits, will sharpen diagnostic precision and understanding of risk factors, enhancing our ability to develop preventive and "personalized" interventions., Competing Interests: None, (Published by Elsevier Inc.)

Background: Little is known about trajectories of PTSD symptoms across the peripartum period in women with trauma histories, specifically those who met lifetime PTSD diagnoses prior to pregnancy. The present study seeks to identify factors that influence PTSD symptom load across pregnancy and early postpartum, and study its impact on postpartum adaptation., Method: The current study is a secondary analysis on pregnant women with a Lifetime PTSD diagnosis (N = 319) derived from a larger community sample who were interviewed twice across pregnancy (28 and 35 weeks) and again at 6 weeks postpartum, assessing socioeconomic risks, mental health, past and ongoing trauma exposure, and adaptation to postpartum., Results: Using trajectory analysis, first we examined the natural course of PTSD symptoms based on patterns across peripartum, and found four distinct trajectory groups. Second, we explored factors (demographic, historical, and gestational) that shape the PTSD symptom trajectories, and examined the impact of trajectory membership on maternal postpartum adaptation. We found that child abuse history, demographic risk, and lifetime PTSD symptom count increased pregnancy-onset PTSD risk, whereas gestational PTSD symptom trajectory was best predicted by interim trauma and labor anxiety. Women with the greatest PTSD symptom rise during pregnancy were most likely to suffer postpartum depression and reported greatest bonding impairment with their infants at 6 weeks postpartum., Conclusions: Screening for modifiable risks (interpersonal trauma exposure and labor anxiety) and /or PTSD symptom load during pregnancy appears critical to promote maternal wellbeing., (© 2016 Wiley Periodicals, Inc.)

The Penn State Worry Questionnaire - Past Week (PSWQ-PW) is an adaptation of the widely used Penn State Worry Questionnaire, measuring pathological worry weekly. However, it contains problematic negatively worded items and has not been validated in a large sample yet. To meet the needs of measurement-based care (MBC), we developed a shortened version (PSWQ-10) based on the PSWQ-PW, retaining only positively worded items, and examined its psychometric properties and clinical utility. Patients with Generalized Anxiety Disorder (GAD), Major Depressive Disorder (MDD), and other anxiety disorders completed the PSWQ-10 and other instruments during routine evaluation in an academic anxiety clinic. A second cohort from a perinatal clinic was evaluated similarly. The PSWQ-10 displayed excellent internal consistency, convergent and discriminant validity, and criterion group validity. Patients with GAD scored significantly higher than those with other anxiety disorders but did not differ from those with MDD. The PSWQ-10 showed sensitivity to change over time and demonstrated excellent psychometric properties in the perinatal population. The PSWQ-10 is a reliable, valid, efficient, and straightforward worry-focused instrument that can be readily used in MBC and help clinicians objectively measure worry as a treatment outcome in broad clinical populations., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Social threat can have adverse effects on cognitive performance, but the brain mechanisms underlying its effects are poorly understood. We investigated the effects of social evaluative threat on working memory (WM), a core component of many important cognitive capabilities. Social threat impaired WM performance during an N-back task and produced widespread reductions in activation in lateral prefrontal cortex and intraparietal sulcus (IPS), among other regions. In addition, activity in frontal and parietal regions predicted WM performance, and mediation analyses identified regions in the bilateral IPS that mediated the performance-impairing effects of social threat. Social threat also decreased connectivity between the IPS and dorsolateral prefrontal cortex, while increasing connectivity between the IPS and the ventromedial prefrontal cortex, a region strongly implicated in the generation of autonomic and emotional responses. Finally, cortisol response to the stressor did not mediate WM impairment but was rather associated with protective effects. These results provide a basis for understanding interactions between social and cognitive processes at a neural systems level., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Worry, social anxiety, and depressive symptoms are dimensions that have each been linked to heterogeneous problems in interpersonal functioning. However, the relationships between these symptoms and interpersonal difficulties remain unclear given that most studies have examined diagnostic categories, not accounted for symptoms' shared variability due to general distress, and investigated only interpersonal problems (neglecting interpersonal traits, interpersonal goals, social behavior in daily life, and reports of significant others). To address these issues, students (Study 1; N=282) endorsed symptoms and interpersonal circumplex measures of traits and problems, as well as event-contingent social behaviors during one week of naturalistic daily interactions (N=184; 7,036 records). Additionally, depressed and anxious patients (N=47) reported symptoms and interpersonal goals in a dyadic relationship, and significant others rated patients' interpersonal goals and impact (Study 2). We derived hypotheses about prototypical interpersonal features from theories about the functions of particular symptoms and social behaviors. As expected, worry was uniquely associated with prototypically affiliative tendencies across all self-report measures in both samples, but predicted impacting significant others in unaffiliative ways. As also hypothesized, social anxiety was uniquely and prototypically associated with low dominance across measures, and general distress was associated with cold-submissive tendencies. Findings for depressive symptoms provided less consistent evidence for unique prototypical interpersonal features. Overall, results suggest the importance of multimethod assessment and accounting for general distress in interpersonal models of worry, social anxiety, and depressive symptoms., (Copyright © 2015. Published by Elsevier Ltd.)

Objectives: Major life stressors, including major surgeries, are often followed by psychiatric symptoms and disorders. Prior retrospective work found abdominal aortic aneurysm (AAA) repair is followed by increased psychiatric morbidity, which may adversely influence physical and functional recovery. Identifying risk factors before surgery, such as dysregulation in stress response systems, might be useful in improving preventative intervention., Methods: Two hundred sixteen patients receiving open AAA or aortofemoral bypass surgeries, endovascular AAA repair, or nonsurgical AAA treatment were recruited from two vascular surgery services. Psychiatric symptoms and salivary cortisol measures (waking, 4 PM, and 11 PM, before and after low-dose dexamethasone) were obtained at intake and 3- and 9-month follow-ups., Results: After open surgeries, 18% of patients had new psychiatric disorders, compared with 4% of patients receiving endovascular AAA repair or nonsurgical treatment (odds ratio = 6.0, 95% confidence interval = 1.6-22.1, p = .007). Having a history of major depression predicted the onset of new disorders in surgical patients. Presurgical cortisol levels were associated with both baseline (r = 0.23, p < .05) and 9-month (r = 0.32, p < .01) psychiatric symptoms (cortisol B = 1.0, standard error = 0.48, p < .05, in repeated-measures mixed model)., Conclusions: Open AAA repair surgery is prospectively linked to the development of psychiatric morbidity, and history of depression elevates risk. Cortisol measures before surgery are associated with current and future psychological functioning, suggesting potential neurobiological mechanisms that may contribute to vulnerability. These results can help identify surgical patients at risk and point to potential targets for risk reduction interventions.

Efficient, adaptive behavior relies on the ability to flexibly move between internally focused (IF) and externally focused (EF) attentional states. Despite evidence that IF cognitive processes such as event imagination comprise a significant amount of awake cognition, the consequences of internal absorption on the subsequent recruitment of brain networks during EF tasks are unknown. The present functional magnetic resonance imaging (fMRI) study employed a novel attentional state switching task. Subjects imagined positive and negative events (IF task) or performed a working memory task (EF task) before switching to a target detection (TD) task also requiring attention to external information, allowing for the investigation of neural functioning during external attention based on prior attentional state. There was a robust increase of activity in frontal, parietal, and temporal regions during TD when subjects were previously performing the EF compared with IF task, an effect that was most pronounced following negative IF. Additionally, dorsolateral prefrontal cortex was less negatively coupled with ventromedial prefrontal and posterior cingulate cortices during TD following IF compared with EF. These findings reveal the striking consequences for brain activity following immersion in an IF attentional state, which have strong implications for psychiatric disorders characterized by excessive internal focus., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Exposure to stressful or traumatic events is associated with increased vulnerability to post-traumatic stress disorder (PTSD). This vulnerability may be partly mediated by effects of stress on the prefrontal cortex (PFC) and associated circuitry. The PFC mediates critical cognitive functions, including cognitive flexibility, which reflects an organism's ability to adaptively alter behavior in light of changing contingencies. Prior work suggests that chronic or acute stress exerts complex effects on different forms of cognitive flexibility, via actions on the PFC. Similarly, PFC dysfunction is reported in PTSD, as are executive function deficits. Animal models that permit study of the effects of stress/trauma on cognitive flexibility may be useful in illuminating ways in which stress-linked cognitive changes contribute to PTSD. Here, we examined the behavioral effects of a rodent model of PTSD - single prolonged stress (SPS) - on performance of two forms of cognitive flexibility: reversal learning and strategy set-shifting. SPS did not impair acquisition of either a response or visual-cue discrimination but did cause slight impairments in the retrieval of the visual-cue rule. During response discrimination reversal, SPS rats made more perseverative errors. In comparison, during set-shifting from the visual-cue to response discrimination, SPS rats did not show enhanced perseveration, but did display increased never-reinforced errors, indicative of impairment in selecting a novel strategy. These data demonstrate that SPS leads to a complex and intriguing pattern of deficits in flexible responding and suggest that impairments in executive functioning associated with PTSD could, in part, be a neuro-cognitive consequence of trauma exposure., (Copyright © 2015 Elsevier B.V. All rights reserved.)

This study characterized the longitudinal evolution of HPA axis functioning from 7 to 16 months of age and identified individual and environmental factors that shape changes in HPA axis functioning over time. Participants were 167 mother-infant dyads drawn from a larger longitudinal study, recruited based on maternal history of being maltreated during childhood. Salivary cortisol levels were assessed before and after age-appropriate psychosocial stressors when infants were 7 and 16 months old. Maternal observed parenting and maternal reports of infant and environmental characteristics were obtained at 7 months and evaluated as predictors of changes in infant baseline cortisol and reactivity from 7 to 16 months. Results revealed that infants did not show a cortisol response at 7 months, but reactivity to psychosocial stress emerged by 16 months. Individual differences in cortisol baseline and reactivity levels over time were related to infant sex and maternal overcontrolling behaviors, underscoring the malleable and socially informed nature of early HPA axis functioning. Findings can inform prevention and intervention efforts to promote healthy stress regulation during infancy., (© 2015 Wiley Periodicals, Inc.)

Background: Research suggests that elevated stress hormones during exposure can facilitate fear extinction in laboratory settings. However, prospective studies on the clinical benefits of endogenous cortisol on clinical improvements in naturalistic exposures are lacking., Methods: Twenty-six patients with panic disorder and agoraphobia completed three weekly in-vivo exposure sessions and a fourth session 2 months following therapy completion, resulting in a total of 94 in-vivo exposure sessions. Salivary cortisol was collected at multiple times during the first exposure day (cortisol morning response, prior, -during, -after exposure) and at subsequent exposure sessions (prior, -during, -after exposure). Cortisol collection on a non-exposure comparison day followed the same time schedule as session 1., Results: Exposure day anxiety and cortisol levels were significantly higher than control day levels. Higher absolute cortisol levels during exposures moderated clinical improvement (avoidance behavior, threat appraisal, perceived control). Therapeutic gains were not just related to exposure day cortisol levels, but were also linked to non-exposure day levels. Greater morning rises in cortisol on exposure day predicted greater treatment gains, but greater rises on the control day were associated with poorer outcomes., Conclusions: The study provides first evidence for a moderating effect of cortisol awakening response and absolute cortisol levels on fear extinction processes during naturalistic, prospective exposure-therapy. Additionally, we replicated and extended prior findings on the therapeutic benefits of high exposure cortisol levels. Together, the findings suggest that cortisol may act as a general moderator of facilitated learning during exposure therapy., (Copyright © 2014 Elsevier Ltd. All rights reserved.)