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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.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).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.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.

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.

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.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.Adults with anxiety or depression had greater striatal engagement when reacting to affective stimuli (Our transdiagnostic approach did not allow for comparisons between specific anxiety disorders, and our cross-sectional approach did not allow for causal inference.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.

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.

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.

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.

Introduction Treatment effectiveness for major depressive disorder (MDD) is often affected by client non-adherence, dropout, and non-response. Identification of client characteristics predicting successful treatment completion and/or response (i.e., symptom reduction) may be an important tool to increase intervention effectiveness. It is unclear whether neural attenuations in reward processing associated with MDD predict behavioral treatment outcome. Methods This study aimed to determine whether blunted neural responses to reward at baseline differentiate MDD (n = 60; 41 with comorbid anxiety) and healthy control (HC; n = 40) groups; and predict MDD completion of and response to 7–10 sessions of behavior therapy. Participants completed a monetary incentive delay (MID) task. The N200, P300, contingent negative variation (CNV) event related potentials (ERPs) and behavioral responses (reaction time [RT], correct hits) were quantified and extracted for cross-sectional group analyses. ERPs and behavioral responses demonstrating group differences were then used to predict therapy completion and response within MDD. Results MDD exhibited faster RT and smaller P300 amplitudes than HC across conditions. Within the MDD group, treatment completers (n = 37) exhibited larger P300 amplitudes than non-completers (n = 21). Limitations : This study comprises secondary analyses of EEG data; thus task parameters are not optimized to examine feedback ERPs from the paradigm. We did not examine heterogenous presentations of MDD; however, severity and comorbidity did not influence findings. Conclusions Previous studies suggest that P300 is an index of motivational salience and stimulus resource allocation. In sum, individuals who deploy greater neural resources to task demands are more likely to persevere in behavioral therapy.

PurposeMood and anxiety disorders affect 20–30 percent of school-age children, contributing to academic failure, substance abuse, and adult psychopathology, with immense social and economic impact. These disorders are treatable, but only a fraction of students in need have access to evidence-based treatment practices (EBPs). Access could be substantially increased if school professionals were trained to identify students at risk and deliver EBPs in the context of school-based support services. However, current training for school professionals is largely ineffective because it lacks follow-up supported practice, an essential element for producing lasting behavioral change. The paper aims to discuss these issues.Design/methodology/approachIn this pilot feasibility study, the authors explored whether a coaching-based implementation strategy could be used to integrate common elements of evidence-based cognitive behavioral therapy (CBT) into schools. The strategy incorporated didactic training in CBT for school professionals followed by coaching from an expert during co-facilitation of CBT groups offered to students.FindingsIn total, 17 school professionals in nine high schools with significant cultural and socioe-conomic diversity participated, serving 105 students. School professionals were assessed for changes in confidence in CBT delivery, frequency of generalized use of CBT skills and attitudes about the utility of CBT for the school setting. Students were assessed for symptom improvement. The school professionals showed increased confidence in, utilization of, and attitudes toward CBT. Student participants showed significant reductions in depression and anxiety symptoms pre- to post-group.Originality/valueThese findings support the feasibility and potential impact of a coaching-based implementation strategy for school settings, as well as student symptom improvement associated with receipt of school-delivered CBT.

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).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.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.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.

Summary 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.

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 Electronic supplementary material The online version of this article (10.1186/s13012-018-0808-8) contains supplementary material, which is available to authorized users.

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.

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.

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.

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.

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.

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.

Background Only 40–60% of patients with generalized anxiety disorder experience long-lasting improvement with gold standard psychosocial interventions. Identifying neurobehavioral factors that predict treatment success might provide specific targets for more individualized interventions, fostering more optimal outcomes and bringing us closer to the goal of “personalized medicine.” Research suggests that reward and threat processing (approach/avoidance behavior) and cognitive control may be important for understanding anxiety and comorbid depressive disorders and may have relevance to treatment outcomes. This study was designed to determine whether approach-avoidance behaviors and associated neural responses moderate treatment response to exposure-based versus behavioral activation therapy for generalized anxiety disorder. Methods/design We are conducting a randomized controlled trial involving two 10-week group-based interventions: exposure-based therapy or behavioral activation therapy. These interventions focus on specific and unique aspects of threat and reward processing, respectively. Prior to and after treatment, participants are interviewed and undergo behavioral, biomarker, and neuroimaging assessments, with a focus on approach and avoidance processing and decision-making. Primary analyses will use mixed models to examine whether hypothesized approach, avoidance, and conflict arbitration behaviors and associated neural responses at baseline moderate symptom change with treatment, as assessed using the Generalized Anxiety Disorder–7 item scale. Exploratory analyses will examine additional potential treatment moderators and use data reduction and machine learning methods. Discussion This protocol provides a framework for how studies may be designed to move the field toward neuroscience-informed and personalized psychosocial treatments. The results of this trial will have implications for approach-avoidance processing in generalized anxiety disorder, relationships between levels of analysis (i.e., behavioral, neural), and predictors of behavioral therapy outcome. Trial registration The study was retrospectively registered within 21 days of first participant enrollment in accordance with FDAAA 801 with ClinicalTrials.gov, NCT02807480. Registered on June 21, 2016, before results.

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 subjective perceptions of values and probabilities 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 reward processing. 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Efforts to identify biological correlates of internalizing symptoms in childhood have involved examinations of HPA-axis functioning, namely Cortisol Awakening Response (CAR). However, research has not assessed the relationship between CAR and internalizing problems among children younger than 8 years. Findings with older samples have been somewhat equivocal, perhaps due to high rates of co-occurring externalizing symptoms during childhood and/or due to age-related differences. This cross-sectional study examined CAR in an at-risk sample of children aged 22 months to 8 years at various levels of risk for internalizing symptoms. Internalizing symptoms were associated with blunted CAR, but only after controlling for externalizing problems. The relationship between CAR and internalizing symptoms disappeared with age. Results demonstrate that a negative association between CAR and internalizing exists during early childhood and illustrate the importance of accounting for comorbid externalizing disorders and developmental stage when assessing the HPA-internalizing link.

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. Dev Psychobiol 57: 356–364, 2015.

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.

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.

Background: Understanding cognitive and biological mechanisms of PTSD treatment can help refine treatments and increase rates of response. Methods: Thirty-six veterans with PTSD were randomly assigned to receive Prolonged exposure therapy (PE) or Present-Centered therapy (PCT). We examined symptoms, trauma-related cognitions, and two indices of HPA axis function (cortisol awakening response and cortisol response to a script-driven imagery task). Results: Thirty veterans started treatment and 26 completed. PE resulted in significantly more symptom reduction than PCT (P = .008). High treatment responders collapsed across treatments showed nominally higher cortisol levels measured at pretreatment 30 min after trauma script exposure compared to low responders (P = .08). At midtreatment, high treatment responders showed higher cortisol levels throughout the imagery task (Ps = .03–.04). There were no differences between high and low treatment responders at posttreatment. Thoughts of incompetence (F (1.6, 35.8) = 16.8, P = .000) and a dangerous world (F (1.3, 29.9) = 8.2, P = .004) significantly improved over time in high treatment responders but showed no change in low responders. Script-associated cortisol response prior to treatment and reductions in thoughts of incompetence accounted for 83% of the variance in reductions in PTSD severity with PE. Conclusions: Both increased cortisol response to personal trauma script prior to PTSD therapy and reductions in cognitive symptoms of PTSD were significantly and uniquely related to reductions in the core symptoms of PTSD in PE. However, contrary to our hypotheses, cortisol measures were not related to cognitive changes. Depres

Summary Background The hypothalamic–pituitary–adrenal (HPA) axis is a critical mediator linking stress to health. Understanding how to modulate its reactivity could potentially help reduce the detrimental health effects of HPA axis activation. Social evaluative threat is a potent activator of this system. Access to control and coping responses can reduce its reactivity to pharmacological activation. Compassionate or affiliative behaviors may also moderate stress reactivity. Impact of these moderators on social evaluative threat is unknown. Here, we tested the hypotheses that interventions to increase control, coping, or compassionate (versus competitive) goals could reduce HPA-axis response to social evaluative threat. Methods Healthy participants (n = 54) were exposed to social evaluative threat using the Trier Social Stress Test (TSST). They were randomly assigned to receive one of four different instructions prior to the stressor: Standard TSST instructions (SI), standard instructions with access to “control” (SI Control), or one of two cognitive interventions (CI) that (1) increased familiarity and helped participants prepare coping strategies (CI Coping), or (2) shifted goal orientation from self-promotion to helping others (CI Compassionate Goals). ACTH and cortisol were obtained before and after stress exposure via intravenous catheter. Results Control alone had no effect. CI Compassionate Goals significantly reduced ACTH and cortisol responses to the TSST; CI Coping raised baseline levels. Compassionate Goals reduced hormonal responses without reducing subjective anxiety, stress or fear, while increasing expression of pro-social intentions and focus on helping others. Conclusions Brief intervention to shift focus from competitive self-promotion to a goal orientation of helping-others can reduce HPA-axis activation to a potent psychosocial stressor. This supports the potential for developing brief interventions as inoculation tools to reduce the impact of predictable stressors and lends support to growing evidence that compassion and altruistic goals can moderate the effects of stress.