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Mindfulness-based interventions are widely used to target pain, yet their neural mechanisms of action are insufficiently understood. The authors studied neural and subjective pain response in a randomized active-control trial of mindfulness-based stress reduction (MBSR) alongside long-term meditation practitioners.Healthy participants (N=115) underwent functional neuroimaging during a thermal acute pain task before and after random assignment to MBSR (N=28), an active control condition (health enhancement program [HEP]) (N=32), or a waiting list control condition (N=31). Long-term meditators (N=30) completed the same neuroimaging paradigm. Pain response was measured via self-reported intensity and unpleasantness, and neurally via two multivoxel machine-learning-derived signatures: the neurologic pain signature (NPS), emphasizing nociceptive pain processing, and the stimulus intensity independent pain signature-1 (SIIPS1), emphasizing stimulus-independent neuromodulatory processes.The MBSR group showed a significant decrease in NPS response relative to the HEP group (Cohen's d=-0.43) and from pre- to postintervention assessment (d=-0.47). The MBSR group showed small, marginal decreases in NPS relative to the waiting list group (d=-0.36), and in SIIPS1 relative to both groups (HEP group, d=-0.37; waiting list group, d=-0.37). In subjective unpleasantness, the MBSR and HEP groups also showed modest significant reductions compared with the waiting list group (d=-0.45 and d=-0.55). Long-term meditators reported significantly lower pain than nonmeditators but did not differ in neural response. Within the long-term meditator group, cumulative practice during intensive retreat was significantly associated with reduced SIIPS1 (r=-0.65), whereas daily practice was not.Mindfulness training showed associations with pain reduction that implicate differing neural pathways depending on extent and context of practice. Use of neural pain signatures in randomized trials offers promise for guiding the application of mindfulness interventions to pain treatment.

Insomnia is highly prevalent among military veterans but access to cognitive behavioral therapy for insomnia (CBT-I) is limited. Thus, this study examined the feasibility, acceptability, and potential efficacy of Insomnia Coach, a CBT-I-based, free, self-management mobile app. Fifty U.S. veterans, who were mostly male (58%) and mean age 44.5 (range = 28 to 55) years with moderate insomnia symptoms were randomized to Insomnia Coach (n = 25) or a waitlist control condition (n = 25) for 6 weeks. Participants completed self-report measures and sleep diaries at baseline, post-treatment, and follow-up (12 weeks post-randomization), and app participants (n = 15) completed a qualitative interview at post-treatment. Findings suggest that Insomnia Coach is feasible to use, with three-quarters of participants using the app through 6 weeks and engaging with active elements. For acceptability, perceptions of Insomnia Coach were very favorable based on both self-report and qualitative interview responses. Finally, for potential efficacy, at post-treatment, a larger proportion of Insomnia Coach (28%) than waitlist control participants (4%) achieved clinically significant improvement (p = .049) and there was a significant treatment effect on daytime sleep-related impairment (d = -0.6, p = .044). Additional treatment effects emerged at follow-up for insomnia severity (d = -1.1, p = .001), sleep onset latency (d = -0.6, p = .021), global sleep quality (d = -0.9, p = .002), and depression symptoms (d = -0.8, p =.012). These findings provide preliminary evidence that among veterans with moderate insomnia symptoms a CBT-I-based self-management app is feasible, acceptable, and promising for improving insomnia severity and other sleep-related outcomes. Given the vast unmet need for insomnia treatment in the population, Insomnia Coach may provide an easily accessible, convenient public health intervention for individuals not receiving care.

BACKGROUND: Depression hinders obesity treatment; elucidating mechanisms may enable treatment enhancements. OBJECTIVES: The aim was to investigate whether changes in neural targets in the negative affect circuit following psychotherapy mediate subsequent changes in weight and behaviors. METHODS: Adults (n = 108) with obesity and depression were randomly assigned to usual care or an intervention that delivered problem-solving therapy (PST) for depression over 2 mo. fMRI for brain imaging was performed at baseline and 2 mo. BMI, physical activity, and diet were measured at baseline and 12 mo. Mediation analysis assessed between-group differences in neural target changes using t test and correlations between neural target changes and outcome changes (simple and interaction effect) using ordinary least-squares regression. RESULTS: Compared with usual care, PST led to reductions in left amygdala activation (−0.75; 95% CI: −1.49, −0.01) and global scores of the negative affect circuit (−0.43; −0.81, −0.06), engaged by threat stimuli. Increases in amygdala activation and global circuit scores at 2 mo correlated with decreases in physical activity outcomes at 12 mo in the usual-care group; these relations were altered by PST. In relation to change in leisure-time physical activity, standardized β-coefficients were −0.67 in usual care and −0.01 in the intervention (between-group difference: 0.66; 0.02, 1.30) for change in left amygdala activation and −2.02 in usual care and −0.11 in the intervention (difference: 1.92; 0.64, 3.20) for change in global circuit scores. In relation to change in total energy expenditure, standardized β-coefficients were −0.65 in usual care and 0.08 in the intervention (difference: 0.73; 0.29, 1.16) for change in left amygdala activation and −1.65 in usual care and 0.08 in the intervention (difference: 1.74; 0.85, 2.63) for change in global circuit scores. Results were null for BMI and diet. CONCLUSIONS: Short-term changes in the negative affect circuit engaged by threat stimuli following PST for depression mediated longer-term changes in physical activity. This trial was registered at www.clinicaltrials.gov as NCT02246413 (https://clinicaltrials.gov/ct2/show/NCT02246413).

One in four veteran primary care patients suffers from a mental health condition; however, most do not receive any treatment for these problems. Mobile health (mHealth) can overcome barriers to care access, but poor patient engagement limits the effectiveness and implementation of these tools. Peers may facilitate patient engagement with mHealth. We designed a protocol for peers to support implementation of mobile mental health tools in primary care and tested the feasibility, acceptability, and clinical utility of this approach. Thirty-nine patients across two Veterans Affairs sites who screened positive for depression during a primary care visit and were not currently in mental health treatment were enrolled. Participants were scheduled for four phone sessions with a peer over 8 weeks and introduced to five mobile apps for a range of transdiagnostic mental health issues (stress, low mood, sleep problems, anger, and trauma). Pre/post phone interviews using quantitative and qualitative approaches assessed participants' self-reported app use, satisfaction with the intervention, symptom change (stress, anxiety, depression, insomnia), and progress with personal health goals. On average, patients reported using 3.04 apps (

BACKGROUND Posttraumatic stress disorder (PTSD) among U.S. military veterans can adversely impact their concerned significant others (CSOs; e.g., family, romantic partners). Mobile apps can be tailored to support CSO mental health with psychoeducation, coping skills, and stress monitoring. OBJECTIVE The present study assessed the feasibility, acceptability, and potential efficacy of PTSD Family Coach 1.0, a free, publicly available app for CSOs of veterans with PTSD. METHODS Two hundred participants who were an average of 39 years old (SD = 8.44), primarily female (97%), and White (80%) were randomized to self-guided use of either PTSD Family Coach 1.0 (n = 104) or a psychoeducation-only app (n = 96) for four weeks. Caregiver burden, stress, depression, anxiety, beliefs about treatment, and relationship functioning were assessed via web survey at baseline and posttreatment. User satisfaction and app helpfulness were assessed at posttreatment. RESULTS 101 (50.5%) randomized participants used their allocated app. Participants found PTSD Family Coach 1.0 somewhat satisfying to use (M=4.88, SD=1.11) and moderately helpful (M=2.99, SD=0.97). Linear mixed effects models revealed no significant differences in outcomes by condition. Post hoc analyses collapsing across conditions revealed a significant between-groups effect on stress for app users versus nonusers (beta = -3.62, t(281)=-2.27, P=.023). CONCLUSIONS Although participants found PTSD Family Coach 1.0 acceptable, suboptimal app use suggests limitations to this version’s feasibility. App use regardless of condition was associated with reduced stress.

Background Posttraumatic stress disorder (PTSD) among US military veterans can adversely impact their concerned significant others (CSOs; eg, family members and romantic partners). Mobile apps can be tailored to support CSO mental health through psychoeducation, coping skills, and stress monitoring. Objective This study assessed the feasibility, acceptability, and potential efficacy of PTSD Family Coach 1.0, a free, publicly available app that includes psychoeducation, stress management tools, self-assessments, and features for connecting to alternative supports, compared with a psychoeducation-only version of the app for cohabitating CSOs of veterans with PTSD. Methods A total of 200 participants with an average age of 39 (SD 8.44) years, primarily female (193/200, 97%), and White (160/200, 80%) were randomized to self-guided use of either PTSD Family Coach 1.0 (n=104) or a psychoeducation-only app (n=96) for 4 weeks. Caregiver burden, stress, depression, anxiety, beliefs about treatment, CSO self-efficacy, and relationship functioning assessed using measures of dyadic adjustment, social constraints, and communication danger signs were administered via a web survey at baseline and after treatment. User satisfaction and app helpfulness were assessed after treatment. Data were analyzed using linear mixed methods. Results Overall, 50.5% (101/200) of randomized participants used their allocated app. Participants found PTSD Family Coach 1.0 somewhat satisfying (mean 4.88, SD 1.11) and moderately helpful (mean 2.99, SD 0.97) to use. Linear mixed effects models revealed no significant differences in outcomes by condition for caregiver burden (P=.45; Cohen d=0.1, 95% CI −0.2 to 0.4), stress (P=.64; Cohen d=0.1, 95% CI −0.4 to 0.6), depression (P=.93; Cohen d= 0.0, 95% CI −0.3 to 0.3), anxiety (P=.55; Cohen d=−0.1, 95% CI −0.4 to 0.2), beliefs about treatment (P=.71; Cohen d=0.1, 95% CI −0.2 to 0.3), partner self-efficacy (P=.59; Cohen d=−0.1, 95% CI −0.4 to 0.2), dyadic adjustment (P=.08; Cohen d=−0.2, 95% CI −0.5 to 0.0), social constraints (P=.05; Cohen d=0.3, 95% CI 0.0-0.6), or communication danger signs (P=.90; Cohen d=−0.0, 95% CI −0.3 to 0.3). Post hoc analyses collapsing across conditions revealed a significant between-group effect on stress for app users versus nonusers (β=−3.62; t281=−2.27; P=.02). Conclusions Approximately half of the randomized participants never used their allocated app, and participants in the PTSD Family Coach 1.0 condition only opened the app approximately 4 times over 4 weeks, suggesting limitations to this app version’s feasibility. PTSD Family Coach 1.0 users reported moderately favorable impressions of the app, suggesting preliminary acceptability. Regarding efficacy, no significant difference was found between PTSD Family Coach 1.0 users and psychoeducation app users across any outcome of interest. Post hoc analyses suggested that app use regardless of treatment condition was associated with reduced stress. Further research that improves app feasibility and establishes efficacy in targeting the domains most relevant to CSOs is warranted. Trial Registration ClinicalTrials.gov NCT02486705; https://clinicaltrials.gov/ct2/show/NCT02486705

The COVID-19 pandemic presents major challenges for mental health care providers. In particular, providers who treat posttraumatic stress disorder (PTSD) are now tasked with determining whether to initiate trauma-focused therapy during the pandemic and, if so, whether and how to adapt treatment. The purpose of this communication is to identify and organize key considerations for whether and how to deliver commonly used evidence-supported therapy protocols for trauma treatment-specifically, cognitive processing therapy (CPT) and prolonged exposure (PE) therapy-during the ongoing COVID-19 pandemic for adults who currently meet the criteria for PTSD. Based on relevant public health and clinical literature, we present a structured guide that can be used by treatment teams and individual providers to evaluate whether initiating CPT or PE is indicated given a particular patient-provider pair and system context amidst pandemic conditions. In addition, we suggest appropriate action steps, including problem-solving strategies, evidence-informed modifications to CPT and PE, and alternative intervention approaches.

Background With widespread smartphone ownership, mobile health apps (mHealth) can expand access to evidence-based interventions for mental health conditions, including posttraumatic stress disorder (PTSD). Research to evaluate new features and capabilities in these apps is critical but lags behind app development. The initial release of PTSD Coach, a free self-management app developed by the US Departments of Veterans Affairs and Defense, was found to have a positive public health impact. However, major stakeholder-driven updates to the app have yet to be evaluated. Objective We aimed to characterize the reach, use, and potential impact of PTSD Coach Version 3.1 in the general public. As part of characterizing use, we investigated the use of specific app features, which extended previous work on PTSD Coach. Methods We examined the naturalistic use of PTSD Coach during a 1-year observation period between April 20, 2020, and April 19, 2021, using anonymous in-app event data to generate summary metrics for users. Results During the observation period, PTSD Coach was broadly disseminated to the public, reaching approximately 150,000 total users and 20,000 users per month. On average, users used the app 3 times across 3 separate days for 18 minutes in total, with steep drop-offs in use over time; a subset of users, however, demonstrated high or sustained engagement. More than half of users (79,099/128,691, 61.46%) accessed one or more main content areas of the app (ie, Manage Symptoms, Track Progress, Learn, or Get Support). Among content areas, features under Manage Symptoms (including coping tools) were accessed most frequently, by over 40% of users (53,314/128,691, 41.43% to 56,971/128,691, 44.27%, depending on the feature). Users who provided initial distress ratings (56,971/128,691, 44.27%) reported relatively high momentary distress (mean 6.03, SD 2.52, on a scale of 0-10), and the use of a coping tool modestly improved momentary distress (mean −1.38, SD 1.70). Among users who completed at least one PTSD Checklist for DSM-5 (PCL-5) assessment (17,589/128,691, 13.67%), PTSD symptoms were largely above the clinical threshold (mean 49.80, SD 16.36). Among users who completed at least two PCL-5 assessments (4989/128,691, 3.88%), PTSD symptoms decreased from the first to last assessment (mean −4.35, SD 15.29), with approximately one-third (1585/4989, 31.77%) of these users experiencing clinically significant improvements. Conclusions PTSD Coach continues to fulfill its mission as a public health resource. Version 3.1 compares favorably with version 1 on most metrics related to reach, use, and potential impact. Although benefits appear modest on an individual basis, the app provides these benefits to a large population. For mHealth apps to reach their full potential in supporting trauma recovery, future research should aim to understand the utility of individual app features and identify strategies to maximize overall effectiveness and engagement.

BACKGROUND With widespread smartphone ownership, mobile health apps (mHealth) can expand access to evidence-based interventions for mental health conditions, including posttraumatic stress disorder (PTSD). Research to evaluate new features and capabilities in these apps is critical but lags behind app development. The initial release of PTSD Coach, a free self-management app developed by the US Departments of Veterans Affairs and Defense, was found to have a positive public health impact. However, major stakeholder-driven updates to the app have yet to be evaluated. OBJECTIVE We aimed to characterize the reach, use, and potential impact of PTSD Coach Version 3.1 in the general public. As part of characterizing use, we investigated the use of specific app features, which extended previous work on PTSD Coach. METHODS We examined the naturalistic use of PTSD Coach during a 1-year observation period between April 20, 2020, and April 19, 2021, using anonymous in-app event data to generate summary metrics for users. RESULTS During the observation period, PTSD Coach was broadly disseminated to the public, reaching approximately 150,000 total users and 20,000 users per month. On average, users used the app 3 times across 3 separate days for 18 minutes in total, with steep drop-offs in use over time; a subset of users, however, demonstrated high or sustained engagement. More than half of users (79,099/128,691, 61.46%) accessed one or more main content areas of the app (ie, Manage Symptoms, Track Progress, Learn, or Get Support). Among content areas, features under Manage Symptoms (including coping tools) were accessed most frequently, by over 40% of users (53,314/128,691, 41.43% to 56,971/128,691, 44.27%, depending on the feature). Users who provided initial distress ratings (56,971/128,691, 44.27%) reported relatively high momentary distress (mean 6.03, SD 2.52, on a scale of 0-10), and the use of a coping tool modestly improved momentary distress (mean −1.38, SD 1.70). Among users who completed at least one PTSD Checklist for DSM-5 (PCL-5) assessment (17,589/128,691, 13.67%), PTSD symptoms were largely above the clinical threshold (mean 49.80, SD 16.36). Among users who completed at least two PCL-5 assessments (4989/128,691, 3.88%), PTSD symptoms decreased from the first to last assessment (mean −4.35, SD 15.29), with approximately one-third (1585/4989, 31.77%) of these users experiencing clinically significant improvements. CONCLUSIONS PTSD Coach continues to fulfill its mission as a public health resource. Version 3.1 compares favorably with version 1 on most metrics related to reach, use, and potential impact. Although benefits appear modest on an individual basis, the app provides these benefits to a large population. For mHealth apps to reach their full potential in supporting trauma recovery, future research should aim to understand the utility of individual app features and identify strategies to maximize overall effectiveness and engagement. CLINICALTRIAL

Mindfulness meditation is increasingly incorporated into mental health interventions, and theoretical concepts associated with it have influenced basic research on psychopathology. Here, we review the current understanding of mindfulness meditation through the lens of clinical neuroscience, outlining the core capacities targeted by mindfulness meditation and mapping them onto cognitive and affective constructs of the Research Domain Criteria matrix proposed by the National Institute of Mental Health. We review efficacious applications of mindfulness meditation to specific domains of psychopathology including depression, anxiety, chronic pain, and substance abuse, as well as emerging efforts related to attention disorders, traumatic stress, dysregulated eating, and serious mental illness. Priorities for future research include pinpointing mechanisms, refining methodology, and improving implementation. Mindfulness meditation is a promising basis for interventions, with particular potential relevance to psychiatric comorbidity. The successes and challenges of mindfulness meditation research are instructive for broader interactions between contemplative traditions and clinical psychological science.

Background Depression exerts a staggering toll that is worsened with co-occurring chronic conditions such as obesity. It is imperative to develop more effective interventions for depression and to identify objective and biological plausible neural mechanisms to understand intervention outcomes. The current study uses functional neuroimaging to determine whether a behavioural intervention changes the negative affect circuit and whether these changes relate to subsequent improvements in both symptom and problem-solving outcomes in depressed patients with co-occurring obesity. Methods This study (‘ENGAGE’) was a pre-planned element of the randomized controlled trial, ‘RAINBOW’ (ClinicalTrials.gov NCT02246413). 108 depressed patients with obesity were randomized to receive an integrated collaborative care intervention (I-CARE) or usual care. Participants underwent functional neuroimaging using an established facial emotion task at baseline and two months (coinciding with the first two months of intervention focused on problem-solving therapy (‘PST’)). Amygdala, insula and anterior cingulate cortex activation was extracted using pre-planned definitions and standardized methods. The primary health and behavioural outcomes were depression symptom severity and problem-solving ability respectively, assessed at baseline, the main 6-month outcome point and at 12-month follow up. Mediation analyses used an intent-to-treat approach. Findings PST, relative to usual care, reduced amygdala activation engaged by threat stimuli at two months. This reduction mediated subsequent improvements in depression severity in an intervention-dependent manner. PST did not change insula activation at two months but did temper the strength of the relationship between insula activation and improvements in problem-solving ability. Interpretation The negative affect circuit may be an important neural target and potential mediator of PST in patients with comorbid obesity. Funding US National Institutes of Health/National Heart Lung and Blood Institute R01 HL119453 and UH2/UH3 HL132368

Recent EEG studies on the early postmortem interval that suggest the persistence of electrophysiological coherence and connectivity in the brain of animals and humans reinforce the need for further investigation of the relationship between the brain’s activity and the dying process. Neuroscience is now in a position to empirically evaluate the extended process of dying and, more specifically, to investigate the possibility of brain activity following the cessation of cardiac and respiratory function. Under the direction of the Center for Healthy Minds at the University of Wisconsin-Madison, research was conducted in India on a postmortem meditative state cultivated by some Tibetan Buddhist practitioners in which decomposition is putatively delayed. For all healthy baseline (HB) and postmortem (PM) subjects presented here, we collected resting state electroencephalographic data, mismatch negativity (MMN), and auditory brainstem response (ABR). In this study, we present HB data to demonstrate the feasibility of a sparse electrode EEG configuration to capture well-defined ERP waveforms from living subjects under very challenging field conditions. While living subjects displayed well-defined MMN and ABR responses, no recognizable EEG waveforms were discernable in any of the tukdam cases.

Background: Behavioral interventions for obesity have modest and variable effectiveness. Emotion dysregulation may hinder effective weight loss interventions, especially among those with comorbid depression. Whether neural mechanisms related to emotion dysregulation mediate the effect of behavioral intervention on improving health behaviors in obesity combined with depression is unknown. Hyperactivation of the amygdala and loss of functional connectivity with the anterior cingulate regions are neural characteristics of unhealthy responses to negative emotion and accompanying emotion dysregulation. Methods: Using data from a randomized clinical trial of 108 primary care adult patients with obesity and depression, we investigated whether changes in amygdala activity and connectivity following problem solving therapy for depression over 2 months mediate weight loss, physical activity, and/or dietary outcomes at 6 and 12 months. Results: Compared with controls (n=49), intervention participants (n=59) had a significant blunting of the otherwise unhealthy increase in activity of the bilateral amygdala at 2 months (right: -0.83, 95% CI -1.55 to -0.11; left: -0.86, -1.63 to -0.10). While increases in amygdala activity significantly correlated with decreases in leisure-time physical activity levels and total energy expenditure at 12 months in the control group, this relationship was tempered or reversed among intervention participants (for physical activity, right: usual care -692.9, -1365.3 to -20.6; interaction 652.2, -115.4 to 1419.9; left: usual care -686.0, -1127.9 to -244.1; interaction 664.7, 73.1 to 1256.4; for energy expenditure, right: usual care -1.82, -3.08 to -0.56; interaction 1.94, 0.50 to 3.38; left: usual care -1.72, -2.51 to -0.93; interaction 1.89, 0.84 to 2.94). Compared with controls, intervention participants had a significant increase of the otherwise unhealthy loss of amygdala-subgenual anterior cingulate connectivity at 2 months (0.78, 0.05 to 1.52). This increase in functional connectivity significantly correlated with a decrease in BMI at 6 months among intervention participants (usual care 0.04, -0.42 to 0.50; interaction -0.61, -1.20 to -0.02) and an increase in fruit and vegetable intake at 12 months across all participants (usual care 1.42, 0.27 to 2.57; interaction -0.95, -2.36 to 0.46). Conclusions: These findings highlight potential neural mechanism for optimizing the efficacy of behavioral intervention in comorbid obesity and depression.Trial registration: ClinicalTrials.gov#NCT02246413.URL: https://clinicaltrials.gov/ct2/show/NCT02246413.

Despite evidence for effective integrated behavior therapy for treating comorbid obesity and depression, treatment response is highly variable and the underlying neurobiological mechanisms remain unknown. This hampers efforts to identify mechanistic targets in order to optimize treatment precision and potency. Funded within the NIH Science of Behavior Change (SOBC) Research Network, the 2-phased ENGAGE research project applies an experimental precision medicine approach to address this gap. The Phase 1 study focused on demonstrating technical feasibility, target engagement and potential neural mechanisms of responses to an integrated behavior therapy. This therapy combines a video-based behavioral weight loss program and problem-solving therapy for depression, with as-needed intensification of antidepressant medications, and its clinical effectiveness was demonstrated within a parent randomized clinical trial. Here, we describe the ENGAGE Phase 2 (ENGAGE-2) study protocol which builds on Phase 1 in 2 ways: (1) pilot testing of an motivational interviewing-enhanced, integrated behavior therapy in an independent, primarily minority patient sample, and (2) evaluation of a priori defined neural targets, specifically the negative affect (threat and sadness) circuits which demonstrated engagement and malleability in Phase 1, as mediators of therapeutic outcomes. Additionally, the Phase 2 study includes a conceptual and methodological extension to explore the role of microbiome-gut-brain and systemic immunological pathways in integrated behavioral treatment of obesity and depression. This protocol paper documents the conceptualization, design and the transdisciplinary methodologies in ENGAGE-2, which can inform future clinical and translational research in experimental precision medicine for behavior change and chronic disease management. Trial registration: ClinicalTrials.gov #NCT 03,841,682.

Introduction: Neural mechanisms underlying behavior therapy in obesity are poorly understood, particularly in patients with comorbid depression. Putative targets include neural circuits for conscious and nonconscious emotion regulation. Hypothesis: Changes in a priori neural circuits for emotion regulation from baseline (0) to 2 mo (mediators, M) mediate changes in BMI, physical activity, and eating behaviors from 0 to 6 or 12 mo (outcomes, Y). Methods: In a trial of integrated behavior therapy, adults with obesity and depression were randomized to intervention (n=59) or usual care (n=49). The yearlong intervention included 6 in-person problem solving therapy (PST) sessions for depression by 2 mo, 3 additional PST sessions for depression and 11 home videos on lifestyle changes for weight loss by 6 mo, and 6 maintenance calls by 12 mo. Participants completed validated conscious and nonconscious facial emotion viewing tasks in fMRI at 0 and 2 mo (time point corresponding to initial PST for depression in the intervention) and weight and height (baseline only) measurements, 7-day physical activity recalls, and 24-hour dietary recalls at 0, 6, and 12 mo. Analyses tested mediation as showing both a significant treatment effect (X) of the intervention vs. usual care on the mediator (X->M, path a ) and a significant correlation of the mediator with the outcome either as a main effect or an interaction effect by treatment group (M->Y, path b ). Results: Compared with usual care, the intervention led to significantly reduced nonconscious reactivity to threat-related facial emotions (fear, anger) at 2 mo for the left (-0.89, 95% CI -1.64 to -0.14; P =.02) and right amygdala (-0.84, 95% CI -1.54 to -0.13; P =.02) ( path a ). These reductions correlated significantly with increased leisure-time physical activity (MET minutes/wk) at 12 mo: main effect -686.0 (95% CI -1127.9 to -244.1; P =.003) and interaction effect 664.7 (95% CI 73.1 to 1256.4; P =.03) for the left amygdala and main effect -692.9 (95% CI -1365.3 to -20.6; P= .04) for the right amygdala. Similarly, the reductions correlated significantly with increased energy expenditure (kcal/kg/d) at 12 mo: main effect -1.72 (95% CI -2.49 to -0.95; P P P =.006) and interaction effect 1.94 (95% CI 0.50 to 3.38; P =.01) for the right amygdala ( path b ). Nonconscious reactivity to threat in bilateral amygdala did not correlate significantly with changes in BMI or eating behaviors. Conclusions: Reduced nonconscious reactivity to threat in bilateral amygdala in response to initial PST for depression significantly mediated improvements in leisure-time physical activity and energy expenditure. Results advance the understanding of neural mechanisms underlying behavior therapy in obesity and inform intervention optimization to enhance efficacy.

Background: There is a need to understand the neural mechanisms targeted by behavioural therapy for depression and how these mechanisms relate to clinical outcomes. We used functional neuroimaging to assess the neural mechanisms that are modified by behavioural therapy and mediate subsequent clinical outcomes in depression. Methods: Participants with depression, co-occurring with obesity, from a parent RAINBOW trial, were randomised to an integrated collaborative care intervention (I-CARE) (n=59) or usual care (n=49). Functional neuroimaging was undertaken at baseline and at 2 months, coinciding with initial 2-months of I-CARE that implemented a 7-step problem-solving therapy process and behavioural activation (for brevity, “PST”). Neural targets were the amygdala, insula, and anterior cingulate cortex (ACC) regions of the negative affect circuit engaged by established tasks presenting threat-related and sad stimuli. Regression models evaluated if early change in neural function mediated the effect of PST on depression severity and problem-solving outcomes at 6- and 12-months post-randomization. Findings: Compared with usual care, PST led to a reduction at 2 months in amygdala activation (Right: b=-0.83, 95% CI -1.55 to -0.11; Left: b=-0.86, -1.63 to -0.10) and amygdala-ACC connectivity (b=0.78, 0.05 to 1.52) engaged by threat stimuli. This PST-dependent reduction in amygdala activation mediated improvement of depression at 6 months relative to usual care. PST also tempered the relationship between insula activation and improved problem solving at 6 and 12 months. Interpretation: PST modifies neural targets within the negative affect circuit to improve symptoms and problem-solving relevant to the clinical and functional recovery of depression. Funding Statement: US National Institutes of Health/National Heart Lung and Blood Institute R01 HL119453 and UH2/UH3 HL132368. Declaration of Interests: LMW is on the Scientific Advisory Board for One Mind Psyberguide and the External Advisory Board for the Laureate Institute for Brain Research. JM is a paid scientific consultant for Health Mentor, Inc. (San Jose, CA). OA is the co-founder of Keywise AI and the servers on the advisory boards of Blueprint Health and Embodied Labs. All other authors do not have anything to declare. Ethics Approval Statement: The Institutional Review Boards for the Stanford University and the University of Illinois at Chicago approved the study.

Reduced hippocampal volume is frequently observed in posttraumatic stress disorder (PTSD), but the psychological processes associated with these alterations remain unclear. Given hippocampal involvement in memory and contextual representations of threat, we investigated relationships between retrospectively reported combat exposure, perceived threat, and hippocampal volume in trauma-exposed veterans. T1-weighted anatomical MRI scans were obtained from 56 veterans (4 women, 52 men; 39 with elevated PTSD symptoms, “PTSS” group) and hippocampal volume was estimated using automatic segmentation tools in FreeSurfer. Hippocampal volume was regressed on self-reported perceived threat from the Deployment Risk and Resilience Inventory, and combat exposure from the Combat Exposure Scale. As a secondary analysis, hippocampal volume was regressed on Clinician-Administered PTSD Scale (CAPS) symptoms. In veterans with elevated PTSD symptoms, hippocampal volume was inversely related to perceived threat while deployed while controlling for self-reported combat exposure. Hippocampal volume was also inversely correlated with avoidance/numbing CAPS symptoms. Future research should clarify the temporal milieu of these effects and investigate whether individual differences in hippocampal structure and function contribute to heightened threat appraisal at the time of trauma vs. subsequently elevated appraisals of traumatic events.

BackgroundPrevious research in post-traumatic stress disorder (PTSD) has identified disrupted ventromedial prefrontal cortex (vmPFC) function in those with v. without PTSD. It is unclear whether this brain region is uniformly affected in all individuals with PTSD, or whether vmPFC dysfunction is related to individual differences in discrete features of this heterogeneous disorder.MethodIn a sample of 51 male veterans of Operation Enduring Freedom/Operation Iraqi Freedom, we collected functional magnetic resonance imaging data during a novel threat anticipation task with crossed factors of threat condition and temporal unpredictability. Voxelwise regression analyses related anticipatory brain activation to individual differences in overall PTSD symptom severity, as well as individual differences in discrete symptom subscales (re-experiencing, emotional numbing/avoidance, and hyperarousal).ResultsThe vmPFC showed greater anticipatory responses for safety relative to threat, driven primarily by deactivation during threat anticipation. During unpredictable threat anticipation, increased PTSD symptoms were associated with relatively greater activation for threat v. safety. However, simultaneous regression on individual symptom subscales demonstrated that this effect was driven specifically by individual differences in hyperarousal symptoms. Furthermore, this analysis revealed an additional, anatomically distinct region of the vmPFC in which re-experiencing symptoms were associated with greater activation during threat anticipation.ConclusionsIncreased anticipatory responses to unpredictable threat in distinct vmPFC subregions were uniquely associated with elevated hyperarousal and re-experiencing symptoms in combat veterans. These results underscore the disruptive impact of uncertainty for veterans, and suggest that investigating individual differences in discrete aspects of PTSD may advance our understanding of underlying neurobiological mechanisms.

Previous studies have identified reduced heart rate variability (HRV) in posttraumatic stress disorder (PTSD), which may temporally precede the onset of the disorder. A separate line of functional neuroimaging research in PTSD has consistently demonstrated hypoactivation of the ventromedial prefrontal cortex (vmPFC), a key aspect of a descending neuromodulatory system that exerts inhibitory control over heart rate. No research to date, however, has simultaneously investigated whether altered vmPFC activation is associated with reduced HRV and elevated PTSD symptoms in the same individuals. Here, we collected fMRI data during alternating conditions of threat of shock and safety from shock in 51 male, combat-exposed veterans with either high or low levels of PTSD symptoms. Pulse rate variability (PRV) - an HRV surrogate calculated from pulse oximetry - was assessed during a subsequent resting scan. Correlational analyses tested for hypothesized relationships between reduced vmPFC activation, lower PRV, and elevated PTSD symptomatology. We found that PTSD re-experiencing symptoms were inversely associated with high-frequency (HF)-PRV, thought to primarily reflect parasympathetic control of heart rate, in veterans with elevated PTSD symptoms. Reduced vmPFC activation for the contrast of safety-threat was associated both with lower HF-PRV and elevated PTSD re-experiencing symptoms. These results tie together previous observations of reduced HRV/PRV and impaired vmPFC function in PTSD and call for further research on reciprocal brain-body relationships in understanding PTSD pathophysiology.

BackgroundReduced hippocampal volume is frequently observed in posttraumatic stress disorder (PTSD), but the exact psychological processes associated with these alterations remain unclear. Given the role of the hippocampus in contextual representations of threat and memory, we investigated relationships between retrospectively reported combat exposure, perceived threat, and hippocampal volume in trauma-exposed veterans.MethodsT1-weighted anatomical MRI scans were obtained from 52 male veterans with a broad range of PTSD symptoms. Hippocampal volume was estimated using automatic segmentation tools in FreeSurfer. An index of perceived threat bias was calculated, reflecting the degree of discordance between subjective perceptions of threat while deployed and self-reported combat exposure. Hippocampal volume was regressed on perceived threat bias and PTSD symptoms on the Clinician-Administered PTSD Scale (CAPS).ResultsPerceived threat bias was unrelated to overall CAPS symptoms, but was positively correlated with CAPS avoidance/numbing symptoms and symptoms of depression, anxiety, and worry. The degree of perceived threat bias was inversely correlated with hippocampal volume. Hippocampal volume was also inversely related to avoidance/numbing CAPS symptoms.ConclusionsThese results indicate that volume of the hippocampus, a region involved in contextual threat processing and memory, is related to recalled associations between traumatic events and accompanying subjective threat appraisals. Future research should clarify the precise temporal milieu of these effects and investigate whether individual differences in hippocampal structure and function contribute to exaggerated threat appraisal at the time of trauma, or in subsequently biased memories or appraisals of traumatic events.

Psychological processes such as expectancy, attention, and affect directly influence clinical outcomes. These factors are grouped together as "nonspecific" factors, or placebo effects, in the medical literature, and their individual contributions are rarely considered. The pain-reducing effects of analgesic treatments may reflect changes in these psychological factors, rather than pure drug effects on pain. Furthermore, drug effects may not be isolated by drug vs. placebo comparisons if drugs interact with relevant psychological processes.We sought to determine whether the analgesic effects of opioid and placebo treatment are mediated by changes in attention, expectancy, or affect.We crossed intravenous administration of a potent opioid analgesic, remifentanil, with information about drug delivery (treatment expectancy or placebo) using a balanced placebo design. We measured drug and treatment expectancy effects on pain, attention, and responses to emotional images. We also examined interactions with cue-based expectations about noxious stimulation or stimulus expectancy.Pain was additively influenced by treatment expectancy, stimulus expectancy, and drug concentration. Attention performance showed a small but significant interaction between drug and treatment expectancy. Finally, remifentanil enhanced responses to both positive and negative emotional images.The pain-relieving effects of opioid drugs are unlikely to be mediated by changes in threat or affective processing. Standard open-label opioid administration influences multiple clinically relevant cognitive and emotional processes. Psychological factors can combine with drug effects to influence multiple outcomes in distinct ways. The influence of specific psychological factors should be considered when developing and testing pharmacological treatments.

Respiration rate is known to correlate with aspects of psychological well-being, and attention to respiration is a central component of mindfulness meditation training. Both traditional contemplative systems and recent empirical evidence support an association between formal mindfulness practice and decreased respiration rate. However, the question of whether long-term mindfulness training is associated with stable, generalized changes in respiration has yet to be directly investigated. We analyzed respiration patterns across multiple time points, separated by two months or more, in a group of long-term mindfulness meditation practitioners (LTMs, n = 31) and a matched group of non-meditators (Controls, n = 38). On average, LTMs showed slower baseline respiration rate (RR) than Controls. Among LTMs, greater practice experience was associated with slower RR, independently of age and gender. Furthermore, this association was specific to intensive retreat practice, and was not seen for routine daily practice. Full days of meditation practice did not produce detectable changes in baseline RR, suggesting distal rather than immediate effects. All effects were independent of physiological characteristics including height, weight, body-mass index and waist-hip ratio. We discuss implications for continued study of the long-term effects of mindfulness training on health and well-being.

The current study attempted a rigorous test of the construct validity of a widely used self-report measure of dispositional mindfulness, the Five Facet Mindfulness Questionnaire (FFMQ), within the context of an active controlled randomized trial (n = 130). The trial included three arms: mindfulness-based stress reduction (MBSR), an active control condition that did not include instruction in mindfulness meditation (Health Enhancement Program [HEP]), and a waitlist control condition. Partial evidence for the convergent validity of the FFMQ was shown in correlations at baseline between FFMQ facets and measures of psychological symptoms and psychological well-being. In addition, facets of the FFMQ were shown to increase over the course of an MBSR intervention relative to a waitlist control condition. However, the FFMQ failed to show discriminant validity. Specifically, facets of the FFMQ were shown to increase over the course of the HEP intervention relative to the waitlist control condition. MBSR and HEP, in contrast, did not differ in changes in FFMQ score over time. Implications of these findings for the measurement and theory of mindfulness and MBSR are discussed. (PsycINFO Database Record

Placebo treatments and opiate drugs are thought to have common effects on the opioid system and pain-related brain processes. This has created excitement about the potential for expectations to modulate drug effects themselves. If drug effects differ as a function of belief, this would challenge the assumptions underlying the standard clinical trial. We conducted two studies to directly examine the relationship between expectations and opioid analgesia. We administered the opioid agonist remifentanil to human subjects during experimental thermal pain and manipulated participants' knowledge of drug delivery using an open-hidden design. This allowed us to test drug effects, expectancy (knowledge) effects, and their interactions on pain reports and pain-related responses in the brain. Remifentanil and expectancy both reduced pain, but drug effects on pain reports and fMRI activity did not interact with expectancy. Regions associated with pain processing showed drug-induced modulation during both Open and Hidden conditions, with no differences in drug effects as a function of expectation. Instead, expectancy modulated activity in frontal cortex, with a separable time course from drug effects. These findings reveal that opiates and placebo treatments both influence clinically relevant outcomes and operate without mutual interference.