Neuroimaging-based classification of PTSD using data-driven computational approaches: A multisite big data study from the ENIGMA-PGC PTSD consortium.

BACKGROUND: Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. However, current machine learning studies limited to small homogeneous samples, different methodologies, and different imaging collection protocols, limit the ability to directly compare and generalize their results. Here we aimed to classify individuals with PTSD versus controls and assess the generalizability using a large heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group. METHODS: We analyzed brain MRI data from 3,477 structural-MRI; 2,495 resting state-fMRI; and 1,952 diffusion-MRI. First, we identified the brain features that best distinguish individuals with PTSD from controls using traditional machine learning methods. Second, we assessed the utility of the denoising variational autoencoder (DVAE) and evaluated its classification performance. Third, we assessed the generalizability and reproducibility of both models using leave-one-site-out cross-validation procedure for each modality. RESULTS: We found lower performance in classifying PTSD vs. controls with data from over 20 sites (60 % test AUC for s-MRI, 59 % for rs-fMRI and 56 % for d-MRI), as compared to other studies run on single-site data. The performance increased when classifying PTSD from HC without trauma history in each modality (75 % AUC). The classification performance remained intact when applying the DVAE framework, which reduced the number of features. Finally, we found that the DVAE framework achieved better generalization to unseen datasets compared with the traditional machine learning frameworks, albeit performance was slightly above chance. CONCLUSION: These results have the potential to provide a baseline classification performance for PTSD when using large scale neuroimaging datasets. Our findings show that the control group used can heavily affect classification performance. The DVAE framework provided better generalizability for the multi-site data. This may be more significant in clinical practice since the neuroimaging-based diagnostic DVAE classification models are much less site-specific, rendering them more generalizable.

A comparison of methods to harmonize cortical thickness measurements across scanners and sites.

Results of neuroimaging datasets aggregated from multiple sites may be biased by site-specific profiles in participants' demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LMEINT), (2) LME that models both site-specific random intercepts and age-related random slopes (LMEINT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1,340 cases with posttraumatic stress disorder (PTSD) (6.2-81.8 years old) and 2,057 trauma-exposed controls without PTSD (6.3-85.2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM was more sensitive to the detection of significant case-control differences (Χ2(3) = 63.704, p < 0.001) as well as case-control differences in age-related cortical thinning (Χ2(3) = 12.082, p = 0.007). Both ComBat and ComBat-GAM outperformed LME methods in detecting sex differences (Χ2(3) = 9.114, p = 0.028) in regional cortical thickness. ComBat-GAM also led to stronger estimates of age-related declines in cortical thickness (corrected p-values < 0.001), stronger estimates of case-related cortical thickness reduction (corrected p-values < 0.001), weaker estimates of age-related declines in cortical thickness in cases than controls (corrected p-values < 0.001), stronger estimates of cortical thickness reduction in females than males (corrected p-values < 0.001), and stronger estimates of cortical thickness reduction in females relative to males in cases than controls (corrected p-values < 0.001). Our results support the use of ComBat-GAM to minimize confounds and increase statistical power when harmonizing data with non-linear effects, and the use of either ComBat or ComBat-GAM for harmonizing data with linear effects.

Altered white matter microstructural organization in posttraumatic stress disorder across 3047 adults: results from the PGC-ENIGMA PTSD consortium.

A growing number of studies have examined alterations in white matter organization in people with posttraumatic stress disorder (PTSD) using diffusion MRI (dMRI), but the results have been mixed which may be partially due to relatively small sample sizes among studies. Altered structural connectivity may be both a neurobiological vulnerability for, and a result of, PTSD. In an effort to find reliable effects, we present a multi-cohort analysis of dMRI metrics across 3047 individuals from 28 cohorts currently participating in the PGC-ENIGMA PTSD working group (a joint partnership between the Psychiatric Genomics Consortium and the Enhancing NeuroImaging Genetics through Meta-Analysis consortium). Comparing regional white matter metrics across the full brain in 1426 individuals with PTSD and 1621 controls (2174 males/873 females) between ages 18-83, 92% of whom were trauma-exposed, we report associations between PTSD and disrupted white matter organization measured by lower fractional anisotropy (FA) in the tapetum region of the corpus callosum (Cohen's d = -0.11, p = 0.0055). The tapetum connects the left and right hippocampus, for which structure and function have been consistently implicated in PTSD. Results were consistent even after accounting for the effects of multiple potentially confounding variables: childhood trauma exposure, comorbid depression, history of traumatic brain injury, current alcohol abuse or dependence, and current use of psychotropic medications. Our results show that PTSD may be associated with alterations in the broader hippocampal network.

Cortical volume abnormalities in posttraumatic stress disorder: an ENIGMA-psychiatric genomics consortium PTSD workgroup mega-analysis.

Studies of posttraumatic stress disorder (PTSD) report volume abnormalities in multiple regions of the cerebral cortex. However, findings for many regions, particularly regions outside commonly studied emotion-related prefrontal, insular, and limbic regions, are inconsistent and tentative. Also, few studies address the possibility that PTSD abnormalities may be confounded by comorbid depression. A mega-analysis investigating all cortical regions in a large sample of PTSD and control subjects can potentially provide new insight into these issues. Given this perspective, our group aggregated regional volumes data of 68 cortical regions across both hemispheres from 1379 PTSD patients to 2192 controls without PTSD after data were processed by 32 international laboratories using ENIGMA standardized procedures. We examined whether regional cortical volumes were different in PTSD vs. controls, were associated with posttraumatic stress symptom (PTSS) severity, or were affected by comorbid depression. Volumes of left and right lateral orbitofrontal gyri (LOFG), left superior temporal gyrus, and right insular, lingual and superior parietal gyri were significantly smaller, on average, in PTSD patients than controls (standardized coefficients = -0.111 to -0.068, FDR corrected P values < 0.039) and were significantly negatively correlated with PTSS severity. After adjusting for depression symptoms, the PTSD findings in left and right LOFG remained significant. These findings indicate that cortical volumes in PTSD patients are smaller in prefrontal regulatory regions, as well as in broader emotion and sensory processing cortical regions.

Initial Psychometric Properties of 7 NeuroUX Remote Ecological Momentary Cognitive Tests Among People With Bipolar Disorder: Validation Study.

BACKGROUND: As smartphone technology has become nearly ubiquitous, there is a growing body of literature suggesting that ecological momentary cognitive testing (EMCT) offers advantages over traditional pen-and-paper psychological assessment. We introduce a newly developed platform for the self-administration of cognitive tests in ecologically valid ways. OBJECTIVE: The aim of this study is to develop a Health Insurance Portability and Accountability Act-compliant EMCT smartphone-based platform for the frequent and repeated testing of cognitive abilities in everyday life. This study examines the psychometric properties of 7 mobile cognitive tests covering domains of processing speed, visual working memory, recognition memory, and response inhibition within our platform among persons with and without bipolar disorder (BD). Ultimately, if shown to have adequate psychometric properties, EMCTs may be useful in research on BD and other neurological and psychiatric illnesses. METHODS: A total of 45 persons with BD and 21 demographically comparable healthy volunteer participants (aged 18-65 years) completed smartphone-based EMCTs 3 times daily for 14 days. Each EMCT session lasted approximately 1.5 minutes. Only 2 to 3 tests were administered in any given session, no test was administered more than once per day, and alternate test versions were administered in each session. RESULTS: The mean adherence to the EMCT protocol was 69.7% (SD 20.5%), resulting in 3965 valid and complete tests across the full sample. Participants were significantly more likely to miss tests on later versus earlier study days. Adherence did not differ by diagnostic status, suggesting that BD does not interfere with EMCT participation. In most tests, age and education were related to EMCT performance in expected directions. The average performances on most EMCTs were moderately to strongly correlated with the National Institutes of Health Toolbox Cognition Battery. Practice effects were observed in 5 tests, with significant differences in practice effects by BD status in 3 tests. CONCLUSIONS: Although additional reliability and validity data are needed, this study provides initial psychometric support for EMCTs in the assessment of cognitive performance in real-world contexts in BD.

Symptoms of Posttraumatic Stress Disorder are Associated with Exaggerated Neural Response to Surprising Errors.

Posttraumatic stress disorder (PTSD) is characterized by exaggerated salience of previously innocuous cues and associated with hyperactivity of salience-related brain regions. Recently, computational models have been deployed to operationalize salience more precisely regarding surprise-driven learning, leading to findings that such learning is altered in anxiety-related disorders. In the present study, a sample of 20 combat veterans completed a probabilistic learning task during fMRI scanning. We applied a computational model to generate a trial-by-trial surprise signal (i.e., unsigned prediction error or difference between the expected probability of an outcome and the actual observed outcome), which allowed us to examine the neural response to surprising events. We did not observe an association between PTSD symptoms and behavioral indices of learning in the task. Surprising errors were associated with increased activity in the left precuneus/inferior parietal lobule and right inferior parietal lobule, two parietal regions that are linked to salience processing. Additionally, PTSD symptom severity was positively associated with precuneus/inferior parietal lobule activation to surprising errors, r = .63, p = .004. Taken together, this pattern of results suggests that PTSD symptoms are specifically associated with an exaggerated response to surprising errors in salience-related regions of the brain. This altered pattern of neural activity could represent a target for intervention to improve PTSD symptoms.

Proactive engagement of cognitive control modulates implicit approach-avoidance bias.

Implicit social-affective biases-reflected in a propensity to approach positive and avoid negative stimuli-have been documented in humans with paradigms, such as the Approach-Avoidance Task (AAT). However, the degree to which preemptively engaging cognitive control can help to down-regulate those behavioral tendencies remains poorly understood. While undergoing functional magnetic resonance imaging (fMRI), 24 healthy participants completed a cued version of the AAT, in which they responded to pictures of happy or angry faces by pulling a joystick toward themselves (approach) or pushing the joystick away (avoidance) based on the color of the stimulus frame. On some trials, they were cued to reverse the frame color/joystick action instructions. Before stimulus onset, a reverse cue was associated with deactivation of a visuo-spatial and motor planning network and subsequent slowing down in response to stimuli. During the stimulus phase, a reverse cue was associated with a) activation of cognitive control areas, including the right inferior frontal gyrus (IFG) and right inferior parietal lobule (IPL); and b) reduced right precentral gyrus activation when having to push (avoid) a happy face. Overall, these results suggest that proactively engaging cognitive control can help fine-tune behavioral and neural adjustment to emotionally incongruent behavioral conditions.

Contributions of posttraumatic stress disorder (PTSD) and mild TBI (mTBI) history to suicidality in the INTRuST consortium.

OBJECTIVE: Mild TBI (mTBI) and posttraumatic stress disorder (PTSD) are independent risk factors for suicidal behaviour (SB). Further, co-occurring mTBI and PTSD increase one's risk for negative health and psychiatric outcomes. However, little research has examined the role of comorbid mTBI and PTSD on suicide risk. METHODS: The present study utilized data from the Injury and TRaUmatic STress (INTRuST) Consortium to examine the prevalence of suicidal ideation (SI) and behaviours among four groups: 1) comorbid mTBI+PTSD, 2) PTSD only, 3) mTBI only, and 4) healthy controls. RESULTS: Prevalence of lifetime SI, current SI, and lifetime SB for individuals with mTBI+PTSD was 40%, 25%, and 19%, respectively. Prevalence of lifetime SI, current SI, and lifetime SB for individuals with PTSD only was 29%, 11%, and 11%, respectively. Prevalence of lifetime SI, current SI, and lifetime SB for individuals with mTBI only was 14%, 1%, and 2%, respectively. Group comparisons showed that individuals with mTBI alone experienced elevated rates of lifetime SI compared to healthy controls. History of mTBI did not add significantly to risk for suicidal ideation and behaviour beyond what is accounted for by PTSD. CONCLUSION: Findings suggest that PTSD seems to be driving risk for suicidal behaviour.

Mild Traumatic Brain Injury Burden Moderates the Relationship Between Cognitive Functioning and Suicidality in Iraq/Afghanistan-Era Veterans.

OBJECTIVES: Suicidal ideation (SI) is highly prevalent in Iraq/Afghanistan-era veterans with a history of mild traumatic brain injury (mTBI), and multiple mTBIs impart even greater risk for poorer neuropsychological functioning and suicidality. However, little is known about the cognitive mechanisms that may confer increased risk of suicidality in this population. Thus, we examined relationships between neuropsychological functioning and suicidality and specifically whether lifetime mTBI burden would moderate relationships between cognitive functioning and suicidal ideation. METHODS: Iraq/Afghanistan-era Veterans with a history of mTBI seeking outpatient services (N = 282) completed a clinical neuropsychological assessment and psychiatric and postconcussive symptom questionnaires. RESULTS: Individuals who endorsed SI reported more severe post-traumatic stress disorder (PTSD), depression, and postconcussive symptoms and exhibited significantly worse memory performance compared to those who denied SI. Furthermore, mTBI burden interacted with both attention/processing speed and memory, such that poorer performance in these domains was associated with greater likelihood of SI in individuals with a history of three or more mTBIs. The pattern of results remained consistent when controlling for PTSD, depression, and postconcussive symptoms. CONCLUSIONS: Slowed processing speed and/or memory difficulties may make it challenging to access and use past experiences to solve current problems and imagine future outcomes, leading to increases in hopelessness and SI in veterans with three or more mTBIs. Results have the potential to better inform treatment decisions for veterans with history of multiple mTBIs. (JINS, 2019, 25, 79-89).

Neural mechanisms of interference control in working memory capacity.

The extent to which one can use cognitive resources to keep information in working memory is known to rely on (1) active maintenance of target representations and (2) downregulation of interference from irrelevant representations. Neurobiologically, the global capacity of working memory is thought to depend on the prefrontal and parietal cortices; however, the neural mechanisms involved in controlling interference specifically in working memory capacity tasks remain understudied. In this study, 22 healthy participants completed a modified complex working memory capacity task (Reading Span) with trials of varying levels of interference control demands while undergoing functional MRI. Neural activity associated with interference control demands was examined separately during encoding and recall phases of the task. Results suggested a widespread network of regions in the prefrontal, parietal, and occipital cortices, and the cingulate and cerebellum associated with encoding, and parietal and occipital regions associated with recall. Results align with prior findings emphasizing the importance of frontoparietal circuits for working memory performance, including the role of the inferior frontal gyrus, cingulate, occipital cortex, and cerebellum in regulation of interference demands.

TBI and Treatment Response in a Randomized Trial of Acceptance and Commitment Therapy.

OBJECTIVE: Traumatic brain injury (TBI) occurs in a substantial minority of military personnel, and commonly is associated with mental health disorders and postconcussive symptoms (PCS). The implications of TBI for mental health treatment are not well understood. The present study sought to describe psychotherapy response in veterans with and without TBI. DESIGN: This is a secondary analysis from a 2-group randomized controlled trial. SETTING, PARTICIPANTS, AND MEASURES: One hundred and sixty male and female veterans participated in a multisite randomized controlled trial of Acceptance and Commitment Therapy versus Present Centered Therapy; a subset of 129 veterans were included in these analyses. Outcomes included the Brief Symptom Inventory-18 (BSI), Short Form 12 Health Survey (SF-12), Rivermead Postconcussion Symptoms Questionnaire (RPQ), and Sheehan Disability Scale (SDS). RESULTS: Regardless of the intervention, treatment response in those with and without TBI did not differ for the BSI, physical health-related SF-12, or SDS. Those with TBI showed less improvement on the mental health SF-12 subscale. The RPQ did not show significant improvement over time. CONCLUSION: Results did not suggest a need for differential psychotherapy treatment based on TBI history. In spite of evidence suggesting high correspondence between emotional symptoms and PCS, PCS did not respond to the current interventions.

Trauma-Related Disgust in Veterans With Interpersonal Trauma.

Although traditionally conceptualized as an anxiety disorder, variability in posttraumatic stress disorder (PTSD) may be explained by individual differences in peri- or posttraumatic disgust. We examined relationships between disgust reactions and other trauma-related symptoms in 100 veterans with a history of interpersonal trauma and gender differences in these variables. We also evaluated the mediating role of posttraumatic disgust and guilt in the relationship between peritraumatic disgust and PTSD symptoms. Participants completed cross-sectional self-report questionnaires of trauma-related emotions, PTSD, and other psychological symptoms as part of clinical intake procedures. Women and men did not differ on trauma-related emotions or symptoms. However, the relationship between peri- and posttraumatic disgust depended on gender, with men reporting a stronger association between peri- and posttraumatic disgust than women (p = .013, ΔR2 = .04). Posttraumatic disgust and guilt mediated the relationship between peritraumatic disgust and PTSD symptoms, controlling for gender (a1 a2 b1 = 0.18, SE = 0.09, PM = .19). Our results converge with those found in other studies suggesting that disgust is a common trauma-related emotion and that men and women may experience differential relationships between peri- and posttraumatic emotional experiences. Further study of the role of trauma-related emotional responses in PTSD etiology and treatment is warranted.

Neuropsychiatric Predictors of Post-Injury Headache After Mild-Moderate Traumatic Brain Injury in Veterans.

OBJECTIVES: To determine differences in neuropsychiatric complaints between Veterans with mild to moderate traumatic brain injury (TBI), with and without headache, compared with Veteran controls, and to identify neuropsychiatric predictors of headache severity. BACKGROUND: Mild to moderate TBI is a common occurrence in Veterans, and is frequently associated with complaints of headache. Neuropsychiatric complaints are also common among individuals who have sustained head injury, although the relationship between these factors and headache after injury is unclear. Research is needed to comprehensively determine differences between individuals with mild to moderate traumatic brain injury who differ with respect to headache, and which injury, psychological, or sleep and fatigue factors predict headache severity. METHODS: A cross-sectional study compared 85 Veterans in three groups (positive for TBI and headache, positive for TBI without significant headache, and a control group) on a set of injury characteristics and neuropsychiatric variables. Correlates of headache severity were examined, and a regression model was used to identify significant independent predictors of headache severity. RESULTS: Individuals with mild to moderate TBI and headache endorsed significantly greater neuropsychiatric symptoms than participants in the other groups (η(p)2 = .23-.36) Neuropsychiatric complaints, as well as presence of posttraumatic amnesia, were correlated with headache in the subsample with TBI (rs = .44-.57). When entering all predictors into a regression model, only fatigue represented a significant independent predictor of headache severity (ß = .59, R2 = .35). CONCLUSIONS: Rather than being a global risk factor, mild to moderate TBI was associated with poorer mental health outcomes, particularly for those who endorse headache. Findings underscore the possibility that Veterans with history of TBI who present with complaints of headache may represent a particularly vulnerable subgroup. Additionally, our findings suggest that clinical outcomes may be improved in those with neurotrauma by incorporating a focus on fatigue in treatment.

Sleep Quality Improvement During Cognitive Behavioral Therapy for Anxiety Disorders.

Despite the ubiquity of sleep complaints among individuals with anxiety disorders, few prior studies have examined whether sleep quality improves during anxiety treatment. The current study examined pre- to posttreatment sleep quality improvement during cognitive behavioral therapy (CBT) for panic disorder (PD; n = 26) or generalized anxiety disorder (GAD; n = 24). Among sleep quality indices, only global sleep quality and sleep latency improved significantly (but modestly) during CBT. Sleep quality improvement was greater for treatment responders, but did not vary by diagnosis. Additionally, poor baseline sleep quality was independently associated with worse anxiety treatment outcome, as measured by higher intolerance of uncertainty. Additional intervention targeting sleep prior to or during CBT for anxiety may be beneficial for poor sleepers.

Change in resting state functional connectivity following working memory training in individuals with repetitive negative thinking.

BACKGROUND: Repetitive negative thinking (RNT) symptoms, which are characterized by pervasive, uncontrollable negative thoughts, are common in individuals with mood, anxiety, and traumatic stress disorders. Inability to regulate the contents of working memory is a hypothesized etiological factor in RNT, suggesting that training to improve working memory may be beneficial. This study examined the effects of working memory training on resting state functional connectivity (rsFC) in individuals with elevated RNT and whether such changes would be associated with clinical improvement. METHODS: We conducted a secondary analysis of pre-post resting state data collected as part of a randomized controlled trial [NCT04912089] of working memory training interventions (n=42) compared to a waitlist control group (n=23). We hypothesized that individuals completing training would show increased rsFC between the two key intrinsic connectivity networks - default mode network (posterior cingulate cortex; PCC) and frontoparietal network (dorsolateral prefrontal cortex; dlPFC). We explored whether magnitude of rsFC change was associated with change in RNT symptom severity. RESULTS: rsFC increased between the PCC and regions including frontal and parietal cortex in the training group relative to waitlist. Increased connectivity between the PCC and superior frontal cortex was associated with RNT symptom reduction. CONCLUSIONS: These data provide evidence that working memory training can modulate neural circuitry at rest in individuals with RNT. Results align with accounts of working memory training effects on large-scale neurocircuitry changes and suggest that these changes may contribute to clinical promise of this type of intervention on transdiagnostic RNT symptoms.

Sleep efficiency predicts improvements in fear extinction and PTSD symptoms during prolonged exposure for veterans with comorbid insomnia.

Prolonged exposure (PE) is an evidenced-based psychotherapy for PTSD, but many Veterans fail to achieve a clinically meaningful response. Sleep issues are prevalent in Veterans and may interfere with PE by disrupting the learning and consolidation of fear extinction memories during PE exposures. Here, we examined whether changes in fear extinction across imaginal exposures and PTSD symptoms during PE were predicted by diary-assessed levels of nightly sleep efficiency (SE; i.e., percent of time in bed spent sleeping), which may indirectly index sleep fragmentation and sleep-facilitated memory processes. Participants were Veterans with PTSD and comorbid insomnia (N = 40) participating in a clinical trial of cognitive-behavioral therapy for insomnia plus PE. SE was measured via nightly sleep diaries, fear extinction was operationalized as a reduction in peak distress between weekly imaginal exposures, and PTSD symptoms were assessed bi-weekly. Cross-lagged panel models revealed that higher sleep efficiency during the week predicted lower peak distress at the subsequent imaginal exposure and lower PTSD symptoms at the subsequent assessment, whereas PTSD symptoms and peak distress did not predict subsequent sleep efficiency. Efficient sleep may facilitate fear extinction and PTSD reduction during PE. Targeting sleep efficiency could improve PE effectiveness for Veterans with comorbid insomnia.

Veterans who focus on sexual assault trauma show slower between-session habituation and symptom reduction during prolonged exposure treatment for posttraumatic stress disorder.

OBJECTIVE: Prolonged exposure (PE) is an effective treatment for posttraumatic stress disorder (PTSD), but veterans with sexual assault (SA) trauma often discontinue it prematurely. Elevated dropout rates may be due to SA triggering more intense and complex emotions that are more difficult to habituate during imaginal exposures; SA during PE has yet to be examined as a moderator of distress habituation or symptom reduction. METHOD: Participants were N = 65 veterans (n = 12 SA treatment focus; n = 10 SA history but not treatment focus; n = 43 no SA history) enrolled in a clinical trial of a preparatory sleep intervention followed by PE. The sample was representative of the veteran population. Growth curve modeling was used to examine differences in peak subjective units of distress scale (SUDS) ratings across imaginal exposures and changes in biweekly PTSD symptom assessments between veterans who did versus did not focus on SA during PE and between veterans who did versus did not endorse a history of SA. RESULTS: Peak SUDS ratings and PTSD symptoms declined slower among veterans who focused on an SA trauma relative to those who did not. In contrast, participants who endorsed SA history showed similar declines in distress and PTSD symptoms relative to veterans with no SA history. CONCLUSIONS: Veterans who focus on SA during PE may take longer to habituate to trauma content and experience resolution of PTSD symptoms. Awareness of this pattern could allow clinicians to deliver PE more effectively to veterans focusing on an SA trauma. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Randomized controlled trial of computerized approach/avoidance training in social anxiety disorder: Neural and symptom outcomes.

Social anxiety is associated with diminished automatic approach toward positive social cues that may limit the ability to connect with others. This diminished approach bias may be a modifiable treatment target. We evaluated the effects of an approach avoidance training procedure on positive emotions, social relationship outcomes, clinical symptoms, and neural indices of social approach and reward processing. Forty-five individuals with social anxiety disorder were randomized (parallel 1:1 randomization) to complete computerized Approach Positive training (n = 21) or Balanced training(n = 24). Sessions included a standardized social interaction task. Participants were blind to training group. Participants completed clinical outcome measures and functional magnetic resonance imaging at baseline and post intervention with an MRI-compatible AAT and the social incentive delay task (SID). Both groups displayed significant improvements of similar magnitude on the primary outcome of social connectedness (between group post-treatment d = -0.21) but not positive affect (d = -0.09), from before to after treatment, persisting through follow-up. Groups demonstrated significant improvements on additional outcomes including anxiety, depression, and anhedonia symptoms. Participants in Approach Positive AAT demonstrated increased activation in the thalamus and medial prefrontal cortex during social versus neutral- approach relative to Balanced AAT during the fMRI AAT. Participants in Balanced AAT showed increased activation in regions within an a priori-defined striatum region of interest mask during anticipation of social reward (vs. baseline) in the SID relative to Approach Positive AAT. At a neural processing level AAT may influence the valuation and motivations associated with positive social cues regulated by the mPFC and thalamus. NCT02136212, NIMH R00MH090243.

Prospective relations between anxiety sensitivity and transdiagnostic anxiety following cognitive-behavioral therapy: Evidence from the Coordinated Anxiety Learning management trial.

Previous research has implicated reductions in anxiety sensitivity (AS) - the dispositional tendency to fear anxiety-related sensations - as critical to change during cognitive behavioral therapy (CBT) for anxiety. However, the relationship of AS to anxiety symptom remittance following CBT remains largely unknown. To address this gap, the current study evaluated prospective associations between AS and symptoms of various anxiety disorders following completion of the Coordinated Anxiety Learning and Management (CALM) study- a large clinical trial evaluating the efficacy of a brief, computer-facilitated CBT intervention for transdiagnostic anxiety within primary care. Participants were randomized to CALM (n = 460) or a control treatment (n = 501) and completed self-report measures of general and disorder-specific anxiety symptoms at pretreatment and at 6-month, 12-month, and 18-month follow-up. Longitudinal relations between AS and each anxiety measure across timepoints and within each treatment group were assessed using cross-lagged panel models. Results indicated that higher AS following CALM predicted greater anxiety symptoms at the subsequent timepoint for all anxiety symptoms except social anxiety symptoms. Higher anxiety following treatment also predicted later AS. These findings implicate AS as an indicator of transdiagnostic anxiety remittance and suggest that targeting AS could be useful for reducing clinical anxiety relapse following CBT.

Remodeling of the Cortical Structural Connectome in Posttraumatic Stress Disorder: Results From the ENIGMA-PGC Posttraumatic Stress Disorder Consortium.

BACKGROUND: Posttraumatic stress disorder (PTSD) is accompanied by disrupted cortical neuroanatomy. We investigated alteration in covariance of structural networks associated with PTSD in regions that demonstrate the case-control differences in cortical thickness (CT) and surface area (SA). METHODS: Neuroimaging and clinical data were aggregated from 29 research sites in >1300 PTSD cases and >2000 trauma-exposed control subjects (ages 6.2-85.2 years) by the ENIGMA-PGC (Enhancing Neuro Imaging Genetics through Meta Analysis-Psychiatric Genomics Consortium) PTSD working group. Cortical regions in the network were rank ordered by the effect size of PTSD-related cortical differences in CT and SA. The top-n (n = 2-148) regions with the largest effect size for PTSD > non-PTSD formed hypertrophic networks, the largest effect size for PTSD < non-PTSD formed atrophic networks, and the smallest effect size of between-group differences formed stable networks. The mean structural covariance (SC) of a given n-region network was the average of all positive pairwise correlations and was compared with the mean SC of 5000 randomly generated n-region networks. RESULTS: Patients with PTSD, relative to non-PTSD control subjects, exhibited lower mean SC in CT-based and SA-based atrophic networks. Comorbid depression, sex, and age modulated covariance differences of PTSD-related structural networks. CONCLUSIONS: Covariance of structural networks based on CT and cortical SA are affected by PTSD and further modulated by comorbid depression, sex, and age. The SC networks that are perturbed in PTSD comport with converging evidence from resting-state functional connectivity networks and networks affected by inflammatory processes and stress hormones in PTSD.