The role of recurrent trauma on post-traumatic stress disorder symptoms and substance use among trauma exposed youth.

Comorbidity between post-traumatic stress disorder (PTSD) and substance use disorder may be explained by a prospective trauma risk conferred by both conditions. The current study modeled concurrent and prospective associations of trauma, PTSD symptoms, and substance use (SU) behavior among trauma exposed youth (ages 8-20). Clinical interviews assessed trauma exposure, PTSD symptom severity, and SU behavior at baseline and at six- and 12-month follow up study visits (N = 2,069). Structural equation models assessed the associations of trauma, PTSD symptoms, and SU behavior. Lifetime trauma was associated with more severe PTSD symptoms and SU behaviors, whereas trauma exposure during the study was only associated with PTSD symptoms. PTSD symptom severity was prospectively associated with trauma exposure. PTSD symptom severity and SU behavior at follow-up study visits were prospectively associated. These results highlight the dynamic interplay between trauma, PTSD symptoms, and SU behavior during youth, a developmental period during which complex psychiatric presentations can have longstanding consequences for health.

The role of resilience in the development of depression, anxiety, and post-traumatic stress disorder after trauma in children and adolescents.

This investigation, conducted within the Texas Childhood Trauma Research Network, investigated the prospective relationships between resiliency and emergent internalizing symptoms among trauma-exposed youth. The cohort encompassed 1262 youth, aged 8-20, from twelve health-related institutions across Texas, who completed assessments at baseline and one- and six-month follow-ups for resiliency, symptoms of depression, generalized anxiety, posttraumatic stress disorder (PTSD), and other demographic and clinical characteristics. At baseline, greater resilience was positively associated with older age, male (vs female) sex assigned at birth, and history of mental health treatment. Unadjusted for covariates, higher baseline resilience was associated with greater prospective depression and PTSD symptoms but not anxiety symptoms. Upon adjusting for demographic and clinical factors, higher baseline resilience was no longer associated with depression, PTSD, or anxiety symptoms. Our analyses demonstrate that the predictive value of resilience on psychopathology is relatively small compared to more readily observable clinical and demographic factors. These data suggest a relatively minor prospective role of resilience in protecting against internalizing symptoms among trauma-exposed youth and highlight the importance of controlling for relevant youth characteristics when investigating a protective effect of resilience on internalizing symptoms.

Decoding context memories for threat in large-scale neural networks.

Humans are often tasked with determining the degree to which a given situation poses threat. Salient cues present during prior events help bring online memories for context, which plays an informative role in this process. However, it is relatively unknown whether and how individuals use features of the environment to retrieve context memories for threat, enabling accurate inferences about the current level of danger/threat (i.e. retrieve appropriate memory) when there is a degree of ambiguity surrounding the present context. We leveraged computational neuroscience approaches (i.e. independent component analysis and multivariate pattern analyses) to decode large-scale neural network activity patterns engaged during learning and inferring threat context during a novel functional magnetic resonance imaging task. Here, we report that individuals accurately infer threat contexts under ambiguous conditions through neural reinstatement of large-scale network activity patterns (specifically striatum, salience, and frontoparietal networks) that track the signal value of environmental cues, which, in turn, allows reinstatement of a mental representation, primarily within a ventral visual network, of the previously learned threat context. These results provide novel insight into distinct, but overlapping, neural mechanisms by which individuals may utilize prior learning to effectively make decisions about ambiguous threat-related contexts as they navigate the environment.

Neural differentiation of emotional faces as a function of interpersonal violence among adolescent girls.

Interpersonal violence (IV) is associated with altered neural threat processing and risk for psychiatric disorder. Representational similarity analysis (RSA) is a multivariate approach examining the extent to which differences between stimuli correspond to differences in multivoxel activation patterns to these stimuli within each ROI. Using RSA, we examine overlap in neural patterns between threat and neutral faces in youth with IV. Participants were female adolescents aged 11-17 who had a history of IV exposure (n = 77) or no history of IV, psychiatric diagnoses, nor psychiatric medications (n = 37). Participants completed a facial emotion processing task during fMRI. Linear mixed models indicated that increasing hippocampal differentiation of fear and neutral faces was associated with increasing IV severity. Increased neural differentiation of these facial stimuli in the left and right hippocampus was associated with increasing physical abuse severity. Increased differentiation by the dACC correlated with increasing physical assault severity. RSA for most ROIs were not significantly associated with univariate activity, except for a positive association between amygdala RSA and activity to fear faces. Differences in statistically significant ROIs for physical assault and physical abuse may highlight distinct effects of trauma type on encoding of threat vs. neutral faces. Null associations between RSA and univariate activation in most ROIs suggest unique contributions of RSA for understanding IV compared to traditional activation. Implications include understanding mechanisms of risk in IV and trauma-specific treatment selection. Future work should replicate these findings in longitudinal studies and identify sensitive periods for neural alterations in RSA.

Latent-state and model-based learning in PTSD.

Post-traumatic stress disorder (PTSD) is characterized by altered emotional and behavioral responding following a traumatic event. In this article, we review the concepts of latent-state and model-based learning (i.e., learning and inferring abstract task representations) and discuss their relevance for clinical and neuroscience models of PTSD. Recent data demonstrate evidence for brain and behavioral biases in these learning processes in PTSD. These new data potentially recast excessive fear towards trauma cues as a problem in learning and updating abstract task representations, as opposed to traditional conceptualizations focused on stimulus-specific learning. Biases in latent-state and model-based learning may also be a common mechanism targeted in common therapies for PTSD. We highlight key knowledge gaps that need to be addressed to further elaborate how latent-state learning and its associated neurocircuitry mechanisms function in PTSD and how to optimize treatments to target these processes.

Decoding neural reactivation of threat during fear learning, extinction, and recall in a randomized clinical trial of L-DOPA among women with PTSD.

BACKGROUND: Laboratory paradigms are widely used to study fear learning in posttraumatic stress disorder (PTSD). Recent basic science models demonstrate that, during fear learning, patterns of activity in large neuronal ensembles for the conditioned stimuli (CS) begin to reinstate neural activity patterns for the unconditioned stimuli (US), suggesting a direct way of quantifying fear memory strength for the CS. Here, we translate this concept to human neuroimaging and test the impact of post-learning dopaminergic neurotransmission on fear memory strength during fear acquisition, extinction, and recall among women with PTSD in a re-analysis of previously reported data. METHODS: Participants (N = 79) completed a context-dependent fear acquisition and extinction task on day 1 and extinction recall tests 24 h later. We decoded activity patterns in large-scale functional networks for the US, then applied this decoder to activity patterns toward the CS on day 1 and day 2. RESULTS: US decoder output for the CS+ increased during acquisition and decreased during extinction in networks traditionally implicated in human fear learning. The strength of US neural reactivation also predicted individuals skin conductance responses. Participants randomized to receive L-DOPA (n = 43) following extinction on day 1 demonstrated less US neural reactivation on day 2 relative to the placebo group (n = 28). CONCLUSION: These results support neural reactivation as a measure of memory strength between competing memories of threat and safety and further demonstrate the role of dopaminergic neurotransmission in the consolidation of fear extinction memories.

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.

The influence of aerobic exercise on model-based decision making in women with posttraumatic stress disorder.

Individuals with PTSD often exhibit deficits in executive functioning. An unexplored aspect of neurocognitive functions associated with PTSD is the type of learning system engaged in during decision-making. A model-free (MF) system is habitual in nature and involves trial-and-error learning that is often updated based on the most recent experience (e.g., repeat action if rewarded). A model-based (MB) system is goal-directed in nature and involves the development of an abstract representation of the environment to facilitate decisions (e.g., choose sequence of actions according to current contextual state and predicted outcomes). The existing neurocognitive literature on PTSD suggests the hypothesis of greater reliance on MF vs MB learning strategies when navigating their environment. While MF systems may be more cognitively efficient, they do not afford flexibility when making prospective predictions about likely outcomes of different decision-tree branches. Emerging research suggests that an acute bout of aerobic exercise improves certain aspects of neurocognition, and thereby could promote the utilization of MB over MF systems during decision making, although prior research has not yet tested this hypothesis. Accordingly, the current study administered a lab-based two-stage Markov decision-making task capable of discriminating MF vs MB decision making, in order to determine if moderate-intensity aerobic exercise (either shortly after or 30-minutes after the exercise bout has ended) promotes greater engagement in MB behavioral strategies compared to light-intensity aerobic exercise in adult women with and without PTSD (N=61). Results revealed that control women generally displayed higher levels of MB behavior that was further increased following immediate exercise, particularly moderate-intensity exercise. By contrast, the PTSD group generally displayed lower levels of MB behavior, and exhibited greater MB behavior when completing the task following moderate-intensity aerobic exercise compared to light-intensity aerobic exercise regardless of whether there was a short or long delay between exercise and the task. Additionally, women with PTSD demonstrated less impairment in MB decision-making compared to controls following moderate-intensity aerobic exercise. These results suggest that an acute bout of moderate-intensity aerobic exercise boosts MB behavior in women with PTSD, and suggests that aerobic exercise may play an important role in enhancing cognitive outcomes for PTSD.

Decision-making for concurrent reward and threat is differentially modulated by trauma exposure and PTSD symptom severity.

Trauma exposure, particularly interpersonal violence (IPV) traumas, are significant risk factors for development of mental health disorders, particularly posttraumatic stress disorder (PTSD). Studies attempting to disentangle mechanisms by which trauma confers risk and maintenance of PTSD have often investigated threat or reward learning in isolation. However, real-world decision-making often involves navigating concurrent and conflicting probabilities for threat and reward. We sought to understand how threat and reward learning interact to impact decision-making, and how these processes are modulated by trauma exposure and PTSD symptom severity. 429 adult participants with a range of trauma exposure and symptom severities completed an online version of the two stage Markov task, where participants make a series of decisions towards the goal of obtaining a reward, that embedded an intermediate threat or neutral image along the sequence of decisions to be made. This task design afforded the possibility to differentiate between threat avoidance vs diminished reward learning in the presence of threat, and whether these two processes reflect model-based vs model-free decision-making. Results demonstrated that trauma exposure severity, particularly IPV exposure, was associated with impairment in model-based learning for reward independent of threat, as well as with model-based threat avoidance. PTSD symptom severity was associated with diminished model-based learning for reward in the presence of threat, consistent with a threat-induced impairment in cognitively-demanding strategies for reward learning, but no evidence of heightened threat avoidance. These results highlight the complex interactions between threat and reward learning as a function of trauma exposure and PTSD symptom severity. Findings have potential implications for treatment augmentation and suggest a need for continued research.

Aerobic exercise after extinction learning reduces return of fear and enhances memory of items encoded during extinction learning.

Fear conditioning paradigms are widely used in laboratory settings to discover treatments that enhance memory consolidation and various fear processes (extinction learning, limit return of fear) that are relevant targets of exposure-based therapies. However, traditional lab-based paradigms often use the exact same conditioned stimuli for acquisition and extinction (typically differentiated with a context manipulation), whereas the opposite is true in clinical settings, as exposure therapy rarely (if ever) uses precisely the exact same stimuli from an individual's learning history. Accordingly, this study utilized a novel three-day category-based fear conditioning protocol (that uses categories of non-repeating objects [animals and tools] as conditioned stimuli during fear conditioning and extinction) to determine if aerobic exercise enhances the consolidation of extinction learning (reduces return of fear) and memory (for items encoded during extinction) during subsequent tests of extinction recall. Participants (n=40) completed a fear acquisition (day 1), fear extinction (day 2), and extinction recall (day 3) protocol. On day 1, participants completed a fear acquisition task in which they were trained to associate a category of conditioned stimuli (CS+) with the occurrence of an unconditioned stimulus (US). On day 2, participants were administered a fear extinction procedure during which CS+ and CS- categorical stimuli were presented in absence of the occurrence of the US. After completing the task, participants were randomly assigned to either receive moderate-intensity aerobic exercise (EX) or a light-intensity control (CON) condition. On day 3, participants completed fear recall tests (during which day 1, day 2, and novel CS+ and CS- stimuli were presented). Fear responding was assessed via threat expectancy ratings and skin conductance responses (SCR). During the fear recall tests, the EX group reported significantly lower threat expectancy ratings to the CS+ and CS- and exhibited greater memory of CS+ and CS- stimuli that were previously presented during day 2. There were no significant group differences for SCR. These results suggests that administration of moderate-intensity aerobic exercise following extinction learning contributes to reduced threat expectancies during tests of fear recall and enhanced memory of items encoded during extinction.

Diminished prospective mental representations of reward mediate reward learning strategies among youth with internalizing symptoms.

BACKGROUND: Adolescent internalizing symptoms and trauma exposure have been linked with altered reward learning processes and decreased ventral striatal responses to rewarding cues. Recent computational work on decision-making highlights an important role for prospective representations of the imagined outcomes of different choices. This study tested whether internalizing symptoms and trauma exposure among youth impact the generation of prospective reward representations during decision-making and potentially mediate altered behavioral strategies during reward learning. METHODS: Sixty-one adolescent females with varying exposure to interpersonal violence exposure (n = 31 with histories of physical or sexual assault) and severity of internalizing symptoms completed a social reward learning task during fMRI. Multivariate pattern analyses (MVPA) were used to decode neural reward representations at the time of choice. RESULTS: MVPA demonstrated that rewarding outcomes could accurately be decoded within several large-scale distributed networks (e.g. frontoparietal and striatum networks), that these reward representations were reactivated prospectively at the time of choice in proportion to the expected probability of receiving reward, and that youth with behavioral strategies that favored exploiting high reward options demonstrated greater prospective generation of reward representations. Youth internalizing symptoms, but not trauma exposure characteristics, were negatively associated with both the behavioral strategy of exploiting high reward options as well as the prospective generation of reward representations in the striatum. CONCLUSIONS: These data suggest diminished prospective mental simulation of reward as a mechanism of altered reward learning strategies among youth with internalizing symptoms.

Aerobic exercise in the treatment of PTSD: An examination of preclinical and clinical laboratory findings, potential mechanisms, clinical implications, and future directions.

Posttraumatic stress disorder (PTSD) is associated with heightened emotional responding, avoidance of trauma related stimuli, and physical health concerns (e.g., metabolic syndrome, type 2 diabetes, cardiovascular disease). Existing treatments such as exposure-based therapies (e.g., prolonged exposure) aim to reduce anxiety symptoms triggered by trauma reminders, and are hypothesized to work via mechanisms of extinction learning. However, these conventional gold standard psychotherapies do not address physical health concerns frequently presented in PTSD. In addition to widely documented physical and mental health benefits of exercise, emerging preclinical and clinical evidence supports the hypothesis that precisely timed administration of aerobic exercise can enhance the consolidation and subsequent recall of fear extinction learning. These findings suggest that aerobic exercise may be a promising adjunctive strategy for simultaneously improving physical health while enhancing the effects of exposure therapies, which is desirable given the suboptimal efficacy and remission rates. Accordingly, this review 1) encompasses an overview of preclinical and clinical exercise and fear conditioning studies which form the basis for this claim; 2) discusses several plausible mechanisms for enhanced consolidation of fear extinction memories following exercise, and 3) provides suggestions for future research that could advance the understanding of the potential importance of incorporating exercise into the treatment of PTSD.

Circulating endocannabinoids and psychological outcomes in women with PTSD.

BACKGROUND: Recent research has attempted to elucidate the relationship between blood-based biomarkers (e.g., endocannabinoids; eCBs: including N-arachidonoylethanolamine [AEA] and 2-arachidonoylglycerol [2-AG]) and mental health outcomes in psychiatric populations such as posttraumatic stress disorder (PTSD). Prior research suggests that adults with PTSD may have altered circulating eCB tone and a blunted mobilization of eCBs (particularly 2-AG) in response to stress (e.g., aerobic exercise), although our understanding has been limited in part due to heterogenous samples and small sample sizes. METHODS: A subset of data was pooled from five studies in which women with and without PTSD (N = 98) completed questionnaires related to mood states and a blood draw prior to and following a bout of moderate-intensity aerobic exercise in order to determine: 1) whether circulating eCBs differ between groups and whether depressive and PTSD symptom severity are associated with baseline eCBs, 2) whether a bout of aerobic exercise increases circulating eCBs in adult women with PTSD, and 3) whether circulating eCBs are associated with overall mood states and exercise-induced improvements in mood states in women with and without PTSD. RESULTS: PTSD diagnoses were not associated with baseline concentrations of eCBs. Greater depressive symptom severity and PTSD symptom severity within the negative alteration in cognition and mood cluster were associated with lower circulating AEA. Circulating AEA significantly increased following aerobic exercise for both groups, whereas circulating 2-AG only increased in women without PTSD. Greater circulating AEA within the PTSD group was associated with lower depressive mood, confusion, and total mood disturbance. CONCLUSIONS: These findings suggest that greater circulating AEA is associated with better overall mood and lower depressive and PTSD symptom severity, and that an acute bout of moderate-intensity aerobic exercise increases circulating AEA (but not 2-AG) in adult women with PTSD. These findings are consistent with the idea that greater eCB tone (particularly AEA) following pharmacological and/or non-pharmacological manipulations may be beneficial for improving psychological outcomes (e.g., mood, cognition) among PTSD, and possibly other psychiatric populations.

Large-scale neural network computations and multivariate representations during approach-avoidance conflict decision-making.

Many real-world situations require navigating decisions for both reward and threat. While there has been significant progress in understanding mechanisms of decision-making and mediating neurocircuitry separately for reward and threat, there is limited understanding of situations where reward and threat contingencies compete to create approach-avoidance conflict (AAC). Here, we leverage computational learning models, independent component analysis (ICA), and multivariate pattern analysis (MVPA) approaches to understand decision-making during a novel task that embeds concurrent reward and threat learning and manipulates congruency between reward and threat probabilities. Computational modeling supported a modified reinforcement learning model where participants integrated reward and threat value into a combined total value according to an individually varying policy parameter, which was highly predictive of decisions to approach reward vs avoid threat during trials where the highest reward option was also the highest threat option (i.e., approach-avoidance conflict). ICA analyses demonstrated unique roles for salience, frontoparietal, medial prefrontal, and inferior frontal networks in differential encoding of reward vs threat prediction error and value signals. The left frontoparietal network uniquely encoded degree of conflict between reward and threat value at the time of choice. MVPA demonstrated that delivery of reward and threat could accurately be decoded within salience and inferior frontal networks, respectively, and that decisions to approach reward vs avoid threat were predicted by the relative degree to which these reward vs threat representations were active at the time of choice. This latter result suggests that navigating AAC decisions involves generating mental representations for possible decision outcomes, and relative activation of these representations may bias subsequent decision-making towards approaching reward or avoiding threat accordingly.

Test-retest reliability of fMRI during an emotion processing task: Investigating the impact of analytical approaches on ICC values.

Test-retest reliability of fMRI is often assessed using the intraclass correlation coefficient (ICC), a numerical representation of reliability. Reports of low reliability at the individual level may be attributed to analytical approaches and inherent bias/error in the measures used to calculate ICC. It is unclear whether low reliability at the individual level is related to methodological decisions or if fMRI is inherently unreliable. The purpose of this study was to investigate methodological considerations when calculating ICC to improve understanding of fMRI reliability. fMRI data were collected from adolescent females (N=23) at pre- and post-cognitive behavioral therapy. Participants completed an emotion processing task during fMRI. We calculated ICC values using contrasts and ß coefficients separately from voxelwise and network (ICA) analyses of the task-based fMRI data. For both voxelwise analysis and ICA, ICC values were higher when calculated using ß coefficients. This work provides support for the use of ß coefficients over contrasts when assessing reliability of fMRI, and the use of contrasts may underlie low reliability estimates reported in the existing literature. Continued research in this area is warranted to establish fMRI as a reliable measure to draw conclusions and utilize fMRI in clinical settings.

Laboratory models of post-traumatic stress disorder: The elusive bridge to translation.

Post-traumatic stress disorder (PTSD) is a debilitating mental illness composed of a heterogeneous collection of symptom clusters. The unique nature of PTSD as arising from a precipitating traumatic event helps simplify cross-species translational research modeling the neurobehavioral effects of stress and fear. However, the neurobiological progress on these complex neural circuits informed by animal models has yet to produce novel, evidence-based clinical treatment for PTSD. Here, we provide a comprehensive overview of popular laboratory models of PTSD and provide concrete ideas for improving the validity and clinical translational value of basic research efforts in humans. We detail modifications to simplified animal paradigms to account for myriad cognitive factors affected in PTSD, which may contribute to abnormalities in regulating fear. We further describe new avenues for integrating different areas of psychological research underserved by animal models of PTSD. This includes incorporating emerging trends in the cognitive neuroscience of episodic memory, emotion regulation, social-emotional processes, and PTSD subtyping to provide a more comprehensive recapitulation of the human experience to trauma in laboratory research.

Value estimation and latent-state update-related neural activity during fear conditioning predict posttraumatic stress disorder symptom severity.

Learning theories of posttraumatic stress disorder (PTSD) purport that fear-learning processes, such as those that support fear acquisition and extinction, are impaired. Computational models designed to capture specific processes involved in fear learning have primarily assessed model-free, or trial-and-error, reinforcement learning (RL). Although previous studies indicated that aspects of model-free RL are disrupted among individuals with PTSD, research has yet to identify whether model-based RL, which is inferential and contextually driven, is impaired. Given empirical evidence of aberrant contextual modulation of fear in PTSD, the present study sought to identify whether model-based RL processes are altered during fear conditioning among women with interpersonal violence (IPV)-related PTSD (n = 85) using computational modeling. Model-free, hybrid, and model-based RL models were applied to skin conductance responses (SCR) collected during fear acquisition and extinction, and the model-based RL model was found to provide the best fit to the SCR data. Parameters from the model-based RL model were carried forward to neuroimaging analyses (voxel-wise and independent component analysis). Results revealed that reduced activity within visual processing regions during model-based updating uniquely predicted higher PTSD symptoms. Additionally, after controlling for model-based updating, greater value estimation encoding within the left frontoparietal network during fear acquisition and reduced value estimation encoding within the dorsomedial prefrontal cortex during fear extinction predicted greater PTSD symptoms. Results provide evidence of disrupted RL processes in women with assault-related PTSD, which may contribute to impaired fear and safety learning, and, furthermore, may relate to treatment response (e.g., poorer response to exposure therapy).

Frontoparietal network activity during model-based reinforcement learning updates is reduced among adolescents with severe sexual abuse.

Trauma and trauma-related disorders are characterized by impaired learning processes, including reinforcement learning (RL). Identifying which aspects of learning are altered by trauma is critical endeavor, as this may reveal key mechanisms of impairment and potential intervention targets. There are at least two types of RL that have been delineated using computational modeling: model-free and model-based RL. Although these RL processes differentially predict decision-making behavior, most research has examined the impact of trauma on model-free RL. Currently unclear whether model-based RL, which involves building abstract and nuanced representations of stimulus-outcome relationships, is impaired among individuals with a history of trauma. The present study sought to test the hypothesis of impaired model-based RL among adolescent females exposed to assaultive trauma. Participants (n = 60; 29 without a history of assault and 31 with a history of assault with and without PTSD) completed a three-arm bandit task during fMRI acquisition. Two computational models compared the degree to which participants' task behavior fit the use of a model-free versus model-based RL strategy. Although a history of assaultive trauma did not predict poorer model-based RL, greater sexual abuse severity predicted less use of model-based compared to model-free RL. Additionally, severe sexual abuse predicted less left frontoparietal network encoding of model-based RL updates. Altered model-based RL, which supports goal-directed behavior, may be an important route through which clinical impairment emerges among individuals with a history of severe sexual abuse and should be examined further in future studies.

Transcranial direct current stimulation targeting the medial prefrontal cortex modulates functional connectivity and enhances safety learning in obsessive-compulsive disorder: Results from two pilot studies.

BACKGROUND: Exposed-based psychotherapy is a mainstay of treatment for obsessive-compulsive disorder (OCD) and anxious psychopathology. The medial prefrontal cortex (mPFC) and the default mode network (DMN), which is anchored by the mPFC, promote safety learning. Neuromodulation targeting the mPFC might augment therapeutic safety learning and enhance response to exposure-based therapies. METHODS: To characterize the effects of mPFC neuromodulation on functional connectivity, 17 community volunteers completed resting-state functional magnetic resonance imaging scans before and after 20 min of frontopolar anodal multifocal transcranial direct current stimulation (tDCS). To examine the effects of tDCS on therapeutic safety learning, 24 patients with OCD completed a pilot randomized clinical trial; they were randomly assigned (double-blind, 50:50) to receive active or sham frontopolar tDCS before completing an in vivo exposure and response prevention (ERP) challenge. Changes in subjective emotional distress during the ERP challenge were used to index therapeutic safety learning. RESULTS: In community volunteers, frontal pole functional connectivity with the middle and superior frontal gyri increased, while connectivity with the anterior insula and basal ganglia decreased (ps < .001, corrected) after tDCS; functional connectivity between DMN and salience network also decreased after tDCS (ps < .001, corrected). OCD patients who received active tDCS exhibited more rapid therapeutic safety learning (ps < .05) during the ERP challenge than patients who received sham tDCS. CONCLUSIONS: Frontopolar tDCS may modulate mPFC and DMN functional connectivity and can accelerate therapeutic safety learning. Though limited by small samples, these findings motivate further exploration of the effects of frontopolar tDCS on neural and behavioral targets associated with exposure-based psychotherapies.

The influence of FAAH genetic variation on physiological, cognitive, and neural signatures of fear acquisition and extinction learning in women with PTSD.

BACKGROUND: Posttraumatic Stress Disorder (PTSD) is commonly treated with exposure-based cognitive therapies that are based on the principles of fear acquisition and extinction learning. Elevations in one of the major endocannabinoids (anandamide) either via inhibition of the primary degrading enzyme (fatty acid amide hydrolase; FAAH) or via a genetic variation in the FAAH gene (C385A; rs324420) has resulted in accelerated extinction learning and enhanced extinction recall among healthy adults. These results suggest that targeting FAAH may be a promising therapeutic approach for PTSD. However, these effects have not yet been comprehensively examined in a PTSD population. METHODS: The current study examined whether genetic variation in the FAAH gene (CC [n = 49] vs AA/AC [n = 36] allele carriers) influences physiological (skin conductance), cognitive (threat expectancy), and neural (network and voxel-wise activation) indices of fear acquisition and extinction learning among a sample of adult women with PTSD (N = 85). RESULTS: The physiological, cognitive, and neural signatures of fear acquisition and extinction learning varied as a function of whether or not individuals possess the FAAH C385A polymorphism. For instance, we report divergent responding between CC and AA/AC allele carriers to CS + vs CS- in limbic and striatum networks and overall greater activation throughout the task among AA/AC allele carriers in several regions [e.g., inferior frontal, middle frontal, parietal] that are highly consistent with a frontoparietal network involved in higher-order executive functions. CONCLUSIONS: These results suggest that genetic variation within the FAAH gene influences physiological, cognitive, and neural signatures of fear learning in women with PTSD. In order to advance our understanding of the efficacy of FAAH inhibition as a treatment for PTSD, future clinical trials in this area should assess genetic variation in the FAAH gene in order to fully depict and differentiate the acute effects of a drug manipulation (FAAH inhibition) from more chronic (genetic) influences on fear extinction processes.