Resting-state connectivity subtype of comorbid PTSD and alcohol use disorder moderates improvement from integrated prolonged exposure therapy in Veterans.

BACKGROUND: Posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) are highly comorbid and are associated with significant functional impairment and inconsistent treatment outcomes. Data-driven subtyping of this clinically heterogeneous patient population and the associated underlying neural mechanisms are highly needed to identify who will benefit from psychotherapy. METHODS: In 53 comorbid PTSD/AUD patients, resting-state functional magnetic resonance imaging was collected prior to undergoing individual psychotherapy. We used a data-driven approach to subgroup patients based on directed connectivity profiles. Connectivity subgroups were compared on clinical measures of PTSD severity and heavy alcohol use collected at pre- and post-treatment. RESULTS: We identified a subgroup of patients associated with improvement in PTSD symptoms from integrated-prolonged exposure therapy. This subgroup was characterized by lower insula to inferior parietal cortex (IPC) connectivity, higher pregenual anterior cingulate cortex (pgACC) to posterior midcingulate cortex connectivity and a unique pgACC to IPC path. We did not observe any connectivity subgroup that uniquely benefited from integrated-coping skills or subgroups associated with change in alcohol consumption. CONCLUSIONS: Data-driven approaches to characterize PTSD/AUD subtypes have the potential to identify brain network profiles that are implicated in the benefit from psychological interventions - setting the stage for future research that targets these brain circuit communication patterns to boost treatment efficacy.

Learning from addiction: Craving of prescription opioids in chronic pain sufferers.

Prescription opioids are a primary driver of opioid-related deaths. Although craving is a substantial component of OUD, the degree to which craving leads to misuse among chronic pain patients on long-term prescription opioids is unknown. A clear understanding of the factors that lead to misuse in this vulnerable population is needed for the development of safe and effective practices for opioid taper. This narrative review summarizes the relevant literature on the role of craving in addiction and chronic pain through epidemiological and behavioral studies. The first part of this review examines the role of craving in predicting opioid use/misuse in individuals with chronic pain with and without OUD. The second part covers methods on how craving is evaluated experimentally using both subjective and objective measures and provides related findings. The overall goal of this review is to facilitate the development of a population-specific description of craving in those who use opioids to control chronic pain and to describe how it may be mechanistically linked to patterns of opioid (mis)use.

Contribution of early-life unpredictability to neuropsychiatric symptom patterns in adulthood.

BACKGROUND: Recent studies in both human and experimental animals have identified fragmented and unpredictable parental and environmental signals as a novel source of early-life adversity. Early-life unpredictability may be a fundamental developmental factor that impacts brain development, including reward and emotional memory circuits, affecting the risk for psychopathology later in life. Here, we tested the hypothesis that self-reported early-life unpredictability is associated with psychiatric symptoms in adult clinical populations. METHODS: Using the newly validated Questionnaire of Unpredictability in Childhood, we assessed early-life unpredictability in 156 trauma-exposed adults, of which 65% sought treatment for mood, anxiety, and/or posttraumatic stress disorder (PTSD) symptoms. All participants completed symptom measures of PTSD, depression and anhedonia, anxiety, alcohol use, and chronic pain. Relative contributions of early-life unpredictability versus childhood trauma and associations with longitudinal outcomes over a 6-month period were determined. RESULTS: Early-life unpredictability, independent of childhood trauma, was significantly associated with higher depression, anxiety symptoms, and anhedonia, and was related to higher overall symptom ratings across time. Early-life unpredictability was also associated with suicidal ideation, but not alcohol use or pain symptoms. CONCLUSIONS: Early-life unpredictability is an independent and consistent predictor of specific adult psychiatric symptoms, providing impetus for studying mechanisms of its effects on the developing brain that promote risk for psychopathology.

Understanding Pain and Trauma Symptoms in Veterans From Resting-State Connectivity: Unsupervised Modeling.

Trauma and posttraumatic stress are highly comorbid with chronic pain and are often antecedents to developing chronic pain conditions. Pain and trauma are associated with greater utilization of medical services, greater use of psychiatric medication, and increased total cost of treatment. Despite the high overlap in the clinic, the neural mechanisms of pain and trauma are often studied separately. In this study, resting-state functional magnetic resonance imaging (rs-fMRI) scans were completed among a diagnostically heterogeneous sample of veterans with a range of back pain and trauma symptoms. Using Group Iterative Multiple Model Estimation (GIMME), an effective functional connectivity analysis, we explored an unsupervised model deriving subgroups based on path similarity in a priori defined regions of interest (ROIs) from brain regions implicated in the experience of pain and trauma. Three subgroups were identified by patterns in functional connection and differed significantly on several psychological measures despite similar demographic and diagnostic characteristics. The first subgroup was highly connected overall, was characterized by functional connectivity from the nucleus accumbens (NAc), the anterior cingulate cortex (ACC), and the posterior cingulate cortex (PCC) to the insula and scored low on pain and trauma symptoms. The second subgroup did not significantly differ from the first subgroup on pain and trauma measures but was characterized by functional connectivity from the ACC and NAc to the thalamus and from ACC to PCC. The third subgroup was characterized by functional connectivity from the thalamus and PCC to NAc and scored high on pain and trauma symptoms. Our results suggest that, despite demographic and diagnostic similarities, there may be neurobiologically dissociable biotypes with different mechanisms for managing pain and trauma. These findings may have implications for the determination of appropriate biotype-specific interventions that target these neurological systems.

Effects of Noninvasive Cervical Vagal Nerve Stimulation on Cognitive Performance But Not Brain Activation in Healthy Adults.

OBJECTIVES: While preliminary evidence suggests that noninvasive vagal nerve stimulation (nVNS) may enhance cognition, to our knowledge, no study has directly assessed the effects of nVNS on brain function and cognitive performance in healthy individuals. The aim of this study was therefore to assess whether nVNS enhances complex visuospatial problem solving in a normative sample. Functional magnetic resonance imaging (fMRI) was used to examine underlying neural substrates. MATERIAL AND METHODS: Participants received transcutaneous cervical nVNS (N = 15) or sham (N = 15) stimulation during a 3 T fMRI scan. Stimulation lasted for 2 min at 24 V for nVNS and at 4.5 V for sham. Subjects completed a matrix reasoning (MR) task in the scanner and a forced-choice recognition task outside the scanner. An analysis of variance (ANOVA) was used to assess group differences in cognitive performance. And linear mixed effects (LMEs) regression analysis was used to assess main and interaction effects of experimental groups, level of MR task difficulty, and recall accuracy on changes in blood oxygen level-dependent (BOLD) signal. RESULTS: Subjects who received nVNS showed higher accuracy for both easy (p = 0.017) and hard (p = 0.013) items of the MR task, slower reaction times for hard items (p = 0.014), and fewer false negative errors during the forced-choice recognition task (p = 0.047). MR task difficulty related to increased activation in frontoparietal regions (p < 0.001). No difference between nVNS and sham stimulation was found on BOLD response during performance of the MR task. CONCLUSIONS: We hypothesize that nVNS increased attention compared to sham, and that this effect led to enhanced executive functions, and consequently to better performance on visuospatial reasoning and recognition tasks. Results provide initial support that nVNS may be a low-risk, low-cost treatment for cognitive disorders.

Higher affective congruency in the approach-avoidance task is associated with insular deactivation to dynamic facial expressions.

Individuals exhibit a natural bias to approach positive social cues (e.g., smiling face) and to avoid negative ones, which may be altered in psychiatric conditions. Computerized approach/avoidance training to promote affectively congruent behavior has proven useful in modulating such biases. Here, we investigate how exposure to a higher rate of congruency impacts neural processing of social-affective cues. While undergoing functional magnetic resonance imaging (fMRI), twenty-four individuals completed two versions of the approach-avoidance task (AAT), in which they had to approach or avoid dynamic facial expressions of either happiness or disgust. In the high congruency condition, congruent responses (i.e. approaching happy faces, avoiding disgusted faces) were more frequent. The balanced condition had equal amounts of congruent and incongruent responses. Processing of congruent approach-avoidance actions towards social cues was associated with lower recruitment of the right anterior insula in the congruency-intensive relative to the balanced condition. Differential activation between the high congruency and balanced condition in the right hippocampus was negatively related to individuals' trait avoidance tendency. These findings are consistent with reduced affective neural processing of social cues when being exposed to congruent AAT contexts. These neural foci could be important targets when assessing the effectiveness of affective congruency training protocols.

Neural affective mechanisms associated with treatment responsiveness in veterans with PTSD and comorbid alcohol use disorder.

Post-traumatic stress disorder (PTSD) is associated with neuro-physiological abnormalities reflecting increased anticipatory anxiety and reactivity to traumatic cues. It remains unclear whether neural mechanisms associated with PTSD treatment responsiveness, i.e. hyperactivation of the affective salience network in the brain, extend to a comorbid PTSD and substance use disorder population. Thirty-one Veterans with PTSD and co-occurring alcohol use disorder (AUD) were randomly assigned to either prolonged exposure or a non-exposure based treatment. They completed an affective anticipation task while undergoing fMRI, immediately prior and after completing treatment. After controlling for type and length of treatment, larger reduction of PTSD symptoms was associated with decreased anticipatory activation to negative trauma-related cues in the right pre-Supplementary Motor Area (pre-SMA), a region associated with emotion regulation. Smaller reduction in PTSD severity was associated with enhanced anticipatory activation to those cues within the right para-hippocampal region, an affective processing region. Our findings suggest that post-treatment reductions in anticipatory reactivity to trauma-related cues in the pre-SMA and para-hippocampal area are associated with larger PTSD symptom reduction in individuals with co-occurring PTSD and AUD. These results may offer neurofeedback training targets as an alternative to or enhancement of other PTSD treatment modalities in this population.

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.

Neurocomputational Changes in Inhibitory Control Associated With Prolonged Exposure Therapy.

Posttraumatic stress disorder (PTSD) is associated with inhibitory control dysfunction that extends beyond difficulties inhibiting trauma-related intrusions. Inhibitory learning has been proposed as a potential mechanism of change underlying the effectiveness of extinction-based therapies such as prolonged exposure (PE), a first-line treatment for PTSD. To identify neurocognitive markers of change in inhibitory learning associated with PE, we applied a Bayesian learning model to the analysis of neuroimaging data collected during an inhibitory control task, both before and after PE treatment. Veterans (N = 20) with combat-related PTSD completed a stop-signal task (SST) while undergoing fMRI at time points immediately before and after PE treatment. Participants exhibited a small, significant improvement in performance on the SST, as demonstrated by longer reaction times and improved inhibition accuracy. Amplitude of neural activation associated with a signed prediction error (SPE; i.e., the discrepancy between actual outcome and model-based expectation of needing to stop) in the right caudate decreased from baseline to posttreatment assessment. Change in model-based activation was modulated by performance accuracy, with a decrease in positive SPE activation observed on successful trials, d = 0.79, and a reduction in negative SPE activation on error trials, d = 0.74. The decrease in SPE-related activation on successful stop trials was correlated with PTSD symptom reduction. These results are consistent with the notion that PE may help broadly strengthen inhibitory learning and the development of more accurate model-based predictions, which may thus facilitate change in cognitions in response to trauma-related cues and help reduce PTSD symptoms.

Expansion of hippocampal and amygdala shape in posttraumatic stress and early life stress.

OBJECTIVE: The aim of this study was to examine the effect of Posttraumatic Stress Disorder (PTSD) and childhood adversity on brain structure. We assessed hippocampal and amygdala shape in veterans with varying levels of PTSD symptom severity and exposure to early life stressors (ELS). METHODS: A total of 70 male veterans, who were deployed to a combat area during OIF/OEF/OND and who had been exposed to trauma during deployment, were included in the study. We applied a vertex-wise shape analysis of 3T MRI scans to measure indentation or expansion in hippocampal and amygdala shape. RESULTS: Analyses showed a positive correlation between number of ELS and vertices in the right amygdala and the right hippocampus, as well as a positive correlation between PTSD symptom severity and right hippocampal vertices. There were no significant interactions between PTSD symptoms, ELS, and brain shape. DISCUSSION: Results indicate a relationship between exposure to more childhood adversity and expansion in amygdala and hippocampal shape as well as between more severe PTSD symptoms and expansion in hippocampal shape. These findings may have important implications for the pathophysiology of trauma-related disorders.

Shared gray matter reductions across alcohol use disorder and posttraumatic stress disorder in the anterior cingulate cortex: A dual meta-analysis.

The considerable comorbidity of posttraumatic stress disorder (PTSD) and alcohol use disorders (AUD) poses a greater public health burden than either condition alone. Although there is a substantial body of evidence linking the direct neurotoxic effect of heavy drinking to gray matter (GM) deficits, as well as a growing body of literature supporting a strong association between PTSD and GM alterations, there is scant research interrogating the direct interaction of the two disorders. In order to generate data-driven, specific hypotheses regarding the overlapping neural substrates of PTSD and AUD, we conducted a meta-analysis of GM volumes in each disorder relative to healthy control subjects. We found shared GM deficits in the anterior cingulate cortex (ACC) across both disorders relative to healthy control participants. These findings suggest that reduced volumes of the ACC across PTSD and AUD may have implications for the development, expression, or treatment of symptoms linked to these frequently co-existing disorders. Recommendations are made for future work aimed at delineating the specific and shared effects of traumatic stress and alcoholism on neural integrity.

Multimodal canonical correlation reveals converging neural circuitry across trauma-related disorders of affect and cognition.

Trauma-related disorders of affect and cognition (TRACs) are associated with a high degree of diagnostic comorbidity, which may suggest that these disorders share a set of underlying neural mechanisms. TRACs are characterized by aberrations in functional and structural circuits subserving verbal memory and affective anticipation. Yet, it remains unknown how the neural circuitry underlying these multiple mechanisms contribute to TRACs. Here, in a sample of 47 combat Veterans, we measured affective anticipation using functional magnetic resonance imaging (fMRI), verbal memory with fluorodeoxyglucose positron emission tomography (FDG-PET), and grey matter volume with structural magnetic resonance imaging (sMRI). Using a voxel-based multimodal canonical correlation analysis (mCCA), the set of neural measures were statistically integrated, or fused, with a set of TRAC symptom measures including mild traumatic brain injury (mTBI), posttraumatic stress, and depression severity. The first canonical correlation pair revealed neural convergence in clusters encompassing the middle frontal gyrus and supplemental motor area, regions implicated in top-down cognitive control and affect regulation. These results highlight the potential of leveraging multivariate neuroimaging analysis for linking neurobiological mechanisms associated with TRACs, paving the way for transdiagnostic biomarkers and targets for treatment.

Neural measures associated with configural threat acquisition.

Contextual threat learning reflects two often competing processes: configural and elemental learning. Configural threat learning is a hippocampal-dependent process of forming a conjunctive representation of a context through binding of several multi-modal elements. In contrast, elemental threat-learning is governed by the amygdala and involves forming associative relationships between individual features within the context. Contextual learning tasks in humans however, rarely probe if a learned fear response is truly due to configural learning vs. simple elemental associations. The aim of the current study was to probe both constructs separately to enable a more refined interpretation of configural vs. elemental threat learning performance and mediating circuits. Subjects (n = 25) performed both a novel feature-identical contextual threat conditioning task and a discrete cue threat acquisition task while undergoing functional magnetic resonance imaging. Results demonstrated increased hippocampus activity for the threat configuration compared to the safe configuration. This pattern was not observed in the amygdala. In contrast, elemental threat learning was associated with increased amygdala, but not hippocampus activity. Whole-brain analyses revealed that both configural and elemental threat acquisition share neural circuitry related to fear expression. These results provide support for the importance of the hippocampus specifically in configural threat acquisition and fear expression.

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.

Emerging Approaches to Neurocircuits in PTSD and TBI: Imaging the Interplay of Neural and Emotional Trauma.

Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) commonly co-occur in general and military populations and have a number of overlapping symptoms. While research suggests that TBI is risk factor for PTSD and that PTSD may mediate TBI-related outcomes, the mechanisms of these relationships are not well understood. Neuroimaging may help elucidate patterns of neurocircuitry both specific and common to PTSD and TBI and thus help define the nature of their interaction, refine diagnostic classification, and may potentially yield opportunities for targeted treatments. In this review, we provide a summary of some of the most common and the most innovative neuroimaging approaches used to characterize the neural circuits associated with PTSD, TBI, and their comorbidity. We summarize the state of the science for each disorder and describe the few studies that have explicitly attempted to characterize the neural substrates of their shared and dissociable influence. While some promising targets in the medial frontal lobes exist, there is not currently a comprehensive understanding of the neurocircuitry mediating the interaction of PTSD and TBI. Future studies should exploit innovative neuroimaging approaches and longitudinal designs to specifically target the neural mechanisms driving PTSD-TBI-related outcomes.

Repeated Exposure to Experimental Pain Differentiates Combat Traumatic Brain Injury with and without Post-Traumatic Stress Disorder.

Mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) are highly comorbid conditions that often co-occur with chronic pain. We have shown that women with PTSD subsequent to intimate partner violence show attenuated brain response to repeated experimental pain that was related to symptoms of avoidance. The aim of this study was to extend our past findings to males with combat trauma and to examine brain response to experimental pain in men with and without PTSD who sustained mTBI during combat. Seventy male veterans performed an experimental pain paradigm during functional magnetic resonance imaging fMRI. Of the 70 total subjects, 46 self-reported a history of mTBI during combat (46 of 70). Of those with mTBI, 26 also met criteria for PTSD (26 of 46). As in our previous study, we examined change in brain activity to repeated heat pain with linear mixed-effects modeling for group by administration interaction effects. We observed a significant group by administration interaction to repeated heat pain within insular, frontal, and parietal cortices, such that the control group showed increased activation over time, whereas mTBI groups (mTBI-only, mTBI + PTSD) showed decreased activation within bilateral anterior insulas (AIs) between administrations. Importantly, change in the right AI response was inversely correlated with avoidance symptoms, but only in those with comorbid mTBI + PTSD. Further, in the comorbid group, greater AI attenuation was associated with decreased connectivity with anterior cingulate (ACC). The current study provides further evidence that repeated exposure to brief painful stimuli results in attenuation of insula activation over time in traumatized individuals. Further, in PTSD, AI shows greatest attenuation in those with the highest level of avoidance-a finding that was replicated across diverse samples. Thus, this mechanism may be a generalized mechanism of maladaptive response to experimental pain in those with significant trauma.

Faking bad: The neural correlates of feigning memory impairment.

OBJECTIVE: The detection of malingering in cognitive performance is a challenge in clinical and legal environments. Neuroimaging may provide an objective method for delineation of malingering. METHOD: A heterogeneous with concern of gender and racial-ethnic identity of 22 healthy volunteers completed the Tombaugh Test of Memory Malingering during an fMRI scan. Subjects were either instructed to perform optimally (not feigning) or to perform "as if they had a mild traumatic brain injury with memory impairment" (feigning). RESULTS: A voxel-based multiple regression analysis revealed that during correct responses there was greater activation in the superior and medial prefrontal cortex during the feigning versus the not-feigning responses. CONCLUSIONS: This finding suggests that falsified memory performance requires greater activation of cognitive control networks to determine a correct selection.

Neural correlates of malingering in mild traumatic brain injury: A positron emission tomography study.

The detection of malingering in cognitive performance is a challenge in clinical and legal environments. Neuroimaging may provide an objective method to determine the source of failure on tests of symptom validity. Participants comprised 45 combat veterans, 31 with mild traumatic brain injury (mTBI), not seeking medical or legal compensation, who completed the Tombaugh Test of Memory Malingering (TOMM) and a positron emission tomography (PET) scan. Based on TOMM performance (i.e., less than 45 of 50 total correct, suggesting suboptimal effort or malingering), subjects were separated into poor TOMM score (PT; n=10) and good TOMM score (GT; n=35) groups. Voxel-based multiple regression analysis with Group (GT/PT) predicting uptake of fluorodeoxyglucose revealed decreased brain metabolism in the ventromedial prefrontal cortex of poor performers. The current findings may suggest that poor TOMM performance in those with combat trauma and mTBI may be related to ventromedial prefrontal cortical dysfunction. These findings have important implications for the disentanglement of feigned versus actual memory impairment, where the latter may be secondary to neural mechanisms not consistent with forgetting or deception.

Maximizing the utility of a single site randomized controlled psychotherapy trial.

PURPOSE OF THE RESEARCH: There is increasing interest in including measures of biological mechanisms as mediators and moderators of treatment outcome in randomized controlled trials (RCT's) of psychotherapy efficacy. However, examining biological mechanisms is often expensive and budget caps of most major funding agencies have remained stable in recent years. The goal of this manuscript is to describe how a psychotherapy efficacy trial is using a model of collaborative, affiliated grants to maximize resources and the potential knowledge to be gained from a single site RCT. Principal results and conclusions: The trial is an ongoing RCT comparing two psychotherapies for the treatment of concurrent posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) with a sample of treatment seeking veterans. Through collaboration with a team of investigators with independently-funded but affiliated grants, measures of select sleep, neurobiological, and genetic biomarkers were integrated into this single site RCT. This model has allowed us to pose research questions regarding the role of biological mechanisms, maximize the utility of recruitment, and be efficient in maximizing knowledge to be gained in a way that would not be possible solely on the funding of a single site RCT. Challenges of this model include high participant burden in regard to assessment and complicated coordinating procedures among studies. Strategies to address these challenges are described.

Whole brain expression of bipolar disorder associated genes: structural and genetic analyses.

Studies of bipolar disorder (BD) suggest a genetic basis of the illness that alters brain function and morphology. In recent years, a number of genetic variants associated with BD have been identified. However, little is known about the associated genes, or brain circuits that rely upon their function. Using an anatomically comprehensive survey of the human transcriptome (The Allen Brain Atlas), we mapped the expression of 58 genes with suspected involvement in BD based upon their relationship to SNPs identified in genome wide association studies (GWAS). We then conducted a meta-analysis of structural MRI studies to identify brain regions that are abnormal in BD. Of 58 BD associated genes, 22 had anatomically distinct expression patterns that could be categorized into one of three clusters (C1-C3). Brain regions with the highest and lowest expression of these genes did not overlap strongly with anatomical sites identified as abnormal by structural MRI except in the parahippocampal gyrus, the inferior/superior temporal gyrus and the cerebellar vermis, regions where overlap was significant. Using the 22 genes in C1-C3 as reference points, additional genes with correlated expression patterns were identified and organized into sets based on similarity. Further analysis revealed that five of these gene sets were significantly associated with BD, suggesting that anatomical expression profile is correlated with genetic susceptibility to BD, particularly for genes in C2. Our data suggest that expression profiles of BD-associated genes do not explain the majority of structural abnormalities observed in BD, but may be useful in identifying new candidate genes. Our results highlight the complex neuroanatomical basis of BD, and reinforce illness models that emphasize impaired brain connectivity.