Ovarian hormones reduce the negative association between worry and cognitive control: A combined neural and behavioral investigation.

BACKGROUND: Increased reactivity to response conflict and errors, processes governed by the dorsal anterior cingulate cortex (dACC), have both been implicated in anxiety. Anxiety is also more common in females than males. Importantly, natural changes in ovarian hormones levels are related to fluctuations in anxiety symptoms in healthy and clinical populations, and ovarian hormones likely modulate prefrontal cortex structure and function. No studies, however, have examined the role of fluctuating ovarian hormones in the association between anxiety and cognitive control across the menstrual cycle. METHODS: In this multimodal proof-of-concept study, naturally cycling females (N = 30 twins from 14 complete twin pairs and 2 participants whose co-twin was not in the final sample; age 18-29) provided saliva samples to assay for estradiol and progesterone and completed the Penn State Worry Questionnaire for 35 consecutive days. At two time points, during projected pre-ovulatory and post-ovulatory phases, they also completed the Flanker task while undergoing functional magnetic resonance imaging to probe cognitive control-related dACC activity. Multilevel modeling was used to examine within- and between-person effects of hormones and worry on cognitive-control indices. RESULTS: On days when estradiol and progesterone were low relative to a female's own average (i.e., within-subjects effect), worry was associated with greater flanker interference. In females with higher estradiol and progesterone levels compared to other females (i.e., between-subject effects), worry was associated with less error-related dACC activity, irrespective of the day that dACC activity was assessed. CONCLUSION: Findings suggest a protective effect of ovarian hormones on the link between worry and cognitive control. Associations between worry and conflict-monitoring were sensitive to daily hormonal fluctuations (within-person states), whereas associations between worry and error-monitoring were sensitive to mean hormone levels (between-person traits), suggesting that ovarian hormones are critical to consider in studies examining associations between anxiety and cognitive control in females.

Changes in Brain Network Connections After Exposure and Response Prevention Therapy for Obsessive-Compulsive Disorder in Adolescents and Adults.

BACKGROUND: Functional alterations of tripartite neural networks during cognitive control (i.e., frontoparietal network [FPN], cingulo-opercular network, and default mode network) occur in patients with obsessive-compulsive disorder (OCD) and may contribute to illness expression. However, the degree to which changes in these networks are elicited by gold standard treatment (e.g., exposure and response prevention [EX/RP]) remains unknown. Understanding how EX/RP modulates network connectivity in adolescent versus adult patients with OCD may aid the identification of developmentally sensitive treatment targets that enhance cognitive control. METHODS: Data from a total of 169 adolescents (13-17 years) and adults (25-40 years; 57% female) were analyzed, including healthy control participants (n = 58) and patients with OCD (n = 111) who were randomized to either EX/RP or an active control therapy (stress management training). Participants performed a flanker task during functional magnetic resonance imaging pre- and posttreatment. To retain sensitivity to individual differences in connectivity, group iterative multiple model estimation was used to assess functional connectivity (i.e., density) within and between brain networks. RESULTS: Significant increases in FPN density and decreases in FPN-default mode network density were observed from pre- to posttreatment in patients who received EX/RP. The opposite patterns of change occurred in patients who received stress management training. These treatment-related changes in network density did not differ across age group. CONCLUSIONS: Results suggest EX/RP-specific changes in task-based connectivity in patients with OCD. Given baseline differences between healthy control participants and patients by age group, these treatment-related changes may indicate restoration of healthy FPN and default mode network development across patients, providing targets for improving response to EX/RP.

Exposure and response prevention versus stress management training for adults and adolescents with obsessive compulsive disorder: A randomized clinical trial.

OBJECTIVE: Though exposure and response prevention (ERP) is a well-proven treatment for OCD across the lifespan, prior RCTs have not studied adolescent and adult patients with the same ERP protocol relative to an active comparator that controls for non-specific effects of treatment. This approach assesses differences in the effect of OCD-specific exposures in affected adolescents and adults and in response to ERP compared to a stress-management control therapy (SMT). METHODS: This assessor-blinded, parallel, 2-arm, randomized, ambulatory clinical superiority trial randomized adolescents (aged 12-18) and adults (24-46) with OCD (N = 126) to 12 weekly sessions of ERP or SMT. OCD severity was measured before, during and after treatment using the child or adult version of the Yale-Brown Obsessive Compulsive Scale (C/Y-BOCS), depending on participant age. We predicted that ERP would produce greater improvement in OCD symptoms than SMT and that there would be no significant post-treatment differences across age groups. RESULTS: ERP (n = 63) produced significantly greater improvements on C/Y-BOCS scores at post-treatment than SMT (n = 63) (Effect size = -0.72, CI = -0.52 to -0.91, p < .001). ERP also produced more treatment responders (ERP = 86%, SMT = 32%; χ2 = 46.37, p < .001) and remitters than SMT (ERP = 39%, SMT = 7%; χ2 = 16.14, p < .001). Finally, there were no statistically significant post-treatment differences in C/Y-BOCS scores between adolescents and adults assigned to ERP. CONCLUSION: A single ERP protocol is superior to SMT in treating both adolescents and adults with OCD. OCD-specific therapy is necessary across the lifespan for optimal outcomes in this highly disabling disorder, though non-specific treatments like SMT are still all-too-commonly provided.

Determining menstrual cycle phase: An empirical examination of methodologies and recommendations for improvement in behavioral and brain sciences.

The recent decade has brought an exciting proliferation of behavioral, psychological and neuroscientific research involving the menstrual cycle. However, the reliability and validity of many popular methodologies for determining menstrual cycle phase lack empirical examination. These under-investigated methods include: (1) predicting menstrual cycle phase using self-report information only (e.g., "count" methods), (2) utilizing ovarian hormone ranges to determine menstrual cycle phase, and (3) using ovarian hormone changes from limited measurements (e.g., two time points) to determine menstrual cycle phase. In the current study, we examine the accuracy of these methods for menstrual cycle phase determination using 35-day within-person assessments of circulating ovarian hormones from 96 females across the menstrual cycle. Findings indicate that all three common methods are error-prone, resulting in phases being incorrectly determined for many participants, with Cohen's kappa estimates ranging from -0.13 to 0.53 indicating disagreement to only moderate agreement depending on the comparison. Such methodological challenges are surmountable through careful study design, more frequent hormone assays (when possible), and utilization of sophisticated statistical methods. With increased methodological rigor in behavioral, psychological and neuroscientific research, the field will be poised to detect biobehavioral correlates of ovarian hormone fluctuations for the betterment of the mental health and wellbeing of millions of females.

Error-related brain activity associated with obsessive-compulsive symptoms in youth.

BACKGROUND: Subclinical obsessive-compulsive symptoms (OCS) are common in children, and increase risk for later onset of obsessive-compulsive disorder (OCD). In pediatric patients with OCD, neuroimaging research implicates altered neural mechanisms for error-processing, but whether abnormal brain response occurs with subclinical OCS remains poorly understood. METHODS: Using functional magnetic resonance imaging (fMRI), 113 youth (8-18 years; 45 female) from a community sample were scanned during an error-eliciting Go/No-Go task. OCS were assessed dimensionally using the obsessive-compulsive subscale of the Child Behavior Checklist. The association between OCS scores and error-related brain activity was examined at the whole-brain level. RESULTS: Lower OCS scores associated with stronger response to errors in dorsal anterior cingulate cortex (dACC), caudate, putamen, thalamus, and occipital cortex. Additionally, lower OCS related to higher capacity for inhibitory control, as indexed by greater accuracy on No-Go trials during fMRI scanning. The relationship between lower OCS and better accuracy on No-Go trials was mediated by greater error-related dACC activity. CONCLUSIONS: The inverse relationship between OCS and error-related activity in the dACC and extended cortical-striatal-thalamic circuitry may index an adaptive process by which subclinical OCS are minimized in youth. Further, these results identify an observable pattern of brain activity that tracks with subclinical OCS severity. Understanding the link between neural networks for error processing and the normal to abnormal range of OCS may pave the way for brain-based strategies to identify children who are more likely to develop OCD and enable the targeting of preventive strategies to reduce risk.

Defining brain-based OCD patient profiles using task-based fMRI and unsupervised machine learning.

While much research has highlighted phenotypic heterogeneity in obsessive compulsive disorder (OCD), less work has focused on heterogeneity in neural activity. Conventional neuroimaging approaches rely on group averages that assume homogenous patient populations. If subgroups are present, these approaches can increase variability and can lead to discrepancies in the literature. They can also obscure differences between various subgroups. To address this issue, we used unsupervised machine learning to identify subgroup clusters of patients with OCD who were assessed by task-based fMRI. We predominantly focused on activation of cognitive control and performance monitoring neurocircuits, including three large-scale brain networks that have been implicated in OCD (the frontoparietal network, cingulo-opercular network, and default mode network). Participants were patients with OCD (n = 128) that included both adults (ages 24-45) and adolescents (ages 12-17), as well as unaffected controls (n = 64). Neural assessments included tests of cognitive interference and error processing. We found three patient clusters, reflecting a "normative" cluster that shared a brain activation pattern with unaffected controls (65.9% of clinical participants), as well as an "interference hyperactivity" cluster (15.2% of clinical participants) and an "error hyperactivity" cluster (18.9% of clinical participants). We also related these clusters to demographic and clinical correlates. After post-hoc correction for false discovery rates, the interference hyperactivity cluster showed significantly longer reaction times than the other patient clusters, but no other between-cluster differences in covariates were detected. These findings increase precision in patient characterization, reframe prior neurobehavioral research in OCD, and provide a starting point for neuroimaging-guided treatment selection.

Resting-State Connectivity and Response to Psychotherapy Treatment in Adolescents and Adults With OCD: A Randomized Clinical Trial.

OBJECTIVE: Cortical-subcortical hyperconnectivity related to affective-behavioral integration and cortical network hypoconnectivity related to cognitive control have been demonstrated in obsessive-compulsive disorder (OCD); the study objective was to examine whether these connectivity patterns predict treatment response. METHODS: Adolescents (ages 12-17) and adults (ages 24-45) were randomly assigned to 12 sessions of exposure and response prevention (ERP) or stress management therapy (SMT), an active control. Before treatment, resting-state connectivity of ventromedial prefrontal cortical (vmPFC), cingulo-opercular, frontoparietal, and subcortical regions was assessed with functional MRI. OCD severity was assessed with the Yale-Brown Obsessive Compulsive Scale before, during, and after treatment. Usable fMRI and longitudinal symptom data were obtained from 116 patients (68 female; 54 adolescents; 60 medicated). RESULTS: ERP produced greater decreases in symptom scores than SMT. ERP was selectively associated with less vmPFC-subcortical (caudate and thalamus) connectivity in both age groups and primarily in unmedicated participants. Greater symptom improvement with both ERP and SMT was associated with greater cognitive-control (cingulo-opercular and frontoparietal) and subcortical (putamen) connectivity across age groups. Developmental specificity was observed across ERP and SMT treatments, such that greater improvements with ERP than SMT were associated with greater frontoparietal-subcortical (nucleus accumbens) connectivity in adolescents but greater connectivity between frontoparietal regions in adults. Comparison of response-predictive connections revealed no significant differences compared with a matched healthy control group. CONCLUSIONS: The results suggest that less vmPFC-subcortical connectivity related to affect-influenced behavior may be important for ERP engagement, whereas greater cognitive-control and motor circuit connectivity may generally facilitate response to psychotherapy. Finally, neural predictors of treatment response may differ by age.

Examining a window of vulnerability for affective symptoms in the mid-luteal phase of the menstrual cycle.

Particular phases of the menstrual cycle may exacerbate affective symptoms for females with a diagnosed mental health disorder. However, there are mixed findings regarding whether affective symptoms change across the menstrual cycle in females without a clinical diagnosis. The window of vulnerability model proposes that natural increases in ovarian hormones in the mid-luteal phase of the menstrual cycle lead to systematic changes in brain networks associated with affective processing. Consequently, the model posits that females may experience stress more intensely and remember negative events more readily in the mid-luteal phase, increasing their risk for higher affective symptoms. Using a 35-day longitudinal study design, we tested the window of vulnerability model in a non-clinical sample. We tracked naturally cycling females' daily stress and three types of affective symptoms: anxious apprehension, anxious arousal, and anhedonic depression. Using multilevel modeling, we simultaneously modeled within- and between-person associations among stress and menstrual phase for each affective symptom. We found increased anhedonic depression in the mid-luteal phase but not anxious apprehension or anxious arousal. Moreover, we detected a positive association between within- and between-person stress and anxious apprehension and anhedonic depression, but not anxious arousal. These associations were not stronger in the mid-luteal phase. Overall, we provide weak evidence for a window of vulnerability for affective symptoms in the mid-luteal phase of the menstrual cycle. Our findings suggest that stress is a better predictor of fluctuations in affective symptoms than the menstrual cycle. Moreover, our findings highlight the importance of measuring multiple negative affective symptoms because they may be differentially related to stress and the menstrual cycle.

Chemical imbalance and etiological beliefs about depression among college students.

Etiological beliefs of depression have differing impacts on motivation, hope, and treatment expectations. However, it is unclear where people are exposed to these beliefs. Objective: This study examined beliefs about depression and their relations to symptoms, attitudes about depression, and treatment preferences. Participants: 426 undergraduates attending a large midwestern university. Methods: Participants completed an online survey asking about causes of depression, if and where they had heard about the "chemical imbalance" explanation of depression, attitudes about depression, as well as measures of their symptoms, treatment history, and hypothetical treatment preferences. Results: Sixty-two percent of the sample had heard of the chemical imbalance explanation, most commonly from the classroom. Biochemical beliefs about depression were most strongly endorsed among participants with a family history of depression and who had had personal experience with treatment. The chemical imbalance belief was uniquely related to dysfunctional beliefs about depression. Etiological beliefs were largely unrelated to treatment preferences. Conclusion: College students are exposed to models of mental health that may not be ideal for treatment and recovery.

Neural Mechanisms of Spatial Attention Deficits in Trauma.

BACKGROUND: Survival requires effective shifting of attention from one stimulus to another as goals change. It has been consistently demonstrated that posttraumatic stress disorder (PTSD) is associated with both faster orienting of attention toward and slower disengagement of attention from affective stimuli. Prior work, however, suggests that attention abnormalities in PTSD may extend beyond the affective domain. METHODS: We used the Attention Network Test-modified to include invalid spatial cues-in conjunction with functional magnetic resonance imaging to examine the neurocognitive underpinnings of visuospatial attention in participants with PTSD (n = 31) and control participants who were (n = 20) and were not (n = 21) exposed to trauma. RESULTS: We observed deficits in the utilization of spatial information in the group with PTSD. Specifically, compared with the non-trauma-exposed group, participants with PTSD showed a smaller reaction time difference between invalidly and validly cued targets, demonstrating that they were less likely to use spatial cues to inform subsequent behavior. We also found that in both the PTSD and trauma-exposed control groups, utilization of spatial information was positively associated with activation of attentional control regions (e.g., right precentral gyrus, inferior and middle frontal gyri) and negatively associated with activation in salience processing regions (e.g., right insula). CONCLUSIONS: This pattern suggests that both trauma exposure and psychopathology may be associated with alterations of spatial attention. Overall, our findings suggest that both attention- and salience-network abnormalities may be related to altered attention in trauma-exposed populations. Treatments that target these neural networks could therefore be a new avenue for PTSD research.

Directionality of change in obsessive compulsive disorder (OCD) and suicidal ideation over six years in a naturalistic clinical sample✰.

BACKGROUND: Obsessive compulsive disorder (OCD) is associated with elevated suicide risk, but the directionality of the association between OCD severity and suicidal ideation has not been established, which was the goal of this study. METHODS: Participants (n = 325) were adults with either a current or past diagnosis of Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) OCD who were assessed annually for suicidal ideation and OCD symptom severity for six years. Cross-lagged panel analyses statistically compared unidirectional and bidirectional models over time. Serious suicide-related adverse events were reported. RESULTS: The best-fitting and most parsimonious model included paths predicting suicidal ideation from OCD symptom severity, but not vice versa. These results were confirmed by comparing a model with cross-lagged paths constrained equal to a freely estimated model. Higher OCD symptom severity in a given year was associated with a higher suicidal ideation severity in the subsequent year. Five suicide-related adverse events were reported throughout the duration of the study, including two suicide deaths and three suicide attempts. LIMITATIONS: The study relied on a single-item, annual measure of suicidal ideation in adults, with substantial variability in severity of suicide risk, and missing data increased with later observations in the study. DISCUSSION: OCD symptom severity predicted next year suicidal ideation severity. In contrast, suicidal ideation severity in a given year did not predict next-year OCD symptom severity in this OCD sample. Thus, rather than waiting for suicidal ideation to resolve, clinicians should consider providing empirically supported treatments for OCD.

Insula activation is modulated by attention shifting in social anxiety disorder.

Social anxiety disorder (SAD) is characterized by exaggerated reactivity to social threat, often documented by biased attention to threatening information, and increased activation in brain regions involved in salience/threat processing. Attention training has been developed to ameliorate the attention bias documented in individuals with SAD, with mixed results. We investigated patterns of brain activation underlying acute attention modulation in 41 participants (29 with SAD and 12 health controls). We then investigated how brain activation changed over time in both groups in response to a 4-session attention training protocol (toward threat, away from threat, no-training control). Results revealed diminished pre-training deactivation in the insula in SAD participants during attention modulation. SAD participants also demonstrated an increase in insula deactivation over time, suggestive of an improvement in attention modulation of emotion, and this was associated with a decrease in symptom severity. Attention training did not, itself, lead to clinical improvement, though there was a trend level effect of training toward threat on increased insula deactivation over time. While deficits in attentional control and emotion modulation are documented in individuals with SAD, current attention training protocols are not robustly effective in ameliorating aberrant functioning. Pursuit of training protocols that have more robust impacts on the relevant neural circuitry may have some value.

Behavioral and neural correlates of disrupted orienting attention in posttraumatic stress disorder.

Prior work has revealed that posttraumatic stress disorder (PTSD) is associated with altered (a) attentional performance and (b) resting-state functional connectivity (rsFC) in brain networks linked to attention. Here, we sought to characterize and link these behavioral and brain-based alterations in the context of Posner and Peterson's tripartite model of attention. Male military veterans with PTSD (N = 49; all deployed to Iraq or Afghanistan) and healthy age-and-gender-matched community controls (N = 26) completed the Attention Network Task. A subset of these individuals (36 PTSD and 21 controls) also underwent functional magnetic resonance imaging (fMRI) to assess rsFC. The behavioral measures revealed that the PTSD group was impaired at disengaging spatial attention, relative to the control group. FMRI measures further revealed that, relative to the control group, the PTSD group exhibited greater rsFC between the salience network and (a) the default mode network, (b) the dorsal attention network, and (c) the ventral attention network. Moreover, problems with disengaging spatial attention increased the rsFC between the networks above in the control group, but not in the PTSD group. The present findings link PTSD to both altered orienting of spatial attention and altered relationships between spatial orienting and functional connectivity involving the salience network. Interventions that target orienting and disengaging spatial attention may be a new avenue for PTSD research.

A Pilot Study of Mindfulness-Based Exposure Therapy in OEF/OIF Combat Veterans with PTSD: Altered Medial Frontal Cortex and Amygdala Responses in Social-Emotional Processing.

Combat-related posttraumatic stress disorder (PTSD) is common among returning veterans, and is a serious and debilitating disorder. While highly effective treatments involving trauma exposure exist, difficulties with engagement and early drop may lead to sub-optimal outcomes. Mindfulness training may provide a method for increasing emotional regulation skills that may improve engagement in trauma-focused therapy. Here, we examine potential neural correlates of mindfulness training and in vivo exposure (non-trauma focused) using a novel group therapy [mindfulness-based exposure therapy (MBET)] in Afghanistan (OEF) or Iraq (OIF) combat veterans with PTSD. OEF/OIF combat veterans with PTSD (N = 23) were treated with MBET (N = 14) or a comparison group therapy [Present-centered group therapy (PCGT), N = 9]. PTSD symptoms were assessed at pre- and post-therapy with Clinician Administered PTSD scale. Functional neuroimaging (3-T fMRI) before and after therapy examined responses to emotional faces (angry, fearful, and neutral faces). Patients treated with MBET had reduced PTSD symptoms (effect size d = 0.92) but effect was not significantly different from PCGT (d = 0.43). Improvement in PTSD symptoms from pre- to post-treatment in both treatment groups was correlated with increased activity in rostral anterior cingulate cortex, dorsal medial prefrontal cortex (mPFC), and left amygdala. The MBET group showed greater increases in amygdala and fusiform gyrus responses to Angry faces, as well as increased response in left mPFC to Fearful faces. These preliminary findings provide intriguing evidence that MBET group therapy for PTSD may lead to changes in neural processing of social-emotional threat related to symptom reduction.

Attentional processes in posttraumatic stress disorder and the associated changes in neural functioning.

Posttraumatic Stress Disorder (PTSD) is associated with alterations in attention at the behavioral and neural levels. However, there are conflicting findings regarding the specific type of attention impairments present in PTSD, as the commonly used tests of attention do not isolate the mechanisms behind attention abnormalities, and the constructs measured do not map onto the neurocircuits governing attention. Here, we review the literature on attention processing in PTSD and offer directions for future research to clarify these unanswered questions. First, using instruments that allow assessment of behavioral and neurophysiological attention components will be necessary to understand attention deficits in PTSD. Second, focus on intra-individual variability in addition to assessment of central tendency may help clarify some of the mixed findings. Third, longitudinal studies on attentional processes are warranted to determine how attention contributes to the development and maintenance of PTSD. Integration of behavioral and neural measures of attention will be useful in understanding the pathophysiology of PTSD.

ALTERED DEFAULT MODE NETWORK (DMN) RESTING STATE FUNCTIONAL CONNECTIVITY FOLLOWING A MINDFULNESS-BASED EXPOSURE THERAPY FOR POSTTRAUMATIC STRESS DISORDER (PTSD) IN COMBAT VETERANS OF AFGHANISTAN AND IRAQ.

BACKGROUND: Recent studies suggest that mindfulness may be an effective component for posttraumatic stress disorder (PTSD) treatment. Mindfulness involves practice in volitional shifting of attention from "mind wandering" to present-moment attention to sensations, and cultivating acceptance. We examined potential neural correlates of mindfulness training using a novel group therapy (mindfulness-based exposure therapy (MBET)) in combat veterans with PTSD deployed to Afghanistan (OEF) and/or Iraq (OIF). METHODS: Twenty-three male OEF/OIF combat veterans with PTSD were treated with a mindfulness-based intervention (N = 14) or an active control group therapy (present-centered group therapy (PCGT), N = 9). Pre-post therapy functional magnetic resonance imaging (fMRI, 3 T) examined resting-state functional connectivity (rsFC) in default mode network (DMN) using posterior cingulate cortex (PCC) and ventral medial prefrontal cortex (vmPFC) seeds, and salience network (SN) with anatomical amygdala seeds. PTSD symptoms were assessed at pre- and posttherapy with Clinician Administered PTSD Scale (CAPS). RESULTS: Patients treated with MBET had reduced PTSD symptoms (effect size d = 0.92) but effect was not significantly different from PCGT (d = 0.46). Increased DMN rsFC (PCC seed) with dorsolateral dorsolateral prefrontal cortex (DLPFC) regions and dorsal anterior cingulate cortex (ACC) regions associated with executive control was seen following MBET. A group × time interaction found MBET showed increased connectivity with DLPFC and dorsal ACC following therapy; PCC-DLPFC connectivity was correlated with improvement in PTSD avoidant and hyperarousal symptoms. CONCLUSIONS: Increased connectivity between DMN and executive control regions following mindfulness training could underlie increased capacity for volitional shifting of attention. The increased PCC-DLPFC rsFC following MBET was related to PTSD symptom improvement, pointing to a potential therapeutic mechanism of mindfulness-based therapies.

Validation of electronic health record phenotyping of bipolar disorder cases and controls.

OBJECTIVE: The study was designed to validate use of electronic health records (EHRs) for diagnosing bipolar disorder and classifying control subjects. METHOD: EHR data were obtained from a health care system of more than 4.6 million patients spanning more than 20 years. Experienced clinicians reviewed charts to identify text features and coded data consistent or inconsistent with a diagnosis of bipolar disorder. Natural language processing was used to train a diagnostic algorithm with 95% specificity for classifying bipolar disorder. Filtered coded data were used to derive three additional classification rules for case subjects and one for control subjects. The positive predictive value (PPV) of EHR-based bipolar disorder and subphenotype diagnoses was calculated against diagnoses from direct semistructured interviews of 190 patients by trained clinicians blind to EHR diagnosis. RESULTS: The PPV of bipolar disorder defined by natural language processing was 0.85. Coded classification based on strict filtering achieved a value of 0.79, but classifications based on less stringent criteria performed less well. No EHR-classified control subject received a diagnosis of bipolar disorder on the basis of direct interview (PPV=1.0). For most subphenotypes, values exceeded 0.80. The EHR-based classifications were used to accrue 4,500 bipolar disorder cases and 5,000 controls for genetic analyses. CONCLUSIONS: Semiautomated mining of EHRs can be used to ascertain bipolar disorder patients and control subjects with high specificity and predictive value compared with diagnostic interviews. EHRs provide a powerful resource for high-throughput phenotyping for genetic and clinical research.

The human ortholog of acid-sensing ion channel gene ASIC1a is associated with panic disorder and amygdala structure and function.

BACKGROUND: Individuals with panic disorder (PD) exhibit a hypersensitivity to inhaled carbon dioxide, possibly reflecting a lowered threshold for sensing signals of suffocation. Animal studies have shown that carbon dioxide-mediated fear behavior depends on chemosensing of acidosis in the amygdala via the acid-sensing ion channel ASIC1a. We examined whether the human ortholog of the ASIC1a gene, ACCN2, is associated with the presence of PD and with amygdala structure and function. METHODS: We conducted a case-control analysis (n = 414 PD cases and 846 healthy controls) of ACCN2 single nucleotide polymorphisms and PD. We then tested whether variants showing significant association with PD are also associated with amygdala volume (n = 1048) or task-evoked reactivity to emotional stimuli (n = 103) in healthy individuals. RESULTS: Two single nucleotide polymorphisms at the ACCN2 locus showed evidence of association with PD: rs685012 (odds ratio = 1.32, gene-wise corrected p = .011) and rs10875995 (odds ratio = 1.26, gene-wise corrected p = .046). The association appeared to be stronger when early-onset (age ≤ 20 years) PD cases and when PD cases with prominent respiratory symptoms were compared with controls. The PD risk allele at rs10875995 was associated with increased amygdala volume (p = .035) as well as task-evoked amygdala reactivity to fearful and angry faces (p = .0048). CONCLUSIONS: Genetic variation at ACCN2 appears to be associated with PD and with amygdala phenotypes that have been linked to proneness to anxiety. These results support the possibility that modulation of acid-sensing ion channels may have therapeutic potential for PD.