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.

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.

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.

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.