Frontopolar multifocal transcranial direct current stimulation reduces conditioned fear reactivity during extinction training: A pilot randomized controlled trial.

Exposure-based therapies for anxiety and related disorders are believed to depend on fear extinction learning and corresponding changes in extinction circuitry. Frontopolar multifocal transcranial direct current stimulation (tDCS) has been shown to improve therapeutic safety learning during in vivo exposure and may modulate functional connectivity of networks implicated in fear processing and inhibition. A pilot randomized controlled trial was completed to determine the effects of frontopolar tDCS on extinction learning and memory. Community volunteers (n = 35) completed a 3-day fear extinction paradigm with measurement of electrodermal activity. Participants were randomized (single-blind) to 20-min of sham (n = 17, 30 s. ramp in/out) or active (n = 18) frontopolar (anode over Fpz, 10-10 EEG) multifocal tDCS (20-min, 1.5 mA) prior to extinction training. Mixed ANOVAs revealed a significant group*trial effect on skin conductance response (SCR) to the conditioned stimulus (CS + ) during extinction training (p = 0.007, Cohen's d = 0.55). The effects of frontopolar tDCS were greatest during the first two extinction trials, suggesting that tDCS may have promoted fear inhibition prior to safety learning. Return of fear to the CS + during tests were comparable across conditions (ps > 0.50). These findings suggest that frontopolar tDCS may modulate the processing of threat cues and associated circuitry or promote the inhibition of fear. This has clear implications for the treatment of anxiety and related disorders with therapeutic exposure.

Interactive association of posttraumatic stress disorder, apolipoprotein ε4 genotype, and age on cognitive functioning.

BACKGROUND: The ε4 allele of the apolipoprotein (APOE) gene and posttraumatic stress disorder (PTSD) are associated with cognitive deficits. Both associations may vary depending on age. No previous study has examined a possible three-way interaction between APOE ε4, PTSD, and age on cognitive functioning. METHODS: Data were analyzed from 1244 European-American U.S. military veterans who participated in the 2011 National Health and Resilience in Veterans Study (NHRVS). Analyses of covariance were used to examine the main effects and interactions of APOE ε4, PTSD, and age on learning/working memory (LWM) and attention/psychomotor (APM) performance. RESULTS: A significant three-way interaction between APOE ε4, PTSD, and age on the LWM composite (ηp 2  = 0.011) was observed such that the main effect of APOE ε4 on LWM was only significant for older participants with PTSD. A significant two-way interaction between PTSD and age on the APM composite (ηp 2  = 0.011) was observed such that the main effect of PTSD on APM was only significant in older participants. CONCLUSION: Older APOE ε4 carriers with probable PTSD showed poorer LWM performance relative to other groups. Aging-related associations on APM performance were most pronounced in veterans with PTSD. These data are preliminary evidence that identification and treatment of PTSD may be beneficial for individuals at risk for age-related cognitive impairment.

Fear of sin and fear of God: Scrupulosity predicts women's daily experiences of mental contamination following sexual trauma.

Mental contamination refers to feelings of dirtiness in response to thoughts, images, or memories. Mental contamination is frequently reported after sexual trauma and is associated with symptoms of posttraumatic stress disorder (PTSD). Differences in individuals' views about morality and purity may influence the severity of mental contamination, though this has been studied primarily outside of samples assessed for trauma and/or PTSD. The present study addressed this gap by investigating scrupulosity as a prospective predictor of daily sexual trauma-related mental contamination and PTSD symptoms. Participants included 40 adult women with a history of sexual trauma and current sexual trauma-related mental contamination who completed baseline diagnostic interviews and questionnaires followed by two assessments every day for 2 weeks. The results indicate that scrupulosity was positively correlated with PTSD symptom severity and sexual trauma-related mental contamination at baseline. Scrupulosity was also a prospective predictor of increased daily sexual trauma-related mental contamination, B = 0.19, SE = 0.07, p = .010, but not daily PTSD symptoms, B = -0.10, SE = .08, p = .198. The findings indicate that scrupulosity may be an important factor in understanding recovery from sexual assault.

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.

KETAMINE'S MECHANISM OF ACTION: A PATH TO RAPID-ACTING ANTIDEPRESSANTS.

Major depressive disorder (MDD) is a common and debilitating psychiatric disorder. Traditional antidepressants are of limited efficacy and take weeks to months to yield full therapeutic effects. Thus, there is a clear need for effective rapid-acting antidepressant medications. The N-methyl-d-aspartate receptor (NMDA-R) antagonist, ketamine, has received a great deal of attention over the last 20 years due to the discovery that a single subanesthetic dose leads to a rapid antidepressant effect in individuals with treatment-resistant depression. Animal and human research suggest that ketamine's antidepressant effects are mediated by a glutamate surge that leads to a cascade of events that result in synaptogenesis and reversal of the negative effects of chronic stress and depression, particularly within the prefrontal cortex (PFC). Preclinical and clinical data have provided compelling insights into the mechanisms underlying the rapid-acting antidepressant effects of ketamine. This review discusses stress-related neurobiology of depression and the safety, tolerability, and efficacy of ketamine for MDD, along with a review of ketamine's mechanism of action and prospective predictors of treatment response. Research limitations and future clinical prospects are also discussed.

Intermittent theta burst stimulation and functional connectivity in people living with HIV/AIDS who smoke tobacco cigarettes: a preliminary pilot study.

Background: People living with HIV (PLWHA) smoke at three times the rate of the general population and respond poorly to cessation strategies. Previous studies examined repetitive transcranial magnetic stimulation (rTMS) over left dorsolateral prefrontal cortex (L. dlPFC) to reduce craving, but no studies have explored rTMS among PLWHA who smoke. The current pilot study compared the effects of active and sham intermittent theta-burst stimulation (iTBS) on resting state functional connectivity (rsFC), cigarette cue attentional bias, and cigarette craving in PLWHA who smoke. Methods: Eight PLWHA were recruited (single-blind, within-subject design) to receive one session of iTBS (n=8) over the L. dlPFC using neuronavigation and, four weeks later, sham iTBS (n=5). Cigarette craving and attentional bias assessments were completed before and after both iTBS and sham iTBS. rsFC was assessed before iTBS (baseline) and after iTBS and sham iTBS. Results: Compared to sham iTBS, iTBS enhanced rsFC between the L. dlPFC and bilateral medial prefrontal cortex and pons. iTBS also enhanced rsFC between the right insula and right occipital cortex compared to sham iTBS. iTBS also decreased cigarette craving and cigarette cue attentional bias. Conclusion: iTBS could potentially offer a therapeutic option for smoking cessation in PLWHA.

Assessment of Comorbid Obsessive-Compulsive Disorder and Posttraumatic Stress Disorder.

Obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD) are commonly comorbid and share prominent features (e.g., intrusions, safety behaviors, and avoidance). Excellent self-report and clinician-administered assessments exist for OCD and PTSD individually, but few assess both disorders, and even fewer provide instruction on differential diagnosis or detection of comorbid OCD and PTSD. To address this gap in the literature, the current paper aims to (1) highlight diagnostic and functional similarities and differences between OCD and PTSD to inform differential diagnosis, (2) outline assessment recommendations for individuals with suspected comorbid OCD and PTSD, OCD with a significant trauma history or posttraumatic symptoms, or PTSD with significant obsessive-compulsive symptoms, and (3) explore future directions to evaluate and improve methods for assessing co-occurring OCD and PTSD.

Obsessive-Compulsive Symptoms and Daily Experiences of Posttraumatic Stress and Mental Contamination Following Sexual Trauma.

Although cross-sectional research highlights similarities between symptoms of obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD) among individuals exposed to sexual trauma, little is known about how these disorders relate over time. The goal of the present study was to examine whether 1) OCD symptoms prospectively predicted daily symptoms of PTSD, and 2) OCD and PTSD symptoms prospectively predicted daily experiences of sexual trauma-related mental contamination (i.e., dirtiness in the absence of a physical pollutant). Forty-one women with a sexual trauma history completed baseline measures of OCD and PTSD, as well as twice-daily assessments of PTSD symptoms and mental contamination over a two-week period. Total OCD symptoms and the unacceptable thoughts dimension significantly predicted daily PTSD symptoms after accounting for other OCD dimensions. Only total OCD symptoms significantly predicted daily mental contamination when examined together with total PTSD symptoms. No individual PTSD or OCD clusters/dimensions significantly predicted daily mental contamination when examined simultaneously. Findings from this study highlight the nuanced associations among OCD symptoms, PTSD symptoms, and experiences of mental contamination. Future research is needed to further understand the development of PTSD, OCD, and mental contamination over time to inform targets for intervention.

Obsessive beliefs predict cognitive behavior therapy outcome for obsessive compulsive disorder.

Cognitive accounts of obsessive compulsive disorder (OCD) assert that core beliefs are crucial to the development, maintenance, and treatment of the disorder. There are a number of obsessive beliefs that are considered fundamental to OCD, including personal responsibility, threat estimation, perfectionism, need for certainty, importance of thoughts, and thought control. The present study investigated if pretreatment severity of obsessive beliefs, as well as the change in obsessive beliefs following treatment, predicted intensive, residential cognitive behavioral therapy (CBT) treatment outcome. A series of hierarchical regression analyses were carried out to investigate the relations between obsessive beliefs and treatment outcome. Results indicated that inflated pretreatment responsibility/threat estimation beliefs were significantly related to less overall obsessive compulsive (OC) symptom reduction at discharge, explaining 2% of the overall variance. Changes in obsessive beliefs broadly, and importance/control of thoughts specifically, were positively related to overall OC symptom reduction at discharge, respectively explaining 18% and 3.6% variance. Results are modestly consistent with a number of theoretical models, which argue that inflated responsibility, threat estimation, and thought control are important to the maintenance and treatment of OCD.

Interactive effects of the BDNF Val66Met polymorphism and posttraumatic stress disorder on cognition in U.S. military veterans.

Posttraumatic stress disorder (PTSD) is associated with mild-to-moderate deficits in cognition. The Met allele of the brain-derived neurotrophic factor (BDNF) Val66Met gene may also be associated with deficits in cognition. However, findings are inconsistent and may be sensitive to moderating variables such as psychopathology. While emerging research suggests that PTSD and the Met allele may interact, few studies have replicated this effect or examined the interactive effect of PTSD and the Met allele on subjective cognition. To address this gap, the current study analyzed data from European-American (EA) U.S. military veterans (n = 1244) who participated in the National Health and Resilience in Veterans Study (NHRVS) to examine the main and interactive effects of BDNF Val66Met genotype and probable PTSD on objective and subjective cognition. Results revealed significant (p's < 0.001) interactions between Met allele carrier status and probable PTSD in objective and subjective cognition. Among individuals with probable PTSD (n = 131), the Met allele was associated with poorer objective (p < .001, d = 0.62) and subjective cognition (p = .001, d = 0.53). Among individuals without PTSD (n = 1113), the Met allele was not significantly associated with objective or subjective cognition. These findings suggest that PTSD may moderate the association between Met allele carrier status and cognition. Implications of these results for the mitigation of cognitive dysfunction in older veterans are discussed.

Evaluating the mediating effects of perceived vulnerability to disease in the relation between disgust and contamination-based OCD.

Contamination-based obsessive-compulsive disorder (OCD) is thought to develop and be maintained by excessive propensity to experience disgust, particularly in response to perceived contaminants, and dysfunctional threat appraisals pertaining to illness. The present studies attempted to integrate these lines of research by testing the degree to which contamination-based OCD is associated with individual differences in disgust propensity and sensitivity, affective distress in response to perceived contaminants, and perceived threat of illness. In Study 1, a convenience sample of 185 adults completed self-report scales assessing obsessive-compulsive symptoms, disgust propensity and sensitivity, germ aversion, and perceived infectability. Multivariate regression showed that disgust propensity and germ aversion were the only significant predictors of contamination-based obsessions and compulsions. Exploratory analyses suggested that there was a significant indirect effect of disgust propensity on contamination-based obsessions and compulsions via germ aversion. Findings from Study 1 were replicated using a sample of twenty-six obsessive-compulsive participants. Despite the substantially smaller sample, the proportion of the total effects attributable to the mediating effect of germ aversion was comparable, consistent with a significant partial mediation in both samples. These results together suggest that contamination-based OCD symptoms are likely maintained and motivated by basic affective processes.

The Effect of Trait and State Disgust on Fear of God and Sin.

There is a growing literature suggesting disgust plays a major role in religiosity. However, the relationships between specific domains of disgust sensitivity and general religious fundamentalism or religious scrupulosity remains unknown and a lack of experimental data prevents the drawing of causal inferences about the potential effects of disgust on religiosity. Two studies are reported that examined the relationship between specific types of disgust sensitivity (i.e., pathogen, sexual, and moral disgust) and specific religious beliefs (i.e., fear of sin and fear of God). In the first study it was found that sexual disgust and pathogen disgust were significantly correlated with fear of sin and fear of God, respectively. In the second study the experimental induction of disgust led to greater fear of sin but not to the fear of God. These findings suggest that pathogen and sexual disgust sensitivities may serve as effective mechanisms for inflated scrupulosity. Taken together the outcomes from both studies converge on a greater understanding of the 'Human Behavioral Immune System' model that can account for social behavior with the evolution of adaptive benefit and perhaps more importantly highlights the possible drivers of specific religious behavior.

The effects of depression on the treatment of OCD in a residential sample.

Studies investigating the impact of depressive symptoms on obsessive-compulsive disorder (OCD) treatment have yielded mixed findings. The purpose of the study is to extend previous research, which primarily used outpatient samples, to determine whether depression affects OCD treatment outcome among patients receiving intensive residential treatment. OCD patients receiving residential treatment based primarily on exposure and response prevention (ERP) provided data regarding symptoms of depression and OCD at admission and discharge. Patients reported large and significant reductions in OCD symptoms over the course of treatment. Change in OCD symptoms was not significantly affected by depressive symptoms, including patients with severe depressive symptoms. Change in depressive symptoms over the course of treatment was, however, robustly related to change in OCD symptoms, especially among patients who began treatment with severe symptoms of depression. These findings suggest that cognitive-behavior therapy delivered in a residential treatment setting drastically reduces OCD symptoms regardless of depressive symptoms.

Posttraumatic Mental Contamination and the Interpersonal Psychological Theory of Suicide: Effects via DSM-5 PTSD Symptom Clusters.

Research has yet to establish a relationship between posttraumatic mental contamination and suicide risk, despite theoretical overlap. The present study examined relationships between posttraumatic mental contamination and suicide risk via posttraumatic stress symptom clusters and appraisals of perceived burdensomeness and thwarted belongingness. Trauma-exposed participants (N=183) completed measures of posttraumatic mental contamination, posttraumatic stress symptoms, thwarted belongingness, perceived burdensomeness, and suicide risk. Findings revealed significant indirect effects of posttraumatic mental contamination on suicide risk via all posttraumatic stress symptom clusters. Significant serial indirect effects of posttraumatic mental contamination on suicide risk were observed via posttraumatic avoidance and arousal/reactivity and, subsequently, via thwarted belongingness and perceived burdensomeness. Serial models via posttraumatic re-experiencing and negative cognitions/mood symptoms were nonsignificant. Results suggest that posttraumatic mental contamination may increase suicide risk via posttraumatic stress symptom severity, and maladaptive interpersonal appraisals may explain these links through distinct symptom pathways. Implications for posttraumatic suicide risk are discussed.

Disgust sensitivity mediates the effects of race on contamination aversion.

African Americans report greater contamination aversion than European Americans. Few studies have attempted to identify potential causes for this elevated contamination aversion, though existing research and theory suggests this may be partly due to concomitant heightened disgust sensitivity. The present study examined the relations between race, disgust sensitivity, and contamination aversion among African and European Americans. A convenience sample of fourhundred and twenty-nine participants completed the Disgust Scale - Revised (DS-R) and the Padua Inventory - Revised (PI-R). African Americans endorsed greater disgust sensitivity (DS-R total) - particularly on the core and contamination subscales of the DS-R - and scored higher on the contamination subscale of the PI-R (but not on other subscales) than European Americans. Mediational analyses revealed a significant total effect of race on contamination aversion and a significant indirect effect of race on contamination aversion through disgust sensitivity; the direct effect of race on contamination aversion remained significant even after controlling for race. These findings suggest that elevated contamination aversions among African Americans may be partly due to elevated disgust sensitivity. If confirmed with larger and clinical samples, and more robust experimental methods, this relationship may prove to have implications for the treatment of contamination-based obsessive-compulsive disorder (OCD) among African Americans.

Developing image sets for inducing obsessive-compulsive checking symptoms.

Visual stimuli are often used for obsessive-compulsive (OC) symptom provocation in research studies. We tested the induction of anxiety and OC checking symptoms across different types of checking provocation stimuli in three populations: individuals with obsessive compulsive disorder (OCD), individuals with checking symptoms but without a diagnosis of OCD, and control individuals with neither checking symptoms nor a clinical diagnosis. One set of provocative images depicted objects that are commonly associated with checking anxiety. Another set ('enhanced provocative images') depicted similar objects but also included contextual cues suggesting a specific harmful scenario that could occur. As expected, the enhanced provocative images were more effective at inducing anxiety and OC symptoms than the standard provocative images. Future studies requiring checking symptom provocation should therefore consider incorporating similarly suggestive images. Individuals with clinical OCD reported the greatest provocation in response to these images, followed by those with nonclinical checking, followed by control individuals. Thus, these stimuli are able to provoke OC checking symptoms and anxiety differentially across groups, with the intensity of provocation reflecting diagnostic status. All groups demonstrated a similar qualitative pattern of provocation across images. Finally, in all groups, reported anxiety closely tracked intrusive thoughts and checking urges.

Posttraumatic Stress Disorder: an integrated overview and neurobiological rationale for pharmacology.

Thirty years of research on the biology of posttraumatic stress disorder now provides a foundation for hypotheses related to the mechanisms underlying the pharmacotherapy of this disorder. Only two medications, sertraline and paroxetine, are approved by the U.S. Food and Drug Administration for the treatment of PTSD. While these medications are somewhat effective, other treatment mechanisms must be explored to address the unmet need for effective treatment. This article provides a concise summary of advances in our understanding of the neurobiology of PTSD that suggest novel approaches to pharmacotherapy.

Spatial Scaling of the Profile of Selective Attention in the Visual Field.

Neural mechanisms of selective attention must be capable of adapting to variation in the absolute size of an attended stimulus in the ever-changing visual environment. To date, little is known regarding how attentional selection interacts with fluctuations in the spatial expanse of an attended object. Here, we use event-related potentials (ERPs) to investigate the scaling of attentional enhancement and suppression across the visual field. We measured ERPs while participants performed a task at fixation that varied in its attentional demands (attentional load) and visual angle (1.0° or 2.5°). Observers were presented with a stream of task-relevant stimuli while foveal, parafoveal, and peripheral visual locations were probed by irrelevant distractor stimuli. We found two important effects in the N1 component of visual ERPs. First, N1 modulations to task-relevant stimuli indexed attentional selection of stimuli during the load task and further correlated with task performance. Second, with increased task size, attentional modulation of the N1 to distractor stimuli showed a differential pattern that was consistent with a scaling of attentional selection. Together, these results demonstrate that the size of an attended stimulus scales the profile of attentional selection across the visual field and provides insights into the attentional mechanisms associated with such spatial scaling.