Faculty Bibliography

BACKGROUND:Recent evidence suggests that repetitive transcranial magnetic stimulation (rTMS) might be effective in treating generalized anxiety disorder (GAD). Cognitive models of GAD highlight the role of intolerance of uncertainty (IU) in precipitating and maintaining worry, and it has been hypothesized that patients with GAD exhibit decision-making deficits under uncertain conditions. Improving understanding of the neural mechanisms underlying cognitive deficits associated with IU may lead to the identification of novel rTMS treatment targets and optimization of treatment parameters. The current report describes two interrelated studies designed to identify and verify a potential neural target for rTMS treatment of GAD. METHODS:Study I explored the integrity of prefrontal cortex (PFC) and amygdala neural networks, which underlie decision making under conditions of uncertainty, in GAD. Individuals diagnosed with GAD (n = 31) and healthy controls (n = 20) completed a functional magnetic resonance imaging (fMRI) gambling task that manipulated uncertainty using high versus low error rates. In a subsequent randomized-controlled trial (Study II), a subset of the GAD sample (n = 16) completed the fMRI gambling task again after 30 sessions of active versus sham rTMS (1 Hz, right dorsolateral prefrontal cortex) to investigate the modulation of functional networks and symptoms. RESULTS:In Study I, participants with GAD demonstrated impairments in PFC-PFC and PFC-amygdala functional connectivity (FC) mostly during the high uncertainty condition. In Study II, one region of interest pair, dorsal anterior cingulate (ACC) - subgenual ACC, showed "normalization" of FC following active, but not sham, rTMS, and neural changes were associated with improvement in worry symptoms. CONCLUSIONS:These results outline a possible treatment mechanism of rTMS in GAD, and pave the way for future studies of treatment optimization.

Generalized anxiety disorder (GAD) and social anxiety disorder (SAD) are currently considered distinct diagnostic categories. Accumulating data suggest the study of anxiety disorders may benefit from the use of dimensional conceptualizations. One such dimension of shared dysfunction is emotion regulation (ER). The current study evaluated dimensional (ER) and categorical (diagnosis) neurocorrelates of resting-state functional connectivity (rsFC) in participants with GAD and SAD and healthy controls (HC). Functional magnetic resonance imaging (fMRI) rsFC was estimated between all regions of the default mode network (DMN), salience network (SN), and bilateral amygdala (N = 37: HC-19; GAD-10; SAD-8). Thereafter, rsFC was predicted by both ER, (using the Difficulties in Emotion Regulation Scale [DERS]), and diagnosis (DSM-5) within a single unified analysis of covariance (ANCOVA). For the ER dimension, there was a significant association between impaired ER abilities and anticorrelated rsFC of amygdala and DMN (L.amygdala-ACC: p = 0.011, beta = -0.345), as well as amygdala and SN (L.amygdala-posterior cingulate cortex [PCC]: p = 0.032, beta = -0.409). Diagnostic status was significantly associated with rsFC differences between the SAD and HC groups, both within the DMN (PCC-MPFC: p = 0.009) and between the DMN and SN (R.LP-ACC: p = 0.010). Although preliminary, our results exemplify the potential contribution of the dimensional approach to the study of GAD and SAD and support a combined categorical and dimensional model of rsFC of anxiety disorders.

BACKGROUND:The Overall Anxiety Severity and Impairment Scale (OASIS) is a brief, transdiagnostic measure used to assess anxiety severity and related interference. The OASIS has demonstrated strong psychometric properties in previous investigations, however, it has yet to be validated using a transdiagnostic clinician-rated measure. METHODS:We evaluated the factor structure, convergent and discriminant validity, and illness severity cut-scores of the OASIS in a sample of outpatients (N=202). RESULTS:A confirmatory factor analysis indicated an unidimensional structure provided the best fit. The OASIS demonstrated good convergent validity and internal consistency. Using the Clinical Global Impression-Severity Scale (CGI-S), ROC curves showed OASIS scores of 6, 10 and 12 to indicate moderate, marked and severe illness severity, respectively. CONCLUSIONS:The OASIS is a unidimensional self-report measure with good convergent validity and data from the current study provide illness severity cut-scores.

BACKGROUND:Repetitive transcranial magnetic stimulation (rTMS) holds promise for treating generalised anxiety disorder (GAD) but has only been studied in uncontrolled research. AIMS:This is the first randomised controlled trial (clinicaltrials.gov: NCT01659736) to investigate the efficacy and neural correlates of rTMS in GAD. METHOD:Twenty five participants (active n = 13; sham, n = 12) enrolled. rTMS was targeted at the right dorsolateral prefrontal cortex (DLPFC, 1 Hz, 90% resting motor threshold). RESULTS:Response and remission rates were higher in the active v. sham groups and there were significant group × time interactions for anxiety, worry and depressive symptoms, favouring active v. sham. In addition, right DLPFC activation during a decision-making gambling task increased at post-treatment for active rTMS only, and changes in neuroactivation correlated significantly with changes in worry symptoms. CONCLUSIONS:Findings provide preliminary evidence that rTMS may improve GAD symptoms in association with modifying neural activity in the stimulation site.

Internet-guided self-help (iGSH) has amassed significant empirical support for a variety of psychiatric conditions; however, it is not known who responds best to these treatments. This open trial examined the clinical outcomes and predictors of a 17-week iGSH program for obsessive-compulsive disorder (OCD). Therapist support was provided either in person or by phone 9 times for an average of 13minutes per session. Twenty-four patients initiated treatment, and 17 of these (70.8%) completed. Results of the intent-to-treat sample indicated statistically significant improvements at posttreatment with large treatment effects for OCD symptoms as assessed by the Yale Brown Obsessive-Compulsive Scale (d=0.87), and small to moderate improvements in depression (d=0.19), functioning (d=0.53), and quality of life (d=-0.18). These outcomes were largely maintained over a 6-month follow-up. Readiness to reduce avoidance of OCD triggers and attendance to therapist sessions were moderately associated with posttreatment response, and correctly classified the responder status (defined as clinically significant change) of nearly 9 out of 10 patients at posttreatment. These same variables did not predict responder status at 6-month follow-up. These results lend further empirical support to iGSH as a treatment for OCD and provide direction on the development of predictor models to identify patients who are and are not likely to acutely respond to iGSH.