3 - (SYM 4) Mechanisms of Action of Exposure and Response Prevention on Fear Extinction Behavioral and Circuit Processes in OCD

Fear extinction is a critical dimension in the pathophysiology of obsessive-compulsive disorder (OCD) and an important treatment target. Effective treatments for OCD are available, but the degree to which individuals respond is variable, and the prevalence of treatment-resistant patients remains high. In the current parallel-design mechanistic clinical trial, we examined the therapeutic modulation of exposure and response prevention (ERP) on fear extinction circuit dynamics in OCD to identify mechanisms of action and response biomarkers. Thirty-four patients with OCD were randomized to either 12-weeks of ERP or a waitlist control condition. Before (“Time 1”), during (week 4; “Time 2” for waitlist), and 12-weeks after treatment (“Time 2” for ERP), patients were assessed using functional magnetic resonance imaging (fMRI) during a 2-day fear extinction paradigm that assessed fear conditioning, extinction learning, and extinction recall (Milad et al., 2013). Neural activation was examined in disease- and construct-relevant circuits and nodes. The ERP group had a significant reduction in OCD symptom severity pre- to post-treatment compared to waitlist (EMM difference: 6.23, 95% Confidence Interval (CI): [1.48, 10.98], p</span>=.012). A voxel-wise GLM analysis of fMRI data Time 2 – Time 1 during fear conditioning revealed clusters of ERP >waitlist activation in the left dorsal amygdala (p=.006, 95% CI [.005, .007]), two clusters in the right dorsal amygdala (p=.016, 95% CI [.015, .018]; p=.031, 95% CI [.028, .033]), and a cluster in the right hippocampus (p=.035, 95% CI [.033, .038]). During extinction learning, we found a significant cluster of ERP >waitlist activation in the right ventrolateral prefrontal cortex within the salience network (p=.043, 95% CI [.04, .045]). These changes in activation did not correlate with OCD severity changes, however. In contrast, reduction in the activation of the left supramarginal gyrus (in the executive control network) during extinction recall correlated with OCD symptom improvement, (Z= 2.7, p=.046, 95% CI [.044, .049]), suggesting a possible role as a response biomarker. This study highlights the relevance of a dimensional approach focused on fear extinction for biomarker discovery in neuropsychiatry, provides insights into the circuit mechanisms of action of ERP in OCD, and identifies a potential treatment target in the parietal cortex that could support the biomarker-driven development of novel circuit therapies (e.g., brain stimulation protocols), including combination treatments with ERP.