Neural mechanisms of anxiety during early and protracted abstinence in alcohol use disorder

Project Summary: Alcohol use disorder (AUD) is a chronic, neuropsychiatric illness characterized by frequent relapses, driven in part by anxiety during abstinence. Identifying the neural mechanisms that underlie anxiety during abstinence may identify targets for novel treatments. The aims in this proposal will train Dr. Srivastava to be uniquely qualified to conduct this research. While pursuing this line of research under the guidance of mentors who are recognized experts in clinical trials in substance use disorders and co-occurring psychiatric illness (Frances Levin, MD), fMRI methodology (Gaurav Patel, MD, PhD), and addiction neuroscience and psychophysiology (Nasir Naqvi, MD, PhD), Dr. Srivastava will engage in a comprehensive training program in the following areas: 1) learning clinical trials methodology to conduct mechanistic research in AUD and co- occurring psychiatric illnesses, 2) fMRI methodology, 3) addiction neuroscience and psychophysiology, and 4) grant writing and management skills. This training will build upon Dr. Srivastava’s training as an addiction psychiatrist who has significant experience treating AUD but relatively little experience in clinical research. To facilitate this training, Dr. Srivastava will investigate how alterations in anxiety circuitry involving the bed nucleus of the stria terminalis (BNST), anterior insula (AI) and dorsolateral prefrontal cortex (DLPFC) may underlie anxiety during abstinence from alcohol and how this circuitry might change as a function of sustained abstinence. This proposal combines 1) participants with AUD stabilized on disulfiram to facilitate abstinence, 2) functional MRI (fMRI) experiments that probe neural activity related to anxiety, and 3) psychophysiological markers of stress and anxiety. AI-BNST and AI-DLPFC connectivity will be investigated using resting state functional connectivity (RSFC), and AI, BNST, and DLPFC activations will be investigated using a threat anticipation task. The fMRI studies will be performed between 1-2 weeks after stabilization on disulfiram order to capture early abstinence and then after 12 weeks of treatment, with the goal of determining 1) if anxiety circuit connectivity and task-evoked activation during unpredictable threat anticipation in early abstinent AUD participants differ from healthy control participants, 2) if anxiety circuit connectivity and task-evoked activation correlate with self-report measures of state anxiety during early abstinence, 3) if anxiety circuit connectivity and task-evoked activation change over the course of abstinence, and 4) if changes over the course of abstinence in anxiety circuit connectivity and task-evoked activation correlate with changes in self-report measures of state anxiety. Thus, the K23 award will support an innovative and clinically relevant program of patient-oriented research while training Dr. Srivastava in critical skills that will ensure his development into an independent translational researcher who leads future studies on mechanisms underlying abstinence in AUD and co- occurring psychiatric illnesses.