Personalized Neuromodulation Targeting Dysregulated Motivational Responses Underlying Social Avoidance Behavior

PROJECT SUMMARY/ABSTRACT Social avoidance behavior (SAB) plays a critical role in the development, maintenance, and chronicity of internalizing disorders such as Major Depressive Disorder (MDD) and Social Anxiety Disorder (SAD). Although current treatments reduce internalizing symptoms, these treatments fail to reduce SAB, which contributes to symptom re-occurrence. Thus, there is an urgent need for innovative approaches that effectively reduce SAB in patients with internalizing disorders. Preliminary data suggest that SAB is associated with dysregulated approach-avoidance (AA) motivational responses to co-occurring social reward and social threat (i.e., social reward-threat conflict). Dysregulated AA motivational responses are associated with disrupted task-related connectivity between the pregenual anterior cingulate (pgACC) and dorsolateral prefrontal cortex (dlPFC) as well as weakened intrinsic connectivity between the larger Salience Network (SN) and Default Mode Network (DMN) systems. Thus, the immediate goal of this proposal is use transcranial magnetic stimulation (TMS) to causally modulate patient-specific pgACC-dlPFC dysfunction during AA motivational responses and intrinsic SN-DMN dysfunction in patients with MDD (n = 20) or SAD (n = 20). The long-term goal of this proposal is to develop neuroscience-guided interventions that reduce SAB by remediating patient-specific neural circuit dysfunction. To meet this goal, the candidate proposes training objectives supported by a mentorship team with expertise in 1) basic and translational applications of TMS (Dr. Michael Esterman and Dr. Joan Camprodon), 2) neural connectomics and individualized brain mapping (Dr. Jorge Sepulcre and Dr. Mark Halko), and 3) conducting and evaluating clinical trials for experimental therapeutics (Dr. Charles Taylor and Dr. Thomas Travison). The central hypothesis of the proposed research is that TMS protocols over patient- specific right dlPFC targets will rescue (continuous theta-burst; cTBS) or not modulate (sham) dysregulated AA motivational responses and task-related pgACC-dlPFC connectivity to social reward-threat conflict as well as intrinsic SN-DMN connectivity. Thus, the current study proposes a cross-over clinical trial with specific aims to characterize transdiagnostic effects of personalized cTBS on these processes. This approach is innovative because it uses personalized neuromodulation guided by both patient-specific neural network topography and functionality underlying dysregulated motivational processes. The proposed study is significant because it has the potential to advance our understanding of the pathophysiology of SAB and provide crucial data towards developing a precision-medicine approach that utilizes personalized neuromodulation to effectively target and reduce SAB. In sum, the candidate is fully committed to using the proposed project and training plan to build an independent program of neuroimaging and neuromodulation research to delineate and remediate neural circuitry underlying social dysfunction across internalizing disorders.