Neurophysiological investigation of the approach-avoidance axis in OCD: applications to neuromodulation - Obsessive-compulsive disorder (OCD) has a lifetime prevalence of 2-3% and is a major cause of global disability. OCD is characterized by obsessions (i.e., unwanted intrusive thoughts) and compulsions (i.e., repetitive ritualistic behaviors) and exemplifies a pathologically avoidant phenotype where greater degrees of avoidance are associated with greater symptom severity and treatment resistance. In the 20-40% of OCD patients that are treatment refractory, deep brain stimulation (DBS) of the ventral capsule and ventral striatum (VC/VS) is an effective therapy that achieves significant benefit in 66% of patients. While VC/VS DBS does not acutely relieve OCD symptoms, DBS often produces a “pro-approach” response including an increase in talkativeness, a desire to engage in activities, extroversion, and affiliative behavior. Our central therapeutic hypothesis is that VC/VS DBS achieves eventual benefit in OCD by providing the “boost” in pro-approach behavior that allows individuals to overcome their pathological fear-based avoidance. Thus, we focus on the approach-avoidance axis as one of the critical neurobehavioral axes underlying the pathophysiology of OCD. Our overall goal is to develop a mechanistic understanding of DBS for OCD by rigorously investigating the relationship between clinical symptoms, behaviors (i.e., approachful vs. avoidant), and neurophysiology. Based on our preliminary data from on-device DBS recordings in OCD patients, we hypothesize that greater variability in neural activity in the VS, a structure known to influence motivated goal-directed behavior, allows the agent to shed maladaptive ritualistic behavior in favor of reasoned behavior aligned with long-term goals. In other words, the transition from repetitive, ritualistic actions in the symptomatic state to more adaptive and flexible behaviors after response is accompanied by increased dispersion and decreased predictability of VS activity. In 10 patients with recording-capable DBS devices, we will collect a broad array of neurobehavioral data in the clinic and the home. The first 2 Aims test our hypothesis by studying the pattern of VS neural activity in the controlled environment of the lab/clinic during two complementary paradigms: one based on a psychophysical behavioral task, the other based on exposure and response prevention, a therapeutic behavioral intervention. The third aim tests this hypothesis in an ambulatory, naturalistic setting with chronic neural on-device recordings paired with time resolved behavioral measures from wearables (e.g., sleep, heart rate, activity) and video diaries (e.g., facial affect, speech). We will investigate a possible common neural basis underlying approach and avoidance across these 3 paradigms. These data will allow us to use VS intracranial recordings to inform and validate the approach-avoidance framework and investigate the degree of explanatory power this framework has for OCD. By understanding the therapeutic mechanism driving OCD symptom improvement after VC/VS DBS, we will pave the way for rigorous, data-driven neuromodulatory strategies to regulate behavior and ameliorate symptoms in other disorders characterized by dysregulated approach-avoidance behavior.
