Electrophysiological biomarkers to guide deep brain stimulation treatment in obsessive-compulsive disorder

/ABSTRACT Obsessive-compulsive disorder (OCD) is a severe psychiatric illness affecting 1–3% of the population, causing debilitating distress and impairing everyday functioning. Up to 20% of individuals with OCD remain severely symptomatic despite standard treatments, making deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) a promising neurosurgical option. However, DBS therapy for OCD remains challenging due to the absence of objective, reliable neural biomarkers of symptom severity, leading to prolonged trial-and-error programming, unpredictable clinical outcomes, and limited access for eligible patients. Early intracranial electrophysiology studies have shown that neural activity in the VC/VS is closely linked to OCD pathophysiology, with low-frequency VC/VS oscillations reflecting processes such as symptom intrusions, error monitoring, and reward processing. These discoveries have advanced our understanding of OCD neurophysiology. Recent advances in sensing-enabled DBS technology now offer a unique opportunity to chronically record neural oscillations (local field potentials, LFPs) directly from DBS electrodes in freely moving patients, enabling longitudinal, real-world tracking of neural activity. Yet critical questions remain regarding the robustness, ecological validity, and clinical utility of VC/VS oscillations as biomarkers of OCD symptom states. This project aims to rigorously establish VC/VS alpha oscillations as an objective biomarker for OCD symptom states and translate this knowledge into clinical practice. First, I will determine whether chronic fluctuations in VC/VS alpha oscillations systematically track real-world transitions between symptomatic and non-symptomatic states by combining at-home DBS recordings with wearable sensor-based behavioral tracking and ecological momentary assessments. Next, I will leverage intraoperative neural recordings—uniquely available during DBS implantation surgeries—to map acute electrophysiological responses in the VC/VS and related frontal circuits during personalized symptom-provocation tasks, providing functional guidance for surgical lead placement. Finally, I will operationalize VC/VS alpha oscillations as a practical biomarker during outpatient DBS programming, using immersive virtual reality-based OCD symptom challenges combined with real-time neural and physiological measurements to identify optimal stimulation parameters. In addition, this award will allow me to complete a multifaceted career development plan. Since my background is primarily in engineering and my clinical exposure to OCD patients is limited, I will acquire fundamental clinical knowledge of OCD symptom dimensions and standard inpatient and outpatient treatments, facilitating the integration of clinical and research efforts. My training will be guided by leading experts at MGH, one of the world’s leading institutions in the clinical and research work with this patient population. I will further attend seminars and conferences, to develop not only a researcher, but also as an independent leader and science communicator. Together, this will provide me with the necessary set of skills for my transition to independence. Project Number: 1K99MH144561-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Matteo Vissani | Institution: MASSACHUSETTS GENERAL HOSPITAL, BOSTON, MA | Award Amount: $129,195 | Activity Code: K99 | Study Section: Special Emphasis Panel[ZRG1 CN-F (91)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11350446