ABSTRACT Introduction: Treatment–refractory obsessive–compulsive disorder (trOCD) is a complex brain network disorder that remains partially understood and may require personalized treatment strategies due to disease heterogeneity. While stereo–electroencephalography (sEEG) is standard of care for surgical epilepsy workups, its use in refractory neuropsychiatric disorders remains investigational. A multi–site, multi–stage, double–blinded, randomized crossover clinical trial is currently underway, using sEEG to guide selection of multi–nodal targets for subsequent deep brain stimulation (DBS) in the treatment of trOCD. Objectives: To describe the study design of this ongoing clinical trial, with an emphasis on personalized surgical targeting strategies that ensure both the feasibility and precision of sEEG electrode placement, and enable adequate sampling of relevant targets in trOCD for network evaluation and modulation. Methods: Adult patients with severe trOCD (Yale–Brown Obsessive Compulsive Scale ≥ 28) who meet eligibility criteria will be enrolled in this study. The clinical trial (NCT05623306) involves three stages. In stage 1, up to 20 sEEG electrodes will be implanted in cortical and subcortical regions implicated in trOCD. Individualized probabilistic–tractography–guided target refinement will be performed for surgical planning. To ensure surgical feasibility of non–conventional surgical trajectories, patient–specific three–dimensional (3D) printed head models may be used for surgical rehearsal. Continuous and synchronous audiovisual and intracranial electroencephalographic (iEEG) recordings will be performed in the psychiatric monitoring unit. Participants undergo psychologist–led symptom provocations, brain stimulation evoked potential mapping, acute stimulation testing and cognitive tasks over a 12-day inpatient evaluation. In stage 2, up to four permanent DBS electrodes will be implanted followed by stimulation optimization for up to 52 weeks. Stage 3 involves a randomized, double-blinded cross–over phase. Expected Outcomes: Safety, feasibility and preliminary efficacy will be assessed in this ongoing study. Primary safety endpoints include the number and type of serious adverse events. Feasibility endpoints include percentage of patients in whom OCD–relevant network or stimulation target can be identified. Treatment response will be determined by change in Y-BOCS II score between active and sham stimulation conditions. We anticipate that sEEG to guide selection of multi-nodal targets for DBS will be safe, feasible and result in clinically meaningful improvements in symptom severity and functional impairment in trOCD. Discussion: We present the clinical protocol of sEEG–guided investigation of brain networks involved in trOCD and describe our tractography–guided surgical targeting strategy designed to optimize individualized network engagement and neuromodulation.

This study is funded by the Foundation for OCD Research (FFOR) and AE Foundation who are not involved in any data acquisition or analysis of the study. R.L.S is supported by NINDS T32NS091008 and NIMH R25MH119043 grants. L.Q is supported by the Brain & Behavior Research Foundation as the Ellen Schapiro & Gerald Axelbaum Investigator. K.W.S is a consultant for J&J. C.H.H is supported by the National Institute of Health (5UH3NS103446-02 and U01NS117838) and has patents related to sensing and brain stimulation for the treatment of neuro-psychiatric disorders in general (USPTO serial number: 63/170,404 and 63/220,432; international publication number: WO 2022/212891 A1) as well as use of tractography for circuit-based brain stimulation (USPTO serial number: 63/210,472; international publication number: WO 2022/266000). He is a consultant for Boston Scientific, Abbott, Medtronic, and Insightec and receives honoraria for educational lectures. The other authors declare no competing interests.

NCT05623306

This Study was funded by the Foundation for OCD Research (FFOR) and AE Foundation

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