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.
Competing Interest StatementThis 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.
Clinical TrialNCT05623306
Funding StatementThis Study was funded by the Foundation for OCD Research (FFOR) and AE Foundation
Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
IRB of the University of Pennsylvania gave ethical approval for this work.
I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.
Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
Yes
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FootnotesDisclosures / Funding 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.
Administrative Information
Title: A Double-Blinded, Randomized, Crossover Trial of Stereoencephalography- Guided Multi-Lead Deep Brain Stimulation for Treatment-Refractory Obsessive- Compulsive Disorder
Trial Acronym: SEEG-Guided DBS for OCD
Trial Registration: NCT05623306 (registration date: 2022-10-14)
Protocol version: 12.1 (17th December 2024)
Funding: Foundation for OCD Research (FFOR) and AE Foundation
Primary Sponsor: Casey H. Halpern, MD
Trial Design: Multi-stage, double-blinded randomized crossover study
Date of first enrollment: 2023-04-13
Study setting: Academic hospital
Country of recruitment: United States of America
Study population: Adult participants suffering from severe symptoms of chronic, treatment-refractory OCD
Ethic Review: Approved by the University of Pennsylvania Institutional Review Board
Estimated Completion Date: 2027-01-01
Estimated Enrollment: 10
Recruitment Status: Active recruitment
Primary Outcome(s): Change in Yale-Brown Obsessive-Compulsive Scale II (Y-BOCS II)
Secondary Outcomes(s): Y-BOCS I, Obsessive-Compulsive Inventory (OCI), Montgomery- Asberg Depression Rating Scale (MADRS), Structured Hamilton-A, Visual Analogue Scales (Obsessions, Compulsions, Depression, Anxiety, Energy, and Stress), Patient Global Impression – Change Scale (PGI-C), Global Assessment of Functioning Scale (GAF), and CGI-I
Data AvailabilityAll data produced in the present work are contained in the manuscript.
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