Stereo-encephalography-guided multi-lead deep brain stimulation for treatment-refractory obsessive compulsive disorder – study design and individualized surgical targeting approach

Stereo-encephalography-guided multi-lead deep brain stimulation for treatment-refractory obsessive compulsive disorder – study design and individualized surgical targeting approach | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Stereo-encephalography-guided multi-lead deep brain stimulation for treatment-refractory obsessive compulsive disorder – study design and individualized surgical targeting approach Robert L. Seilheimer , View ORCID Profile Liming Qiu , View ORCID Profile Giovanna Rocchio , Young-Hoon Nho , Gustavo Campos , View ORCID Profile Andreas Horn , Camarin E. Rolle , Vivek P. Buch , T. Mindy Ganguly , Mario Cristancho , View ORCID Profile Desmond J. Oathes , Lily Brown , Bijan Pesaran , Andrew D. Krystal , View ORCID Profile Eddie F. Chang , Moses E Lee , Kai J. Miller , View ORCID Profile Nolan R. Williams , Daniel A.N. Barbosa , Katherine W. Scangos , Casey H. Halpern doi: https://doi.org/10.1101/2025.04.17.25325961 Robert L. Seilheimer 1 Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA 2 Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Liming Qiu 2 Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Liming Qiu Giovanna Rocchio 2 Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Giovanna Rocchio Young-Hoon Nho 2 Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Gustavo Campos 2 Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Andreas Horn 3 MGH Neurosurgery & Center for Neurotechnology and Neurorecovery (CNTR) at MGH Neurology Massachusetts General Hospital , Harvard Medical School, Boston, MA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Andreas Horn Camarin E. Rolle 4 Department of Psychiatry and Behavioral Sciences, Stanford University , Palo Alto, CA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Vivek P. Buch 5 Department of Neurosurgery, Stanford University , Palo Alto, CA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site T. Mindy Ganguly 6 Department of Neurology, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Mario Cristancho 1 Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Desmond J. Oathes 1 Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Desmond J. Oathes Lily Brown 1 Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Bijan Pesaran 2 Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA 7 Department of Bioengineering, University of Pennsylvania , Philadelphia, PA, USA 8 Department of Neuroscience, University of Pennsylvania , Philadelphia, PA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Andrew D. Krystal 9 Department of Psychiatry and Behavioral Sciences, University of California , San Francisco, CA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Eddie F. Chang 10 Department of Neurological Surgery, University of California , San Francisco, CA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Eddie F. Chang Moses E Lee 10 Department of Neurological Surgery, University of California , San Francisco, CA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kai J. Miller 11 Department of Neurosurgery, Mayo Clinic , Rochester, MN, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Nolan R. Williams 4 Department of Psychiatry and Behavioral Sciences, Stanford University , Palo Alto, CA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Nolan R. Williams Daniel A.N. Barbosa 12 Departments of Neurology, Psychiatry and Behavioral Sciences, Medical University of South Carolina , Charleston, SC, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Katherine W. Scangos 1 Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA 2 Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Casey H. Halpern 1 Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA 13 Department of Surgery, Corporal Michael J. Crescenz Veterans Affairs Medical Center , Philadelphia, PA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: casey.halpern{at}pennmedicine.upenn.edu Abstract Full Text Info/History Metrics Data/Code Preview PDF ABSTRACT Introduction Treatment-refractory obsessive-compulsive disorder (trOCD) is a complex network disorder that may require personalized treatment strategies due to disease heterogeneity. A multi-site, multi-stage, double-blinded, randomized crossover clinical trial is underway, using stereo electroencephalography (sEEG) to guide selection of multi-nodal targets for deep brain stimulation (DBS) for trOCD. Objectives To describe the clinical trial design, emphasizing personalized surgical targeting strategies that ensure the feasibility and precision of sEEG electrode placement, and enable adequate sampling of relevant targets in trOCD for network evaluation and modulation. Methods Adults with severe trOCD (Yale-Brown Obsessive Compulsive Scale ≥ 28) who meet eligibility criteria are enrolled in this three-stage clinical trial ( NCT05623306 ). Stage 1 involves SEEG electrode implantation in trOCD implicated regions and inpatient evaluation. Individualized probabilistic-tractography-guided target refinement is performed for surgical planning. Multimodal recordings are taken while participants stay in the psychiatric monitoring unit for 12 days. In stage 2, up to four permanent DBS electrodes are implanted followed by stimulation optimization. Stage 3 is the randomized, double blinded cross over phase. Expected Outcomes Safety, feasibility and preliminary efficacy will be assessed in this ongoing study. We anticipate that the use of 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. INTRODUCTION & STUDY RATIONALE Obsessive-compulsive disorder (OCD) is a common psychiatric disorder with a lifetime prevalence of 2.3% in the United States and can lead to significant disability 1 , 2 . Despite the availability of evidence-based psychotherapy and pharmacotherapy, only an estimated 30-40% of OCD patients seek treatment, and less than half of these patients respond and few patients achieve remission with conventional interventions 1 . Of note, an accepted favorable treatment response is defined as a reduction of Yale-Brown Obsessive Compulsive Scale (Y-BOCS) of 25-35% 3 . Deep brain stimulation (DBS) targeting the anterior limb of the internal capsule (ALIC) is a Food and Drug Administration (FDA)-approved surgical intervention for treatment-refractory OCD (trOCD), under a Humanitarian Device Exemption (HDE) since 2009, but overall remains investigational 4 . Not surprisingly, outcomes of DBS in trOCD vary considerably, and the optimal stimulation target remains a subject of study amongst experts in the field 5 – 7 . A recent meta-analysis of 34 DBS trials in OCD comprising 352 patients with heterogenous stimulation sites (including ALIC, ventral capsule/ventral striatum, nucleus accumbens, bed nucleus of striae terminalis and subthalamic nucleus) reported an overall responder rate of 66% 8 . While this is approximately two-fold the response rate achieved with medication and psychotherapy, it is possible that optimization of stimulation and target selection could render more robust response rates and potential remissions. OCD is now recognized as a disorder involving dysfunction across multiple, interactive brain networks 9 . While earlier models highlighted the central role of cortico-striato-thalamo-cortical (CSTC) circuitry, more recent work has implicated additional circuits – including limbic, frontoparietal, and salience networks – in contributing to the heterogeneity of OCD presentations 9 , 10 . Crucially, different patients may exhibit dysfunction in distinct circuits, supporting a model of OCD as a network-level disorder with individualized circuit pathology. This heterogeneity may underlie the limited success of DBS to date. Multiple circuit-level aberrancies may give rise to similar phenotypes, while shared circuit dysfunctions may produce divergent symptom profiles, underscoring the need for individualized therapies and patient-specific targeting 11 , 12 . To address this knowledge gap, a novel multi-site, multi-stage clinical trial is currently underway, employing stereo-electroencephalography (sEEG) to guide personalized, network-informed DBS for trOCD. This approach has recently been utilized to understand affective behaviors and personalize stimulation targets in treatment-resistant depression to personalize stimulation targets 13 – 15 . Here, we also describe the individualized targeting strategy used in Stage 1 of the trial, which involves inpatient sEEG monitoring to interrogate brain circuits and identify the optimal patient-specific stimulation targets. STUDY GOALS AND OBJECTIVES The goal of this study is to assess the safety, feasibility, and preliminary efficacy of multi-lead DBS guided by sEEG in 10 participants suffering from severe symptoms of chronic, treatment-refractory OCD. Primary Objectives To determine each patient’s optimal targets involved in OCD symptomatology for DBS To assess the safety profile of a novel DBS approach, based on invasive brain monitoring mapping, compared to sham stimulation To assess the feasibility of a customized, novel DBS approach in brain targets previously defined by invasive brain monitoring in reducing OCD symptoms Secondary Objectives To assess the efficacy of novel stimulation parameters used in invasive brain monitoring to guide stimulation To assess the efficacy of a novel DBS targeting technique, based on invasive brain monitoring mapping, compared to placebo METHODS This clinical trial is registered on clinicaltrials.gov ( NCT05623306 , NCT06347978 ) and first opened enrollment in April 2023. Patients with trOCD who meet eligibility criteria ( Table 1 ) will provide informed consent to participate in this multi-stage study. The study involves an inpatient evaluation with up to 20 implanted intracranial sEEG electrodes (stage 1), followed by implantation of the permanent multi-lead DBS system and optimization of stimulation settings (stage 2). Lastly, participants enter a randomized cross-over study lasting six months to assess the efficacy of DBS therapy (stage 3) ( Figure 1A-B ). The trial is being conducted across three academic institutions working collaboratively: the University of Pennsylvania (Penn), Stanford University and the University of California, San Francisco (UCSF). Download figure Open in new tab Figure 1. (A) Overall study outline of clinical trial of double-blinded, randomized, crossover study of stereo-encephalography guided multi-lead deep brain stimulation for treatment-refractory obsessive-compulsive disorder ( NCT05623306 ). (B) Schematic of activities in stage 1 of clinical trial (sEEG phase). (C) Coronal (left) and mid sagittal view (right) of cortical targets in template space – orbitofrontal cortices (green), ventrolateral prefrontal cortices (yellow), frontal pole (blue), anterior cingulate cortices (orange), amygdala (pink) and hippocampi (purple). (D) Coronal (left) and mid sagittal view (right) of subcortical targets in template space – nucleus accumbens (yellow), ventral pallidum (dark blue), bed nucleus of stria terminalis (red), subthalamic nucleus (green), caudate (light blue). Streamlines of OCD response tract is overlaid in gray. (E) Screenshot of tablet interface for subject’s moment-to-moment input of multi-dimensional symptoms. (F) System set up to allow integration of multi-modal data capture in synchronized fashion. (G) A set of real-world provocation trials was designed by the psychologist, each consisting of 5-minute neutral trials and 5-minute exposure trials, followed by a relaxation/recovery period before the next round (No Stim Trials). During each trial, behavioral symptom ratings were collected every minute on a tablet (arrows). In Stim Trials, selected stimulation was applied during exposure trials to investigate its potential effect on the biomarker and symptom ratings. View this table: View inline View popup Table 1. Major Inclusion and Exclusion Criteria for Subject Recruitment to Parent Clinical Trial Targets Selection for sEEG lead placement Stage 1 sEEG targets were selected through literature review as well as multi-disciplinary discussions and consensus amongst neuroanatomists, neurosurgeons, neuroimaging experts, neurologists, and interventional psychiatrists (see co-author list). Targets included structures within the fronto-striatal limbic circuitry, such as anterior and posterior orbitofrontal cortices, frontal pole, ventrolateral prefrontal cortices, anterior cingulate cortices, anterior limb of the internal capsule, anterior caudate, nucleus accumbens, ventral pallidum, subthalamic nucleus, basolateral amygdala and dorsolateral hippocampus ( Figure 1C-D ) 16 – 18 . As the aim of stage 1 evaluation is to investigate specific circuits of OCD, up to 20 sEEG electrodes are implanted to ensure sufficient coverage of cortical and subcortical regions implicated in OCD-related network dysfunction. Personalized Tractography-Guided Surgical Targeting All participants will undergo high-resolution magnetic resonance imaging (MRI), consisting of T1-weighted Magnetization-Prepared Rapid Gradient-Echo (MPRAGE) with and without gadolinium contrast, T2-weighted, and Fast Gray Matter Acquisition T1 Inversion Recovery (FGATIR) sequences. Multi-shell diffusion-weighted MRI (b=1500, 3000) acquired at 1.5mm isotropic voxels and 64 diffusion directions, along with a reversed phase-encoding b0 (blip-down) image. For each individual subject, the DWI will be pre-processed using the QSIPrep software 19 and co-registered to the structural T1-weighted imaging using boundary-based non-linear registration. Atlas-based anatomical segmentation will be performed following a two-step linear and non-linear co-registration using Advanced Normalization Tools (ANTs) framework with affine and asymmetric normalization 20 . To identify critical subregions within each anatomical structure, probabilistic tractography will be performed using FMRIB Software Library (FSL)’s Probtrackx2 21 . Segmented anatomical structures will serve as seed regions and patient-specific cortical ROIs will be defined as target and waypoint masks for probabilistic tractography. Fiber orientation probability distribution will be estimated using FSL’s Bayesian Estimation of Diffusion Parameters Obtained using Sampling techniques (BEDPOSTX) model, and voxel-wise Monte Carlo sampling (5000 streamlines per voxel). The total number of streamlines reaching each ROI will be defined as the ‘waytotal’. K-means clustering will then be applied to subsegment the critical portions of the anatomical structure to guide electrode placement 22 . These resulting clusters will be converted into DICOM targeting objects using custom scripts and integrated into the Brainlab Stereotaxy Workflow (Brainlab AG, Munich, Germany) 23 . This will enable direct visualization of personalized target in native space for surgical planning ( Figure 2A ). Download figure Open in new tab Figure 2. (A) Individualized probabilistic tractography was performed using high-resolution diffusion-weighted imaging, This illustrates the steps of identifying subregions with highest streamlines within four targets (anterior cingulate cortex, nucleus accumbens, ventral pallidum and subthalamic nucleus. Based on planned trajectories modelled on a standard Montreal Neurological Institute (MNI) template brain (top row), the segmented anatomical targets were used as seeds for probabilistic tractography to target frontal regions of interests. K-means clustering was used to identify subregions with the highest streamlines (yellow) within the target structure (red) (middle row). These subregions were then converted into dicom images and ported into surgical planning software (bottom row). (B) Use of subject-specific 3-dimensional head model to ensure feasibility of all trajectories and to guide frame placement. Live-size head models were 3-d printed and placed in Leksell Vantage frame for surgical rehearsal. Each trajectory was visited. Non-feasible trajectories happened when guide holders collided with stereotactic rings, or if targets exceeded frame coordinates. In such instances, trajectories were noted and revised to ensure feasibility and safety. On the day of procedure, the frame was positioned in the same manner as the model. (C) Postoperative electrodes localization in RAVE software. Left, A representative example of electrodes placement in a single subject. Inserts illustrate the electrode location of one electrode contact in axial and coronal plane. Right, Position of all electrodes from first four participants from UPenn in a standard template MNI brain. Surgical Implantation Stereotactic implantation of sEEG electrodes will be performed under general anesthesia at each clinical trial site, following institutional standard protocol (i.e. frame-based technique using Leksell frame at Penn; robot-assisted with ROSA at Stanford and frame-based approach using Cosman-Roberts-Wells frame at UCSF) 13 , 24 – 26 . On the day of surgery, the participant’s head will be secured to the operative bed and stereotactic frame or robotic guidance system will be positioned. In frame-based cases, a localizer will be attached for coordinate calculation. An intraoperative computed tomography (CT) approximation will be performed using an O-arm (Medtronic, Minneapolis, MN). The CT image will then be registered to the pre-operative MRI, to obtain stereotactic coordinates of each planned trajectory. sEEG electrodes (Ad-Tech, Oak Creek, WI; PMT, Chanhassen, MN) will be implanted sequentially from posterior to anterior entry points, alternating between ipsilateral and contralateral sides. For each trajectory, a stab incision will be made with a #11 blade and a 2.4 mm drill hole made along the planned trajectory with a handheld power drill using a guide holder. An appropriately sized AdTech or PMT anchor bolt will then be placed, followed by passing an obturator to target. The sEEG electrode will then be measured to length, placed to target depth, and secured with a bolt cap. This process will be repeated for all electrodes. Two intraoperative CT will typically be performed, one after half the electrodes are placed, and one post-implantation. All electrode positions will be reviewed for accuracy of electrode position by primary site investigator, and intraoperative adjustments will be made as needed to ensure engagement of the intended anatomical targets. A radial error of less than 1.5mm from the planned trajectory will generally be considered acceptable. Pre-Surgical Rehearsal for the Leksell G Frame At the time of trial initiation, the Leksell G frame was retired, and clinical experience with the newer Leksell Vantage frame was scarce. Unlike its precursor, which allowed more flexible placement (e.g. inverted or mohawk configurations), the Vantage frame imposes more restrictions, particularly for non-conventional surgical trajectories. To ensure surgical feasibility, full-scale 3-dimensional printed head model of each participant was created for pre-operative rehearsals ( Figure 2B ). These models allowed simulation of frame placement and identification of non-feasible trajectories. Any issues can then be addressed in advanced and rectified to avoid intraoperative complications. Postoperative Electrode Localization After electrode implantation, a high-resolution, full-tissue-range head CT will be obtained. The CT will be co-registered to pre-operative MRI using BrainLAB elements as well as YAEL module of Reproducible Analysis and Visualization of iEEG software (RAVE) 27 , 28 . This enables calculation of precise 3D coordinates of each sEEG electrode, supporting downstream analyses ( Figure 2C ). Neuro-Psychiatric Monitoring Unit Evaluation Following sEEG surgery, participants will be admitted to the neuro-psychiatric monitoring unit for intensive evaluation ( Figure 1B ). Over a 12-day inpatient stay, they will undergo a series of assessments, including single-pulse brain evoked potential connectivity assessments, psychologist-led OCD symptom provocations, acute stimulation assessments, and computer-based cognitive tasks ( Table 2 ). Throughout the evaluation period, participants will use a tablet to provide moment-to-moment self-ratings of obsessive and compulsive symptoms, mood, energy, anxiety, and distress levels using visual analog scales ( Figure 1E ). All behavioral tasks are synchronized with electrophysiological recordings using digital inputs through the BCI2000 software platform 29 and g.tec system (g.tec medical engineering GmbH, Schiedlberg, Austria) ( Figure 1F ). This multi-modal data collection enables detailed mapping of symptom-related brain network activity and biomarker identification across fluctuating symptom states for each participant. Following data collection, electrodes will be removed percutaneously at the bedside using aseptic techniques. View this table: View inline View popup Table 2. Description of Computer-based Cognitive Tasks i) Acute electrical stimulation testing A systematic safety screening will be performed for all bipolar contact pairs using both high-frequency (100-130Hz) and low-frequency (5Hz) stimulation, at 90μs with current ranging from 0.5-6mA over 5-seconds trials. Continuous electrophysiological, video, and behavioral monitoring will be conducted during testing by a study physician and epileptologist. Electrophysiological after-discharges and any adverse clinical effects will be recorded and defined as stimulation thresholds for the remainder of the study. Following safety validation, contact configurations will be chosen for further stimulation testing based on the relationship to targets of interests, DTI streamlines, and connectivity profiles. Selected contacts will be tested for 30-second stimulation trials and the behavioral effects will be recorded via tablet. If no adverse effects occurred, longer stimulation trials of 60-seconds, 5-minutes,10-minutes, or 20-minutes will be conducted to assess for behavioral responses. Once candidate targets are identified, randomized sham-controlled trials will be performed. Combinatorial stimulation across multiple contact pairs will also be evaluated. Both the participant and assessing physician are to be blinded to the stimulation site and condition (sham vs. active); only the study member delivering stimulation will remain unblinded. ii) Psychologist-led individualized OCD Exposure Prior to start of stage 1, a trained clinical psychologist or psychiatrist will conduct a comprehensive interview to identify each participant’s OCD symptom domains and relevant triggers. This clinician will collaborate with the study team to design personalized exposure tasks, consisting of five-minute-long neutral condition (to account for the nature of the provocation task using a neutral cue, including controlling for motor movement, speech or other factors where possible), five-minute-long symptom provocation, followed by relaxation / recovery phase. During the task, behavioral symptom ratings will be captured every minute ( Figure 1G ). To maximize chances of capturing symptom provoked states, individualized stimuli (videos, physical objects) will be used and repeated when highly effective or switched when less effective. To maximize discrimination between provoked and neutral/positive states, short breaks between provocations will be implemented in addition to distracting stimuli such as ‘funny/cute’ videos or conversations about hobbies, hopes for the future, etc. based on effectiveness at counteracting the symptom provocations. This paradigm serves as a platform for identifying electrophysiological biomarkers linked to OCD symptom states. We also collected symptom self-reports of spontaneous changes in OCD and related symptoms. Stimulation effects will be further evaluated by applying selected stimulation pairs or combination stimulation during the exposure tasks. Each trial will begin with a neutral condition, followed by symptom provocation, then application of stimulation for five minutes, and finally a relaxation phase. This allows evaluation of stimulation-related behavioral modulation and concurrent neural activity. iii) Brain stimulation evoked potentials (BSEPs) On the second day after sEEG implantation (allowing for a 1-day recovery), brain stimulation evoked potentials will be performed for connectivity assessments. Single-pulse bipolar electrical stimulation (6mA, 200us) will be delivered across all adjacent contact pairs (30 trials each), and evoked responses recorded from all other electrode contacts. These evoked responses will be processed post-hoc and analyzed for measures of effective connectivity 30 , 31 . After completion of stage 1 of the clinical trial, participants will undergo percutaneous removal of sEEG electrodes at the bedside per clinical practice. Following electrodes explantation, participants will enter maintenance phase, allowing for recovery. Analysis of multi-modal data obtained in Stage 1 will be performed during this time for up to six months. Stage 2 and 3 of Clinical Trial Following data analysis and interpretation for each participant, the research team will recommend up to four targets for chronic DBS implantation. Standard DBS surgery will then be performed under general anesthesia using a frame-based approach previously described 24 with either the Boston Scientific’s Vercise Genus™ R32, Medtronic Percept™ PC, or Medtronic Percept™ RC. Intraoperative awake testing will not be required, as extensive functional testing has been performed during the Stage 1 inpatient evaluation. Intraoperative brain stimulation evoked potentials may be conducted between DBS electrodes for connectivity analysis. After a four-week post-operative recovery period, participants will return for initiation of DBS stimulation. A systematic monopolar assessment will be performed by a trained interventional psychiatrist, with DBS electrodes activated in sequential fashion. Participants will be evaluated biweekly during the DBS optimization phase (Stage 2), which lasts up to 52 weeks. The goal of the optimization phase is to achieve a Y-BOCS II score reduction of at least 35% from baseline and sustaining clinical stability for at least four weeks. Once these clinical goals are achieved, participants will advance to stage 3, the randomized cross-over phase of the study, designed to rigorously assess the clinical efficacy of DBS for OCD. In Stage 3, DBS will first be gradually tapered off for a washout period of up to four weeks, or until the participant’s Y-BOCS-II score returns to within 20% of their pre-treatment baseline. The participants will then be randomized into either active or sham stimulation for 12 weeks. At the end of this period, a second washout phase occurs (up to four weeks), which will be followed by a crossover to the alternate condition for another 12 weeks. Throughout Stage 3, participants will undergo biweekly psychiatric evaluations. Predefined safety thresholds are set in place by the protocol to allow early rescue or progression to the next phase if needed. These include CGI-I score of 5 and active suicidal ideation with specific plan and intent as indicated with question 5 on the C-SSRS answered as ‘yes’. In the event these safety thresholds are met, the safety committee would convene to recommend appropriate actions. During the blinded stimulation phase, the optimized stimulation parameters determined from Stage 2 will be maintained. After completion of Stage 3, participants then enter an open-label follow-up phase, during which they may choose to continue DBS therapy, withdraw or explant the device. Follow-up visits will occur every eight weeks for six months. RESULTS AND EXPECTED OUTCOMES Safety and Feasibility At time of writing, each participating site is in active recruitment. Using our deliberate, individualized surgical targeting strategy to ensure electrode placement within key network nodes, we successfully implanted all sEEG electrodes for each enrolled participant, demonstrating feasibility of the approach in Stage 1 of the clinical trial. No unexpected serious adverse events related to the surgical implantation occurred in any participant. Figure 2C depicts the normalized locations of sEEG electrode contacts for the first four subjects recruited at Penn in a common template space. All participants progressed to Stage 2 of the clinical trial with distinct DBS target combinations, reinforcing the rationale for a personalized, sEEG-guided approach. In participants who underwent surgical implantation using the Leksell Vantage frame, the use of 3D-printed head models proved valuable for planning. These models not only helped inform optimized frame placement but enabled refinement of electrode trajectories prior to surgery. Surgical rehearsal revealed that accessing targets such as the frontal pole and orbitofrontal cortices often required the use of short posterior pins to avoid exceeding the frame’s maximum Y-coordinate (175mm). Additionally, although BrainLAB Elements software correctly reflected coordinates and arc settings, it did not fully account for potential collisions between the guide holder or guide stop with the stereotactic frame, especially with lateral-to-medial trajectories ( Figure 2B , top panel). Removal of one guide holder allowed for a greater range of arc angles; however, an average collision range of 13-14 degree per side remained, rendering some lateral-to-medial trajectories infeasible ( Figure 2B , bottom panels). The permissible range of ring and arc angles varied based on the specific X,Y and Z coordinates of each target 32 , underscoring the importance of feasibility checks for each trajectory. Treatment Efficacy The treatment efficacy of the clinical trial will be assessed in Stage 3, using the Y-BOCS II as primary outcome measure. Secondary measures include 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 Clinical Global Impression – Improvement Scale (CGI-I). Other clinical measures that will be reported include the following scales: the Columbia-Suicide Severity Rating Scale, the Young Mania Rating Scale, the Hamilton Depression Rating Scale, the Yale Global Tic Severity Scale, the Patient Global Impression – Severity Scale, the Clinical Global Impression – Severity Scale, the Generalized Anxiety Disorder 7-item Scale, the Mini International Neuropsychiatric Interview, and the Abnormal Involuntary Movement Scale. DISCUSSION Since its initial description by Jean Talairach, and particularly over the last two decades, sEEG has become a cornerstone in the pre-surgical evaluation of epileptogenic networks 33 . As surgical safety improved, sEEG has emerged as a powerful tool for probing brain network disorders – especially those involving both cortical as well as deep structures of the brain – at high spatial (at contacts) and temporal resolution that far exceeds current non-invasive methods. Concurrently, neuropsychiatric disorders are increasingly being conceptualized as disorders of distributed brain networks. While these conditions remain incompletely understood, the application of sEEG offers a unique opportunity to interrogate network-level dysfunction from direct brain recordings. Despite its potential, sEEG has thus far been applied only in small clinical studies of depression and chronic pain conditions, where it has provided insights that informed closed-loop neurostimulation or programming strategies 13 , 14 , 31 , 34 , 35 . Here, we present the design of the first multi-site clinical trial using sEEG to characterize brain-wide networks associated with trOCD. This trial integrates monitored, personalized OCD exposures, brain stimulation evoked potential mapping, and systematic acute stimulation testing to probe OCD-relevant networks in a rigorous, safe, and individualized manner. We emphasize the importance of precise sEEG electrode placement within targeted circuits, which is fundamental to downstream network analysis and stimulation planning. In addition, we demonstrate that a similar targeting and surgical strategy can be successfully applied across different stereotactic systems, and we provide guidance for surgical rehearsal in cases where trajectory feasibility is uncertain. The ultimate goal of the study is to synthesize multi-modal data to guide personalized, circuit-based, multi-nodal DBS therapy for trOCD. Such an approach holds promise for improving treatment outcome for this debilitating condition affecting millions of people worldwide. Recent advances in neuroimaging and neuromodulation technologies have accelerated interests in network-informed brain stimulation therapies. Prior reports have described practical frameworks for conducting complex studies that combine imaging, physiology and behavioral data collection 26 , 36 – 38 . Our study builds upon this by incorporating individualized, tractography-informed targeting strategies designed to maximize engagement of relevant network, which is crucial to subsequent data collection and analyses using electrophysiological recordings. Using standard template atlases co-registered in individual subject’s space, we first identified specific regions of interests. These targets were then sub-segmented using probabilistic tractography to isolate subregions with the highest network connectivity. This strategy is conceptually similar to defining motor subregions within standard DBS targets for movement disorders, or the identification of subnuclei within the thalamus 39 , 40 . Although there is currently no standardized atlas for psychiatric DBS targeting, this individualized approach also enables incorporation of recently developed normative datasets, such as the OCD response network and connectivity sweet spots into our participants’ imaging as targeting references 6 , 7 , 17 . We did not include direct targeting of the BNST as it is a very small structure, and our consensus agreed that DBS and recordings of this structure would lack anatomical specificity. However, the volume of tissue modulated by electrodes in the VeP likely captured the BNST due to its proximity. Our early experience with this ongoing clinical trial demonstrates the feasibility and safety of using sEEG to personalize DBS for trOCD. Data from our small initial cohort suggest that individualized targeting is not only feasible but necessary, as each participant has required a distinct combination of stimulation targets and neuromodulation protocols. Additionally, we describe a practical and reproducible frame-based targeting approach for network engagement, which could be adapted to other institutions interested in adopting similar methodologies. CONCLUSION SEEG-guided exploration to identify DBS targets for neuromodulation therapy in OCD may enable a personalized understanding of the brain networks involved. In this approach, optimal placement electrode placement is essential. We present a practical targeting strategy and describe surgical planning steps that enhance confidence, improve workflow efficacy, and support safe, reproducible implantation across varying clinical settings. Data Availability All data produced in the present work are contained in the manuscript. Disclosures / 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. A.K recueves research grants from Alkermes; Janssen Pharmaceuticals, Axsome Pharmaceutics, Attune, Eisai, Harmony, Neumora; Neurocrine Biosciences, Reveal Biosensors, The Ray and Dagmar Dolby Family Fund, Weill Institute for Neurosciences, and National Institutes of Health Grant UH3NS123310. A.K. is a consultant for Axsome Therapeutics, Abbvie, Big Health, Eisai, Evecxia, Harmony Biosciences, Idorsia, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Neurocrine Biosciences, Neumora, Neurawell, Otsuka Pharmaceuticals, Sage, Takeda; he holds stock options for Neurawell and Big-Health. 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), NCT06347978 (registration date: 2024-03-20) Protocol version: 12.1 (17 th 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 Clinical Global Impression – Improvement Scale (CGI-I). Acknowledgement We gratefully acknowledge the Dr Bart Nuttin (KU Leuven), Dr Philip Mosley and Dr Terry Coyne (Queensland Brain Institute) team for their expert advice on surgical targeting. Their guidance played a key role in refining targeting strategies and ensuring the precision of electrode implantation. Footnotes Updated disclosure information and author list. REFERENCES 1. ↵ Swierkosz-Lenart K , Dos Santos JFA , Elowe J , et al. Therapies for obsessive-compulsive disorder: Current state of the art and perspectives for approaching treatment-resistant patients . Front Psychiatry . 2023 ; 14 : 1065812 . doi: 10.3389/fpsyt.2023.1065812 OpenUrl CrossRef PubMed 2. ↵ Stein DJ , Costa DLC , Lochner C , et al. Obsessive–compulsive disorder . Nat Rev Dis Primer . 2019 ; 5 ( 1 ): 1 – 21 . doi: 10.1038/s41572-019-0102-3 OpenUrl CrossRef 3. ↵ Ramakrishnan D , Farhat LC , Vattimo EFQ , et al. 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