{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:09:36Z","timestamp":1785424176657,"version":"3.56.0"},"posted":{"date-parts":[[2026,6,10]]},"group-title":"Neurology","reference-count":56,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"award":["R01MH139889"],"award-info":[{"award-number":["R01MH139889"]}],"id":[{"id":"https:\/\/ror.org\/04xeg9z08","id-type":"ROR","asserted-by":"publisher"}]},{"award":["UM1NS32207"],"award-info":[{"award-number":["UM1NS32207"]}],"id":[{"id":"https:\/\/ror.org\/01pg81m90","id-type":"ROR","asserted-by":"publisher"}]},{"award":["UH3NS100549"],"award-info":[{"award-number":["UH3NS100549"]}],"id":[{"id":"https:\/\/ror.org\/01pg81m90","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/01pg81m90","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Obsessive-compulsive disorder (OCD) is characterized by disturbing thoughts (obsessions) that initiate anxiety-reducing thoughts or behaviors (compulsions). For patients with treatment-resistant OCD (tr-OCD), neuromodulation techniques, like capsulotomy (a lesion in the anterior limb of the internal capsule) and deep brain stimulation (DBS), have emerged as interventions that likely regulate connectivity between the prefrontal cortex (PFC) and subcortical targets. Three patients (Cap-DBS1-3) underwent a failed capsulotomy followed by successful DBS. Here, we aimed to understand the brain connections disrupted by failed capsulotomy vs modulated by successful DBS.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We used diffusion-weighted magnetic resonance imaging (dMRI) tractography in a control cohort with tr-OCD (n=12) and in two of the Cap-DBS patients themselves to determine connectivity profiles of the capsulotomy, volume of tissue activated (VTA), and potentially necessary tracts (VTA minus capsulotomy tracts). We used whole-brain, PFC-focused, and subcortically-focused tractography algorithms to fully explore the space of possible connections.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Capsulotomy regions-of-interest (ROIs) connected with a variety of PFC and subcortical regions. VTA ROIs and potentially necessary tracts had limited and inconsistent PFC connectivity but substantial subcortical connectivity. While correlated to the average OCD connectome (r = 0.214, 95% CI [0.177, 0.251]; r = 0.756, 95% CI [0.739, 0.772]), the Cap-DBS connectomes had many edges that were stronger (z-score &gt; 3).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>The connectivity profile of potentially necessary tracts for successful DBS treatment after failed capsulotomy revealed a surprising proportion of subcortical regions and inconsistent PFC involvement, highlighting an often-ignored set of connections that may be critical to effective DBS.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Key Messages<\/jats:title>\n                  <jats:sec>\n                    <jats:title>What is already known on this topic<\/jats:title>\n                    <jats:p>OCD has been conceptualized as a disorder of cortico-striato-thalamo-cortical (CSTC) circuits. Treatment targets have largely involved connections to the PFC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>What this study adds<\/jats:title>\n                    <jats:p>Our study shows that potentially necessary tracts for DBS treatment after failed capsulotomy involve connections to subcortical regions and not PFC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>How this study might affect research, practice, or policy<\/jats:title>\n                    <jats:p>This evidence of primarily subcortical involvement in treatment should encourage the use of more detailed subcortical atlases in neuromodulation circuit research and suggests that local circuit remodeling may be a mechanism of neuromodulatory OCD treatment.<\/jats:p>\n                  <\/jats:sec>\n                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