{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:34:08Z","timestamp":1785429248460,"version":"3.56.0"},"reference-count":53,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:00:00Z","timestamp":1779148800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["Bando Ricerca Finalizzata RF-2021-12374133"],"award-info":[{"award-number":["Bando Ricerca Finalizzata RF-2021-12374133"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"award":["Bando Ricerca Finalizzata RF-2021-12374133"],"award-info":[{"award-number":["Bando Ricerca Finalizzata RF-2021-12374133"]}],"id":[{"id":"https:\/\/ror.org\/00789fa95","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Background: Treatment-resistant obsessive\u2013compulsive disorder (OCD) is a heterogeneous and clinically challenging condition. Growing evidence suggests alterations in glutamatergic signaling within cortico\u2013striatal\u2013thalamo\u2013cortical circuits, including those involving medium spiny neurons (MSNs), as well as genetic factors affecting synaptic organization, although the biological mechanisms underlying differential treatment response remain incompletely understood. Methods: This multicenter study presents a translational research framework aimed at investigating potential molecular and cellular correlates of treatment response in a cohort of patients with OCD, stratified according to their response to pharmacological treatments and transcranial magnetic stimulation (TMS). Peripheral blood mononuclear cells from clinically defined subgroups are reprogrammed into human induced pluripotent stem cells and differentiated into MSN-enriched neuronal cultures, enabling in vitro investigation of morphological, biochemical, and transcriptomic features associated with different clinical profiles. Optogenetic and pharmacological stimulation paradigms are applied to probe selected aspects of neuronal activation in vitro, providing a controlled and simplified experimental framework to explore cellular responses under different treatment conditions. By integrating clinical phenotyping with patient-derived cellular models, this study establishes a translational platform for hypothesis generation in the investigation of treatment response in OCD. Results and Conclusions: Preliminary clinical observations from an initial cohort undergoing neuromodulation are also reported to document feasibility and early clinical implementation of the study, providing an initial characterization of the cohort.<\/jats:p>","DOI":"10.3390\/brainsci16050537","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T16:07:26Z","timestamp":1779206846000},"page":"537","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Investigating Treatment Response in Obsessive\u2013Compulsive Disorder Through Neuromodulation and Patient-Derived Induced Pluripotent Stem Cell Models: Preliminary Clinical Observations from a Translational Study"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0539-7150","authenticated-orcid":false,"given":"Beatrice","family":"Benatti","sequence":"first","affiliation":[{"name":"Department of Health Sciences, Universit\u00e0 degli Studi di Milano, 20122 Milan, Italy"},{"name":"CRC \u2018Aldo Ravelli\u2019 for Neurotechnology & Experimental Brain Therapeutics, 20122 Milan, Italy"},{"name":"Department of Biomedical and Clinical Sciences, Psychiatry Unit 2, ASST Fatebenefratelli-Sacco, Universit\u00e0 degli Studi di Milano, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Marcatili","sequence":"additional","affiliation":[{"name":"Department of Mental Health, Fondazione IRCSS San Gerardo dei Tintori, 20900 Monza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodolfo","family":"Leuzzi","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences, Psychiatry Unit 2, ASST Fatebenefratelli-Sacco, Universit\u00e0 degli Studi di Milano, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Clerici","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Universit\u00e0 degli Studi di Milano-Bicocca, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2050-9846","authenticated-orcid":false,"given":"Luciano","family":"Conti","sequence":"additional","affiliation":[{"name":"Department of Cellular, Computational and Integrative Biology\u2014CIBIO, University of Trento, 38122 Trento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Gennarelli","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Molecolare e Traslazionale, Universit\u00e0 di Brescia, 25121 Brescia, Italy"},{"name":"Unit\u00e0 di Genetica, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, 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Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Castiglioni","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences, Psychiatry Unit 2, ASST Fatebenefratelli-Sacco, Universit\u00e0 degli Studi di Milano, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6898-4374","authenticated-orcid":false,"given":"Camilla","family":"Gesi","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences, Psychiatry Unit 2, ASST Fatebenefratelli-Sacco, Universit\u00e0 degli Studi di Milano, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0761-2096","authenticated-orcid":false,"given":"Nicolaja","family":"Girone","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences, Psychiatry Unit 2, ASST Fatebenefratelli-Sacco, 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