Structural connectome architecture and biological vulnerability shape cortical atrophy in cocaine use disorder

Structural connectome architecture and biological vulnerability shape cortical atrophy in cocaine use disorder | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (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],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Structural connectome architecture and biological vulnerability shape cortical atrophy in cocaine use disorder Ziteng Han, Tiantian Liu, Kexin Wang, Guoyuan yang, Tianyi Yan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7656463/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Background Cocaine use disorder (CUD) is highly prevalent and characterized by widespread gray matter atrophy across the cerebral cortex. Yet, it remains unclear whether and how connectome-based circuits and biological features shape these structural abnormalities. Methods We mapped cortical atrophy patterns in CUD (discovery cohort: N = 53; replication cohort: N = 74; controls: N = 364) onto the brain’s structural connectome, functional connectivity, transcriptomic similarity and receptor similarity architecture. Using a multimodal and multiscale connectivity-based framework, we identified CUD epicenters and evaluated their spatial correspondence with therapeutic brain stimulation targets and individual variations in clinical symptoms. Results We found that CUD-related regional atrophy is constrained by the white matter (WM) structural connectome. Along these WM pathways, regions that share similar haemodynamic activity and molecular features are more likely to exhibit convergent atrophy profiles. By integrating the structural connectome with multiple connectivity blueprints, we subsequently identified CUD epicenters and revealed that the prefrontal and visual cortices serve as core systems. Furthermore, we linked these epicenters to cortical gene expression patterns and delineated CUD-related transcriptomic enrichment in biological processes, including inter-neuronal communication, synaptic function and neural homeostasis. Finally, we demonstrated that the spatial distribution of these epicenters correlates with cocaine craving-response maps derived from repeated transcranial magnetic stimulation and can track individual variations in clinical behavioural representations, suggesting their potential as targets for therapeutic intervention. Conclusions Altogether, our findings establish a structurally constrained framework for the spread of pathology underlying cortical atrophy in CUD, where initial perturbations propagate via structural connectome pathways to vulnerable regions shaped by neural activity and molecular landscapes. brain-behaviour relationships brain connectome cocaine use disorder microscale molecular features disease epicenter Full Text Additional Declarations No competing interests reported. Supplementary Files SupplementaryData1.xlsx Supplementarymaterials250727.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 09 Dec, 2025 Reviewers agreed at journal 02 Nov, 2025 Reviews received at journal 28 Oct, 2025 Reviews received at journal 15 Oct, 2025 Reviewers agreed at journal 10 Oct, 2025 Reviewers agreed at journal 08 Oct, 2025 Reviewers invited by journal 08 Oct, 2025 Editor invited by journal 23 Sep, 2025 Editor assigned by journal 22 Sep, 2025 Submission checks completed at journal 22 Sep, 2025 First submitted to journal 19 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7656463","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":532402174,"identity":"541276e5-6f20-4bb2-bc37-d2f95b41c893","order_by":0,"name":"Ziteng Han","email":"","orcid":"","institution":"Beijing Institute of Technology","correspondingAuthor":false,"prefix":"","firstName":"Ziteng","middleName":"","lastName":"Han","suffix":""},{"id":532402175,"identity":"213b7bbc-2a71-4c16-a886-8b61122839fd","order_by":1,"name":"Tiantian Liu","email":"","orcid":"","institution":"Beijing Institute of 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disorder","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmed","sideBox":"Learn more about [BMC Medicine](http://bmcmedicine.biomedcentral.com/)","snPcode":"12916","submissionUrl":"https://submission.nature.com/new-submission/12916/3","title":"BMC Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"brain-behaviour relationships, brain connectome, cocaine use disorder, microscale molecular features, disease epicenter","lastPublishedDoi":"10.21203/rs.3.rs-7656463/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7656463/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eCocaine use disorder (CUD) is highly prevalent and characterized by widespread gray matter atrophy across the cerebral cortex. Yet, it remains unclear whether and how connectome-based circuits and biological features shape these structural abnormalities.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe mapped cortical atrophy patterns in CUD (discovery cohort: N\u0026thinsp;=\u0026thinsp;53; replication cohort: N\u0026thinsp;=\u0026thinsp;74; controls: N\u0026thinsp;=\u0026thinsp;364) onto the brain\u0026rsquo;s structural connectome, functional connectivity, transcriptomic similarity and receptor similarity architecture. Using a multimodal and multiscale connectivity-based framework, we identified CUD epicenters and evaluated their spatial correspondence with therapeutic brain stimulation targets and individual variations in clinical symptoms.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eWe found that CUD-related regional atrophy is constrained by the white matter (WM) structural connectome. Along these WM pathways, regions that share similar haemodynamic activity and molecular features are more likely to exhibit convergent atrophy profiles. By integrating the structural connectome with multiple connectivity blueprints, we subsequently identified CUD epicenters and revealed that the prefrontal and visual cortices serve as core systems. Furthermore, we linked these epicenters to cortical gene expression patterns and delineated CUD-related transcriptomic enrichment in biological processes, including inter-neuronal communication, synaptic function and neural homeostasis. Finally, we demonstrated that the spatial distribution of these epicenters correlates with cocaine craving-response maps derived from repeated transcranial magnetic stimulation and can track individual variations in clinical behavioural representations, suggesting their potential as targets for therapeutic intervention.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eAltogether, our findings establish a structurally constrained framework for the spread of pathology underlying cortical atrophy in CUD, where initial perturbations propagate via structural connectome pathways to vulnerable regions shaped by neural activity and molecular landscapes.\u003c/p\u003e","manuscriptTitle":"Structural connectome architecture and biological vulnerability shape cortical atrophy in cocaine use disorder","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-22 00:20:41","doi":"10.21203/rs.3.rs-7656463/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-09T11:28:19+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"251144213779921445239601319409557721768","date":"2025-11-03T03:27:09+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-28T18:09:49+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-15T04:01:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"71506002066046423847702300865279074006","date":"2025-10-10T16:56:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"154150348144911298847029456950618652940","date":"2025-10-09T03:46:24+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-08T16:50:17+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-09-23T16:53:44+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-22T05:50:16+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-22T05:27:42+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Medicine","date":"2025-09-19T08:40:40+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmed","sideBox":"Learn more about [BMC Medicine](http://bmcmedicine.biomedcentral.com/)","snPcode":"12916","submissionUrl":"https://submission.nature.com/new-submission/12916/3","title":"BMC Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"476c3a85-75c7-49f9-bd59-4882377befe6","owner":[],"postedDate":"October 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-29T16:09:06+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-22 00:20:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7656463","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7656463","identity":"rs-7656463","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}