Identification of a Diagnosis-Selective Neurobiological Substrate for Bipolar Disorder, Major Depressive Disorder, and Schizophrenia: A Meta-Analysis of 57,717 Subjects

Identification of a Diagnosis-Selective Neurobiological Substrate for Bipolar Disorder, Major Depressive Disorder, and Schizophrenia: A Meta-Analysis of 57,717 Subjects | 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 Article Identification of a Diagnosis-Selective Neurobiological Substrate for Bipolar Disorder, Major Depressive Disorder, and Schizophrenia: A Meta-Analysis of 57,717 Subjects Donato Liloia, Paola Rocca, Claudio Brasso, Masaru Tanaka, Jordi Manuello, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6715229/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Neuroimaging studies have consistently revealed neuroanatomical abnormalities in individuals with bipolar disorder, major depressive disorder, and schizophrenia. However, it remains unknown whether and to what extent disorder-selective gray matter variations occur in these prominent psychiatric disorders. This study conducted a meta-analysis of 25 years of published voxel-based morphometry research to assess the presence of selective and robust neuroanatomical substrates of gray matter variation in bipolar disorder, major depressive disorder, and schizophrenia. Peer-reviewed experiments encompassing subjects with target disorders were systematically searched in the MEDLINE database. Additionally, peer-reviewed data on 30 other psychiatric disorders and 65 neurological diseases were obtained from the BrainMap database. Experiments reporting whole-brain group comparisons between patients and healthy controls were included if they identified significant gray matter reductions. The data were analyzed using the Bayes fACtor mOdeliNg algorithm. 1,021 voxel-based morphometry experiments were included, comprising 29,540 patients and 28,177 healthy controls. Primary analyses of psychiatric data revealed strong evidence of gray matter reduction in the right middle temporal gyrus for bipolar disorder and the posterior dorsal anterior cingulate cortex for schizophrenia (P ≥ 95% selectivity). The robustness of these findings was confirmed using the fail-safe method tailored to the neuroimaging meta-analytic environment. No selective findings were observed in additional analyses that included neurological diseases. Taken together, these findings offer a framework that underscores the significance of diagnosis-selective neural substrates in psychopathology, a new perspective that could inform distinct pathophysiological processes and assist in diagnosis and treatment. Biological sciences/Neuroscience Health sciences/Diseases/Psychiatric disorders Activation likelihood estimation Bayes factor Structural MRI Anterior cingulate Reverse inference Psychiatric disorders Figures Figure 1 Figure 2 Figure 3 Full Text Additional Declarations The authors have declared there is NO conflict of interest to disclose Supplementary Files Supplement.pdf Supplementary Online Content Cite Share Download PDF Status: Posted Version 1 posted 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. We do this by developing innovative software and high quality services for the global research community. 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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-6715229","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":511654094,"identity":"fbbbd84c-193b-4b82-9e97-15ff56b40f99","order_by":0,"name":"Donato Liloia","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3klEQVRIiWNgGAWjYDCCAxBKho0dxK5gYGADcRMIaQFiHjZmEH0GqAWkJwGfHpgWBqAWBsY2BsLW8B3vPfj5QwUDDx8z88EDP+cdzuOTbz7A8PAHbi2SZ84lSxw4A3IYW8LB3m2Hi9nY2BLwOszgRo6BxME2kBYegwO82w4ntrHxGBDSYvwDpuXg3znEaTGD23KYt4EILZJnzphZnDkjAfbLYZlj6UAtaQkHEtJwa+E73mN8o6LCRk6+vfnwxzc11onzmw8ffPjDBrcWKJBA5R4gqGEUjIJRMApGAV4AADQbTZFOfjGSAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-9481-8510","institution":"University of Turin","correspondingAuthor":true,"prefix":"","firstName":"Donato","middleName":"","lastName":"Liloia","suffix":""},{"id":511654095,"identity":"95369a86-2782-4305-9f50-cb49801b82d9","order_by":1,"name":"Paola Rocca","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Paola","middleName":"","lastName":"Rocca","suffix":""},{"id":511654096,"identity":"002395af-b9c8-4c9d-b697-8942cdb88c21","order_by":2,"name":"Claudio Brasso","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Claudio","middleName":"","lastName":"Brasso","suffix":""},{"id":511654097,"identity":"83bebe79-3328-49d1-80a6-760c738976a7","order_by":3,"name":"Masaru Tanaka","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Masaru","middleName":"","lastName":"Tanaka","suffix":""},{"id":511654098,"identity":"ef7d3ee4-9e95-41be-9870-67517264f6e5","order_by":4,"name":"Jordi Manuello","email":"","orcid":"","institution":"University of Turin","correspondingAuthor":false,"prefix":"","firstName":"Jordi","middleName":"","lastName":"Manuello","suffix":""},{"id":511654099,"identity":"ccdf26ec-75fa-43f9-a95b-afcb0be9c85b","order_by":5,"name":"Annachiara Crocetta","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Annachiara","middleName":"","lastName":"Crocetta","suffix":""},{"id":511654100,"identity":"b0707c2e-1791-48fb-9898-b9dff26c2776","order_by":6,"name":"Sergio Duca","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Sergio","middleName":"","lastName":"Duca","suffix":""},{"id":511654101,"identity":"eaf0f859-ac79-4076-8407-1fef7699818a","order_by":7,"name":"Tommaso Costa","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Tommaso","middleName":"","lastName":"Costa","suffix":""},{"id":511654102,"identity":"b218774d-78ac-4742-9c3c-16d0e77687d4","order_by":8,"name":"Franco Cauda","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Franco","middleName":"","lastName":"Cauda","suffix":""}],"badges":[],"createdAt":"2025-05-21 09:56:30","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6715229/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6715229/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":91306466,"identity":"c3e7e9b2-b514-4bb6-ad2e-f8e6ead35376","added_by":"auto","created_at":"2025-09-15 06:32:28","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":3983802,"visible":true,"origin":"","legend":"\u003cp\u003eOverview of the analytical procedures A) A total of 8,740 coordinates of significant gray matter variation from 29,540 patients were extracted from 1,021 published voxel-based morphometry experiments. B) Graphical representation of the data analytic pipeline, from the variation coordinates to the selectivity whole-brain map. The final statistical parametric map, which represents the values of the selective probability of the disorder of interest, is obtained with the Bayes factor computation implemented in the Bayes fACtor mOdeliNg plugin. C) Data groupings for estimating the selectivity of the gray matter landscape in bipolar disorder (analysis 1), major depressive disorder (analysis 2), and schizophrenia disorder (analysis 3) patients. D) Robustness and supplementary functional and behavioral analyses of the Bayes fACtor mOdeliNg results. BACON = Bayes fACtor mOdeliNg; BD = bipolar disorder; BF = Bayes factor; EXP. = experiment; MDD = major depressive disorder; SZ = schizophrenia.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-6715229/v1/4152ff24ee9c736818c908a7.png"},{"id":91306460,"identity":"6d83824d-a322-48dd-a96a-2bd8b1062cc6","added_by":"auto","created_at":"2025-09-15 06:32:28","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":693940,"visible":true,"origin":"","legend":"\u003cp\u003eOverview of literature selection and coding (PRISMA flowchart) BD = bipolar disorder; MDD = major depressive disorder; N = number of; ROI = regionof-interest; SZ = schizophrenia disorder; SVC = small volume correction; WM = white matter; VBM = voxel-based morphometry\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-6715229/v1/49f0cab440ca064b2ac9baf6.png"},{"id":91306461,"identity":"ea2498ac-bdb2-42ac-ac3f-760f7283846b","added_by":"auto","created_at":"2025-09-15 06:32:28","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2182817,"visible":true,"origin":"","legend":"\u003cp\u003eRobust clusters of selective gray matter variation in bipolar disorder and schizophrenia and their network-level functional and behavioral characterizations A) Brain cluster of selective gray matter variation in bipolar disorder derived from Bayes fACtor mOdeliNg analysis of psychiatric disorders data thresholded at P (bipolar disorder | variation) ≥ 0.95 (95%) and remaining stable over 30% of injected random experiments via fail-safe analysis. On the right side, the meta-analytic coactivation map (MACM) shows areas coactivated with the cluster of variation in healthy participant task-based activation experiments in the BrainMap database, as well as its statistically linked physiological mental processes derived from the behavioral analysis of the BrainMap database. B) Brain cluster of selective gray matter variation in schizophrenia derived from Bayes fACtor mOdeliNg analysis of psychiatric disorders data thresholded at P (schizophrenia | variation) ≥ 0.95 (95%) and remaining stable over 30% of injected random experiments via fail-safe analysis. On the right side, the meta-analytic coactivation map (MACM) shows areas coactivated with the cluster of variation in healthy participant task-based activation experiments in the BrainMap database, as well as its statistically linked physiological mental processes derived from the behavioral analysis of the BrainMap database. 23 The Bayes fACtor mOdeliNg results are visualized as hemispheric surfaces (three-dimensional view). MACM results are visualized as axial slices (two-dimensional cortical and subcortical views). Templates are in neurological convention. ACC = posterior dorsal anterior cingulate cortex; ALE = activation likelihood estimation; MTG = middle temporal gyrus.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-6715229/v1/660df918dff9480b6059e091.png"},{"id":92656786,"identity":"00780efd-950b-48a5-b319-7c9f56145fe2","added_by":"auto","created_at":"2025-10-02 13:49:09","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2494899,"visible":true,"origin":"","legend":"Article File","description":"","filename":"Manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6715229/v1_covered_32934557-c559-40f3-be9c-89e3879a4001.pdf"},{"id":91306463,"identity":"2234a732-1c9f-42f2-adca-812018cc27b1","added_by":"auto","created_at":"2025-09-15 06:32:28","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":772094,"visible":true,"origin":"","legend":"Supplementary Online Content","description":"","filename":"Supplement.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6715229/v1/3ec5a2acb57981771be48689.pdf"}],"financialInterests":"The authors have declared there is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose","formattedTitle":"Identification of a Diagnosis-Selective Neurobiological Substrate for Bipolar Disorder, Major Depressive Disorder, and Schizophrenia: A Meta-Analysis of 57,717 Subjects","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Activation likelihood estimation, Bayes factor, Structural MRI, Anterior cingulate, Reverse inference, Psychiatric disorders","lastPublishedDoi":"10.21203/rs.3.rs-6715229/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6715229/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Neuroimaging studies have consistently revealed neuroanatomical abnormalities in individuals with bipolar disorder, major depressive disorder, and schizophrenia. However, it remains unknown whether and to what extent disorder-selective gray matter variations occur in these prominent psychiatric disorders. This study conducted a meta-analysis of 25 years of published voxel-based morphometry research to assess the presence of selective and robust neuroanatomical substrates of gray matter variation in bipolar disorder, major depressive disorder, and schizophrenia. Peer-reviewed experiments encompassing subjects with target disorders were systematically searched in the MEDLINE database. Additionally, peer-reviewed data on 30 other psychiatric disorders and 65 neurological diseases were obtained from the BrainMap database. Experiments reporting whole-brain group comparisons between patients and healthy controls were included if they identified significant gray matter reductions. The data were analyzed using the Bayes fACtor mOdeliNg algorithm. 1,021 voxel-based morphometry experiments were included, comprising 29,540 patients and 28,177 healthy controls. Primary analyses of psychiatric data revealed strong evidence of gray matter reduction in the right middle temporal gyrus for bipolar disorder and the posterior dorsal anterior cingulate cortex for schizophrenia (P ≥ 95% selectivity). The robustness of these findings was confirmed using the fail-safe method tailored to the neuroimaging meta-analytic environment. No selective findings were observed in additional analyses that included neurological diseases. 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