Gray–white matter structural signatures across migraine subtypes characterized by multimodal MRI and JuSpace correlation analysis

Gray–white matter structural signatures across migraine subtypes characterized by multimodal MRI and JuSpace correlation analysis | 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 Gray–white matter structural signatures across migraine subtypes characterized by multimodal MRI and JuSpace correlation analysis Yuhao Zhang, Yayin Luo, Zhixuan He, Haochong Xie, Yu Su, Donghai Chen, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9287582/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 Background: Migraine is a common neurological disorder with a substantial disabling burden, yet its pathophysiological mechanisms remain incompletely understood. Previous MRI and diffusion MRI studies have reported gray and white matter abnormalities in migraine, but many were based mainly on conventional diffusion metrics, focused on a single subtype or tissue compartment, and rarely linked structural findings to molecular or cellular substrates. We integrated multimodal MRI with cross-modal spatial correlation analyses to evaluate gray and white matter structural alterations in migraine without aura (MwA) and migraine with aura (MA), and to explore their spatial associations with neurotransmitter and cell-surface marker maps. Methods: Thirty healthy controls (HC), 40 patients with MwA, and 15 patients with MA underwent 3D T1-weighted and diffusion MRI for DTI, NODDI, and DKI. White matter alterations were assessed using TBSS, gray matter microstructure using GBSS, and GMV using VBM. Mean values from significant TBSS and VBM clusters were extracted for ROI-based correlations. JuSpace analyses were performed on GM images showing between-group differences. Results: Compared with HC, TBSS revealed increased MD and RD and decreased neurite density index (NDI) in MwA, whereas in MA only free water fraction (FWF) survived correction (HC > MA); no DKI metric showed significant group differences after correction. Corrected GBSS analyses were negative, although uncorrected analyses suggested frontal-cingulate midline abnormalities. VBM demonstrated reduced GMV in MwA, mainly in the left cerebellar Crus I, and in MA, mainly in the right inferior frontal gyrus, pars triangularis; no significant GMV differences were detected between MwA and MA. JuSpace analyses based on VBM-derived difference maps showed significant spatial correlations with multiple neurotransmitter and cell-surface marker templates in both contrasts, with a broader set in MA vs HC. No ROI-based clinical correlation survived multiple-comparison correction. Conclusions: These findings support subtype-weighted structural phenotypes in migraine. MwA was characterized mainly by white matter microstructural abnormalities suggestive of altered neurite/axon-related tissue properties, whereas MA showed a more prominent free-water-related signal on the white matter skeleton. The spatial coupling between GMV alterations and neurotransmitter/cell templates further suggests that migraine-related structural changes may be embedded within a broader neurochemical and cellular context. migraine without aura (MwA) migraine with aura (MA) diffusion MRI (dMRI) neurite orientation dispersion and density imaging (NODDI) diffusional kurtosis imaging (DKI) voxel-based morphometry (VBM) white matter skeleton gray matter skeleton neurotransmitters cell-surface markers Full Text Additional Declarations No competing interests reported. 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-9287582","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":621567573,"identity":"efd651a7-e817-4645-8f16-360e9bda28b8","order_by":0,"name":"Yuhao Zhang","email":"","orcid":"","institution":"First Affiliated Hospital of Dalian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yuhao","middleName":"","lastName":"Zhang","suffix":""},{"id":621567574,"identity":"8cdb3c5a-6149-45a0-a7bc-70f07b30327a","order_by":1,"name":"Yayin Luo","email":"","orcid":"","institution":"First Affiliated Hospital of Dalian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yayin","middleName":"","lastName":"Luo","suffix":""},{"id":621567579,"identity":"f739ce83-5dea-4e03-8934-5ba155e905b1","order_by":2,"name":"Zhixuan He","email":"","orcid":"","institution":"First Affiliated Hospital of Dalian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zhixuan","middleName":"","lastName":"He","suffix":""},{"id":621567581,"identity":"b4166e33-d5fc-44a0-a825-bebf5a705a4f","order_by":3,"name":"Haochong Xie","email":"","orcid":"","institution":"Dalian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Haochong","middleName":"","lastName":"Xie","suffix":""},{"id":621567582,"identity":"74384261-b01b-477c-9d24-62ee815bb102","order_by":4,"name":"Yu Su","email":"","orcid":"","institution":"Dalian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"Su","suffix":""},{"id":621567584,"identity":"2198e038-01c4-4e8f-b572-8fd740d84a1e","order_by":5,"name":"Donghai Chen","email":"","orcid":"","institution":"First Affiliated Hospital of Dalian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Donghai","middleName":"","lastName":"Chen","suffix":""},{"id":621567585,"identity":"727d8d02-dcf8-4895-b8ab-4035fab8962a","order_by":6,"name":"Yanwei Miao","email":"","orcid":"","institution":"First Affiliated Hospital of Dalian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yanwei","middleName":"","lastName":"Miao","suffix":""},{"id":621567587,"identity":"0e2de0cb-58be-415e-b55e-547ebb174fc9","order_by":7,"name":"Renwang Pu","email":"","orcid":"","institution":"First Affiliated Hospital of Dalian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Renwang","middleName":"","lastName":"Pu","suffix":""},{"id":621567590,"identity":"b80a012a-43d9-4d81-ac67-836d1ed5f03f","order_by":8,"name":"Jian Jiang","email":"","orcid":"","institution":"First Affiliated Hospital of Dalian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jian","middleName":"","lastName":"Jiang","suffix":""},{"id":621567595,"identity":"c4c2b01d-f944-4ef5-b538-eca3089c577f","order_by":9,"name":"Zhe Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyklEQVRIiWNgGAWjYLACxgYGxj72xsaHH0jS0sZzuNlYgjQtEultAjzEqDY4fvbwy587bGTbJB+2MUgw2MnpNhDSciYvzULyTJpxm3Ri24MChmRjswMEtJgdyDEzMGw7nAjU0m4gwXAgcRtBLeffmBkktv1PbJM82CbBQ5SWGznGDw62HUhsk2AkUov9jTdmjI1tycZtPInAQDYgwi+S/TnGH3+22cn2sx9/+PBDhZ0cQS1AwIYUgQaElYMAM/HJZBSMglEwCkYmAADQpUXjWELQgAAAAABJRU5ErkJggg==","orcid":"","institution":"First Affiliated Hospital of Dalian Medical University","correspondingAuthor":true,"prefix":"","firstName":"Zhe","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2026-04-01 06:40:28","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9287582/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9287582/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108691399,"identity":"bd7123f6-7705-4bfa-af48-904afd70cea4","added_by":"auto","created_at":"2026-05-07 10:57:43","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1807264,"visible":true,"origin":"","legend":"","description":"","filename":"GraywhitematterstructuralsignaturesacrossmigrainesubtypescharacterizedbymultimodalMRIandJuSpacecorrelationanalysis.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9287582/v1_covered_165c02a6-488e-4b4a-8aec-ffac2f1d6e8c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Gray–white matter structural signatures across migraine subtypes characterized by multimodal MRI and JuSpace correlation analysis","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":"migraine without aura (MwA), migraine with aura (MA), diffusion MRI (dMRI), neurite orientation dispersion and density imaging (NODDI), diffusional kurtosis imaging (DKI), voxel-based morphometry (VBM), white matter skeleton, gray matter skeleton, neurotransmitters, cell-surface markers","lastPublishedDoi":"10.21203/rs.3.rs-9287582/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9287582/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e \u003cp\u003eMigraine is a common neurological disorder with a substantial disabling burden, yet its pathophysiological mechanisms remain incompletely understood. Previous MRI and diffusion MRI studies have reported gray and white matter abnormalities in migraine, but many were based mainly on conventional diffusion metrics, focused on a single subtype or tissue compartment, and rarely linked structural findings to molecular or cellular substrates. We integrated multimodal MRI with cross-modal spatial correlation analyses to evaluate gray and white matter structural alterations in migraine without aura (MwA) and migraine with aura (MA), and to explore their spatial associations with neurotransmitter and cell-surface marker maps.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e \u003cp\u003eThirty healthy controls (HC), 40 patients with MwA, and 15 patients with MA underwent 3D T1-weighted and diffusion MRI for DTI, NODDI, and DKI. White matter alterations were assessed using TBSS, gray matter microstructure using GBSS, and GMV using VBM. Mean values from significant TBSS and VBM clusters were extracted for ROI-based correlations. JuSpace analyses were performed on GM images showing between-group differences.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e \u003cp\u003eCompared with HC, TBSS revealed increased MD and RD and decreased neurite density index (NDI) in MwA, whereas in MA only free water fraction (FWF) survived correction (HC\u0026thinsp;\u0026gt;\u0026thinsp;MA); no DKI metric showed significant group differences after correction. Corrected GBSS analyses were negative, although uncorrected analyses suggested frontal-cingulate midline abnormalities. VBM demonstrated reduced GMV in MwA, mainly in the left cerebellar Crus I, and in MA, mainly in the right inferior frontal gyrus, pars triangularis; no significant GMV differences were detected between MwA and MA. JuSpace analyses based on VBM-derived difference maps showed significant spatial correlations with multiple neurotransmitter and cell-surface marker templates in both contrasts, with a broader set in MA vs HC. No ROI-based clinical correlation survived multiple-comparison correction.\u003c/p\u003e\u003ch2\u003eConclusions:\u003c/h2\u003e \u003cp\u003eThese findings support subtype-weighted structural phenotypes in migraine. MwA was characterized mainly by white matter microstructural abnormalities suggestive of altered neurite/axon-related tissue properties, whereas MA showed a more prominent free-water-related signal on the white matter skeleton. The spatial coupling between GMV alterations and neurotransmitter/cell templates further suggests that migraine-related structural changes may be embedded within a broader neurochemical and cellular context.\u003c/p\u003e","manuscriptTitle":"Gray–white matter structural signatures across migraine subtypes characterized by multimodal MRI and JuSpace correlation analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-13 06:43:23","doi":"10.21203/rs.3.rs-9287582/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","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}}],"origin":"","ownerIdentity":"13dbc0f7-6e39-4a94-89c1-67a3741d3652","owner":[],"postedDate":"April 13th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Rejected","date":"2026-05-07T10:51:05+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-05T01:25:19+00:00","index":23,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-05-07T10:56:32+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-13 06:43:23","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9287582","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9287582","identity":"rs-9287582","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}