Biophysical Mechanisms of Microscopic Diffusional Kurtosis in diffusion MRI

Biophysical Mechanisms of Microscopic Diffusional Kurtosis in diffusion MRI | 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 Biophysical Mechanisms of Microscopic Diffusional Kurtosis in diffusion MRI Noam Shemesh, Rafael Neto Henriques, Rita Alves, Lisa Novello, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8960143/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract The Standard Model of diffusion MRI represents diffusion in tissue using multiple Gaussian components, an approximation that misses key non-Gaussian effects from intra-compartmental structural disorder and/or intercompartmental water exchange. These biophysical mechanisms are conflated in conventional measures such as diffusional kurtosis, and exchange is commonly described using the Kärger model. Here, we develop a Correlation Tensor MRI (CTI) framework that derives the full three-dimensional microscopic-kurtosis tensor and related directional metrics that separate disorder- and Kärger exchange effects. Monte Carlo simulations demonstrate robust disentanglement of these features. In vivo human CTI revealed dominant radial K_μ^⊥ in white matter, consistent with structural disorder. In a rodent ischemic stroke model, elevated axial K_μ^∥ in lesions corresponded to neurite beading, confirmed histologically. In medulloblastoma, reduced directional CTI metrics reflected infiltration by uniformly shaped tumor cells, while in glioma, phenotypes with distinct cellular anisotropy and packing were resolved. These findings show that microscopic kurtosis cannot be neglected under most biological scenarios, and that structural disorder dominates non-Gaussian diffusion, with disease-specific alterations reflecting underlying pathology. Consequently, Kärger exchange alone is unlikely to be an adequate biophysical model in tissues. Our work provides unravels biophysical mechanisms of diffusional kurtosis biology, from humans to animal models. Biological sciences/Biological techniques/Imaging/Diffusion tensor imaging Biological sciences/Biological techniques/Imaging/Magnetic resonance imaging Biological sciences/Biophysics/Computational biophysics Diffusion MRI Microstructure Kurtosis Stroke Cancer Full Text Additional Declarations Yes there is potential Competing Interest. N.S. serves on the Scientific Advise Board of Bruker Biospin. T.F. is employed by, owns stocks of and holds patents filed by Siemens Healthineers AG. Cite Share Download PDF Status: Under Review 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-8960143","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":606908698,"identity":"f9e5f78a-4c2b-401d-b90f-b23e9014970d","order_by":0,"name":"Noam Shemesh","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0001-6681-5876","institution":"Champalimaud Foundation","correspondingAuthor":true,"prefix":"","firstName":"Noam","middleName":"","lastName":"Shemesh","suffix":""},{"id":606908699,"identity":"0caaeae8-73da-44ab-beaa-7ed6d1c333ac","order_by":1,"name":"Rafael Neto Henriques","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Rafael","middleName":"Neto","lastName":"Henriques","suffix":""},{"id":606908700,"identity":"f1917a11-661d-4f65-b1ef-aa328864f1af","order_by":2,"name":"Rita Alves","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Rita","middleName":"","lastName":"Alves","suffix":""},{"id":606908701,"identity":"7d408472-542e-41b6-9006-4c70445f16cc","order_by":3,"name":"Lisa Novello","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Lisa","middleName":"","lastName":"Novello","suffix":""},{"id":606908702,"identity":"043b06ba-c5ac-4951-a1f4-203df107ca18","order_by":4,"name":"Patricia Das Neves Borges","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Patricia","middleName":"Das Neves","lastName":"Borges","suffix":""},{"id":606908703,"identity":"c5670e40-6576-49ce-a25f-b6c15d9c115f","order_by":5,"name":"Rui Simoes","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Rui","middleName":"","lastName":"Simoes","suffix":""},{"id":606908704,"identity":"5e518f83-d5d4-4066-9124-344223142b15","order_by":6,"name":"Tania Carvalho","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Tania","middleName":"","lastName":"Carvalho","suffix":""},{"id":606908705,"identity":"467396e3-c082-4b84-9817-b237832e34e3","order_by":7,"name":"Thorsten Feiweier","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Thorsten","middleName":"","lastName":"Feiweier","suffix":""},{"id":606908706,"identity":"ec303c5b-a737-47d7-94b3-7230cb5f0239","order_by":8,"name":"Andrada Ianus","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Andrada","middleName":"","lastName":"Ianus","suffix":""},{"id":606908707,"identity":"c337a082-fe13-424f-b6a7-6f5fd2414763","order_by":9,"name":"Adriana Sanchez Danes","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Adriana","middleName":"Sanchez","lastName":"Danes","suffix":""},{"id":606908708,"identity":"bd5c07b6-55ac-44a0-a1fb-b59c1727f723","order_by":10,"name":"Sune Nørhøj Jespersen,","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"","middleName":"Sune Nørhøj","lastName":"Jespersen","suffix":""}],"badges":[],"createdAt":"2026-02-24 18:01:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8960143/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8960143/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105035121,"identity":"d7897718-51a2-4de1-9c5b-9948c7bd75f9","added_by":"auto","created_at":"2026-03-20 07:25:31","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1274015,"visible":true,"origin":"","legend":"Article File","description":"","filename":"Henriquesetal2025CTImanuscriptFINAL3.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8960143/v1_covered_0e1f60af-4766-415e-8d57-f583e0811832.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nN.S. serves on the Scientific Advise Board of Bruker Biospin. T.F. is employed by, owns stocks of and holds patents filed by Siemens Healthineers AG.","formattedTitle":"Biophysical Mechanisms of Microscopic Diffusional Kurtosis in diffusion MRI","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Diffusion MRI, Microstructure, Kurtosis, Stroke, Cancer","lastPublishedDoi":"10.21203/rs.3.rs-8960143/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8960143/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"The Standard Model of diffusion MRI represents diffusion in tissue using multiple Gaussian components, an approximation that misses key non-Gaussian effects from intra-compartmental structural disorder and/or intercompartmental water exchange. These biophysical mechanisms are conflated in conventional measures such as diffusional kurtosis, and exchange is commonly described using the Kärger model. Here, we develop a Correlation Tensor MRI (CTI) framework that derives the full three-dimensional microscopic-kurtosis tensor and related directional metrics that separate disorder- and Kärger exchange effects. Monte Carlo simulations demonstrate robust disentanglement of these features. In vivo human CTI revealed dominant radial K_μ^⊥ in white matter, consistent with structural disorder. In a rodent ischemic stroke model, elevated axial K_μ^∥ in lesions corresponded to neurite beading, confirmed histologically. In medulloblastoma, reduced directional CTI metrics reflected infiltration by uniformly shaped tumor cells, while in glioma, phenotypes with distinct cellular anisotropy and packing were resolved. These findings show that microscopic kurtosis cannot be neglected under most biological scenarios, and that structural disorder dominates non-Gaussian diffusion, with disease-specific alterations reflecting underlying pathology. Consequently, Kärger exchange alone is unlikely to be an adequate biophysical model in tissues. Our work provides unravels biophysical mechanisms of diffusional kurtosis biology, from humans to animal models.","manuscriptTitle":"Biophysical Mechanisms of Microscopic Diffusional Kurtosis in diffusion MRI","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-19 04:50:01","doi":"10.21203/rs.3.rs-8960143/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"communications-biology","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"commsbio","sideBox":"Learn more about [Communications Biology](http://www.nature.com/commsbio/)","snPcode":"","submissionUrl":"","title":"Communications Biology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Communications Series","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"ce433ae0-3778-40fb-8733-4d45a41c5665","owner":[],"postedDate":"March 19th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":64580777,"name":"Biological sciences/Biological techniques/Imaging/Diffusion tensor imaging"},{"id":64580778,"name":"Biological sciences/Biological techniques/Imaging/Magnetic resonance imaging"},{"id":64580779,"name":"Biological sciences/Biophysics/Computational biophysics"}],"tags":[],"updatedAt":"2026-04-21T05:10:43+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-19 04:50:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8960143","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8960143","identity":"rs-8960143","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}