Longitudinal Resting-State fMRI Reveals Temporal Evolution of Network-Level Alterations in a Mouse Model of Tinnitus

Longitudinal Resting-State fMRI Reveals Temporal Evolution of Network-Level Alterations in a Mouse Model of Tinnitus | 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 Longitudinal Resting-State fMRI Reveals Temporal Evolution of Network-Level Alterations in a Mouse Model of Tinnitus Tengfei Qu, Wei Zhang, Binbin Nie, Jie Wang, Zhengde Du This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9089544/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Tinnitus, one of the most common hearing disorders, profoundly impacts patients’ quality of life, often leading to severe emotional distress and sleep disturbances. Despite its clinical burden, therapeutic options remain limited due to an incomplete understanding of its pathophysiology. While cochlear damage is a known trigger, accumulating evidence suggests that maladaptive central plasticity—particularly in non-auditory networks—plays a central role in the chronicity of tinnitus. Specifically, limbic structures (hippocampus, amygdala) and striatal regions (caudate putamen) show altered functional connectivity with auditory nuclei in both human fMRI and animal models. To systematically map these network-level changes, we employed a noise-induced tinnitus mouse model and performed longitudinal resting-state BOLD fMRI across 27 brain regions of interest (ROIs). Our multi-time point analysis revealed early phase hyperactivity (days 1 and 7 post-injury) in auditory thalamocortical pathways, consistent with compensatory gamma oscillation mechanisms. This was followed by delayed limbic-striatal engagement (day 28), characterized by enhanced hippocampal-amygdala connectivity and caudate putamen dysregulation, which aligns with human studies of tinnitus-related emotional processing. We observed a dynamic network expansion over time, where initially localized auditory abnormalities progressively recruited the default mode and salience networks. These findings validate the ‘central gain reorganization’ hypothesis and highlight novel therapeutic targets. Notably, the caudate putamen emerged as a key modulator in the gating of phantom sound perception, suggesting the potential efficacy of striatal-directed neuromodulation. This work bridges translational gaps by demonstrating that tinnitus is a whole-brain disorder requiring network-level interventions, paving the way for personalized neuromodulatory strategies. Tinnitus Resting-state functional magnetic resonance imaging (rs-fMRI) Functional connectivity Fractional amplitude of low-frequency fluctuations (fALFF) Regional homogeneity (ReHo) Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviewers invited by journal 23 Mar, 2026 Editor assigned by journal 13 Mar, 2026 Submission checks completed at journal 12 Mar, 2026 First submitted to journal 10 Mar, 2026 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-9089544","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":610810045,"identity":"b4f412c6-f7d8-41e1-87da-77271746e0a3","order_by":0,"name":"Tengfei Qu","email":"","orcid":"","institution":"Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Tengfei","middleName":"","lastName":"Qu","suffix":""},{"id":610810046,"identity":"c35566dc-e91f-41a1-953f-814f8a0a9971","order_by":1,"name":"Wei Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABC0lEQVRIie3QMUvDQBTA8QuB0+HZri+0Gj/Ck0JcDvtBXB4ErksEp04dAoF2dBX0c2SOHMRF8CucCM51UCJIa9KOkrSj4P2Xg+P94N4J4XL9xXB7gDzIHiwTQt/3jd2L9KCMyV6rYbCQmvYh4gSTKLBLregZTrFLhHfZ28vHXA0lakYmAyMDgsRMXbYR7748Hx3PNUh4LaghkTkqrCj1VdpCfORoEOSmXl8zb0mPyUtNK5E4+azJGqRIqNg8LAPCLgLN1u95AfIwOUuZNJC/gyAm04G3iutdylgwKUBTfzJ37BLeTvKgeroYh4vs8av6xnH/xhi7nKlWsvkC+HXFHeNNXrVjwOVyuf55P6UXVb/RvXI2AAAAAElFTkSuQmCC","orcid":"","institution":"China Academy of Chinese Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Wei","middleName":"","lastName":"Zhang","suffix":""},{"id":610810047,"identity":"ed03e8ef-afbd-4b41-95bc-487dc6408e6f","order_by":2,"name":"Binbin Nie","email":"","orcid":"","institution":"The Institute of High Energy Physics of the Chinese Academy of Sciences","correspondingAuthor":false,"prefix":"","firstName":"Binbin","middleName":"","lastName":"Nie","suffix":""},{"id":610810048,"identity":"caf98699-07e3-4a2c-a59e-bd6637d02124","order_by":3,"name":"Jie Wang","email":"","orcid":"","institution":"National Center for Magnetic Resonance in Wuhan, Chinese Academy of Sciences-Wuhan National Laboratory for Optoelectronics","correspondingAuthor":false,"prefix":"","firstName":"Jie","middleName":"","lastName":"Wang","suffix":""},{"id":610810049,"identity":"281705ca-1908-4127-9346-925a3f3b7446","order_by":4,"name":"Zhengde Du","email":"","orcid":"","institution":"Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zhengde","middleName":"","lastName":"Du","suffix":""}],"badges":[],"createdAt":"2026-03-11 03:54:55","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9089544/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9089544/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105415996,"identity":"98ca5000-da62-43d4-b950-9698992f150a","added_by":"auto","created_at":"2026-03-25 18:55:02","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1126486,"visible":true,"origin":"","legend":"","description":"","filename":"manraw.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9089544/v1_covered_c86f0122-2b50-47f1-822c-5194fb23b4b0.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Longitudinal Resting-State fMRI Reveals Temporal Evolution of Network-Level Alterations in a Mouse Model of Tinnitus","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":"applied-magnetic-resonance","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"apmr","sideBox":"Learn more about [Applied Magnetic Resonance](http://link.springer.com/journal/723)","snPcode":"723","submissionUrl":"https://submission.nature.com/new-submission/723/3","title":"Applied Magnetic Resonance","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Tinnitus, Resting-state functional magnetic resonance imaging (rs-fMRI), Functional connectivity, Fractional amplitude of low-frequency fluctuations (fALFF), Regional homogeneity (ReHo)","lastPublishedDoi":"10.21203/rs.3.rs-9089544/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9089544/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eTinnitus, one of the most common hearing disorders, profoundly impacts patients\u0026rsquo; 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Despite its clinical burden, therapeutic options remain limited due to an incomplete understanding of its pathophysiology. While cochlear damage is a known trigger, accumulating evidence suggests that maladaptive central plasticity\u0026mdash;particularly in non-auditory networks\u0026mdash;plays a central role in the chronicity of tinnitus. Specifically, limbic structures (hippocampus, amygdala) and striatal regions (caudate putamen) show altered functional connectivity with auditory nuclei in both human fMRI and animal models. To systematically map these network-level changes, we employed a noise-induced tinnitus mouse model and performed longitudinal resting-state BOLD fMRI across 27 brain regions of interest (ROIs). Our multi-time point analysis revealed early phase hyperactivity (days 1 and 7 post-injury) in auditory thalamocortical pathways, consistent with compensatory gamma oscillation mechanisms. This was followed by delayed limbic-striatal engagement (day 28), characterized by enhanced hippocampal-amygdala connectivity and caudate putamen dysregulation, which aligns with human studies of tinnitus-related emotional processing. We observed a dynamic network expansion over time, where initially localized auditory abnormalities progressively recruited the default mode and salience networks. These findings validate the \u0026lsquo;central gain reorganization\u0026rsquo; hypothesis and highlight novel therapeutic targets. Notably, the caudate putamen emerged as a key modulator in the gating of phantom sound perception, suggesting the potential efficacy of striatal-directed neuromodulation. 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