Circuitry dynamics of the cerebellum inform differential therapeutic responses and patient stratification in essential tremor

Circuitry dynamics of the cerebellum inform differential therapeutic responses and patient stratification in essential tremor | 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 Circuitry dynamics of the cerebellum inform differential therapeutic responses and patient stratification in essential tremor Ming-Kai Pan, Liang-Ying Chen, Yi-Mei Wang, Alexander White, Jou-Yu Ho, and 15 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8705665/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 Essential tremor (ET) is the most common movement disorder, yet fewer than 50% of patients respond to current pharmacological treatments. This study identifies spatiotemporal cerebellar neurodynamics as key determinants of differential therapeutic responses in two clinically linked ET mouse models: harmaline-induced (harmane toxicity) and Grid2dupE3 (climbing fiber overgrowth) mice. In vivo electrophysiology and two-photon imaging revealed that harmaline mice exhibit regional PC synchrony and respond to propranolol, whereas Grid2dupE3 mice show global PC synchrony and resistance to propranolol. Computational models revealed that inferior olivary pacemaking via HCN and T-type calcium channels drives harmaline tremors, while Grid2dupE3 tremors arise from self-sustained circuitry oscillations independent of olivary pacemaking. The models not only predicted the outcomes of a preclinical drug trial, but also generated an electrophysiological biomarker of frequency dynamic index (FDI) for patient stratification. These findings uncover a neurodynamic mechanism and modeling platform for therapeutic discovery and biomarker development in ET. Biological sciences/Neuroscience/Neural circuits Health sciences/Neurology/Neurological disorders/Movement disorders Biological sciences/Neuroscience/Diseases of the nervous system Full Text Additional Declarations Yes there is potential Competing Interest. M.-K.P. is a consultant for Praxis Precision Medicines, Cambridge, Massachusetts, USA; BioPro Scientific, Taiwan; and Sumitomo Pharma Co., Japan. M.-K.P. confirmed that this research is unrelated to the consulting roles. The other authors declare that they have no competing interests. Supplementary Files SA1MKPalexv8checked.pdf SA1 DatafileS1.xlsx Data File S1 videoS1Harmalinepropranololv2.mov Video S1. Force-plate-based tremor recording for drug response assessment in harmaline-induced mice. videoS2Grid2propranololv2.mov Video S2. Force-plate-based tremor recording for drug response assessment in Grid2dupE3 mice. videoS3synchronypattern.mov Video S3. Two-photon imaging of Purkinje dendrite synchrony patterns in tremor models. 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-8705665","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":585480159,"identity":"760055f3-b8a7-4fe6-8810-0b6543be4833","order_by":0,"name":"Ming-Kai 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The other authors declare that they have no competing interests.","formattedTitle":"Circuitry dynamics of the cerebellum inform differential therapeutic responses and patient stratification in essential tremor","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"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":"","lastPublishedDoi":"10.21203/rs.3.rs-8705665/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8705665/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Essential tremor (ET) is the most common movement disorder, yet fewer than 50% of patients respond to current pharmacological treatments. This study identifies spatiotemporal cerebellar neurodynamics as key determinants of differential therapeutic responses in two clinically linked ET mouse models: harmaline-induced (harmane toxicity) and Grid2dupE3 (climbing fiber overgrowth) mice. In vivo electrophysiology and two-photon imaging revealed that harmaline mice exhibit regional PC synchrony and respond to propranolol, whereas Grid2dupE3 mice show global PC synchrony and resistance to propranolol. Computational models revealed that inferior olivary pacemaking via HCN and T-type calcium channels drives harmaline tremors, while Grid2dupE3 tremors arise from self-sustained circuitry oscillations independent of olivary pacemaking. The models not only predicted the outcomes of a preclinical drug trial, but also generated an electrophysiological biomarker of frequency dynamic index (FDI) for patient stratification. 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