Targeted Stimulation of the Sensory Afferents Improves Motoneuron Function in Humans With Spinal Muscular Atrophy

Targeted Stimulation of the Sensory Afferents Improves Motoneuron Function in Humans With Spinal Muscular Atrophy | 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 Biological Sciences - Article Targeted Stimulation of the Sensory Afferents Improves Motoneuron Function in Humans With Spinal Muscular Atrophy Marco Capogrosso, Genis Prat-Ortega, Scott Ensel, Serena Donadio, and 19 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3970994/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 05 Feb, 2025 Read the published version in Nature Medicine → Version 1 posted You are reading this latest preprint version Abstract Spinal Muscular Atrophy (SMA) is an inherited neurodegenerative disease causing motoneuron dysfunction, muscle weakness and early mortality 1,2 . Three therapies can slow disease progression enabling people to survive albeit with lingering motoneuron dysfunction and severe motor impairments 3,4 . Here we introduce a neurotechnological approach that improved spinal motoneuron function, muscle strength and walking in three adults with SMA. Starting from preclinical evidence showing that motoneuron dysfunction in SMA originates from the loss of excitatory inputs from primary afferents 5,6 , we hypothesized that augmentation of sensory neural activity with targeted electrical stimulation could compensate for this loss thereby improving motoneuron function. To test this hypothesis we implanted three adults with SMA with epidural electrodes over the lumbosacral spinal cord to stimulate the sensory axons of the legs 7,8 . We stimulated participants for 4 weeks 2 hours per day while they executed walking and strength tasks. Remarkably, our neurostimulation regime led to robust improvements in strength, walking and fatigue paralleled by reduced neuronal hyperexcitability, increased sensory inputs and higher motoneuron firing rates. Our data indicates that targeted neurostimulation can reverse degenerative processes of circuit dysfunction thus promoting disease modifying effects in a human neurodegenerative disease. Biological sciences/Neuroscience/Diseases of the nervous system/Neurodegeneration Biological sciences/Neuroscience/Motor control/Motor neuron Biological sciences/Neuroscience/Motor control/Spinal cord Biological sciences/Neuroscience/Motor control/Brain–machine interface Full Text Additional Declarations Yes there is potential Competing Interest. This study was supported by an exploratory research grant from F. Hoffmann–La Roche to MC and RMF. F. Hoffmann–La Roche holds rights to IP related to this study via a license agreement with the University of Pittsburgh. MC, GPO and ME hold patent applications that relate to this work. Supplementary Files SupplementaryInformation.docx Supplementary Information VIDEO1.mp4 Video 1 VIDEO2.mp4 Video 2 VIDEO3.mp4 Video 3 VIDEO4.mp4 Video 4 VIDEO5new.mp4 Video 5 VIDEO6.mp4 Video 6 Cite Share Download PDF Status: Published Journal Publication published 05 Feb, 2025 Read the published version in Nature Medicine → 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-3970994","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":274053952,"identity":"067c874c-5c20-4f33-b980-f51aec71508d","order_by":0,"name":"Marco 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Hoffmann–La Roche to MC and RMF. F. Hoffmann–La Roche holds rights to IP related to this study via a license agreement with the University of Pittsburgh. MC, GPO and ME hold patent applications that relate to this work.","formattedTitle":"\u003cp\u003eTargeted Stimulation of the Sensory Afferents Improves Motoneuron Function in Humans With Spinal Muscular Atrophy\u003c/p\u003e","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":true,"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":"","lastPublishedDoi":"10.21203/rs.3.rs-3970994/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3970994/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eSpinal Muscular Atrophy (SMA) is an inherited neurodegenerative disease causing motoneuron dysfunction, muscle weakness and early mortality\u003csup\u003e1,2\u003c/sup\u003e. Three therapies can slow disease progression enabling people to survive albeit with lingering motoneuron dysfunction and severe motor impairments\u003csup\u003e3,4\u003c/sup\u003e. Here we introduce a neurotechnological approach that improved spinal motoneuron function, muscle strength and walking in three adults with SMA. \u0026nbsp;Starting from preclinical evidence showing that motoneuron dysfunction in SMA originates from the loss of excitatory inputs from primary afferents\u003csup\u003e5,6\u003c/sup\u003e, we hypothesized that augmentation of sensory neural activity with targeted electrical stimulation could compensate for this loss thereby improving motoneuron function. To test this hypothesis we implanted three adults with SMA with epidural electrodes over the lumbosacral spinal cord to stimulate the sensory axons of the legs\u003csup\u003e7,8\u003c/sup\u003e. We stimulated participants for 4 weeks 2 hours per day while they executed walking and strength tasks. Remarkably, our neurostimulation regime led to robust improvements in strength, walking and fatigue paralleled by reduced neuronal hyperexcitability, increased sensory inputs and higher motoneuron firing rates. Our data indicates that targeted neurostimulation can reverse degenerative processes of circuit dysfunction thus promoting disease modifying effects in a human neurodegenerative disease.\u0026nbsp;\u003c/p\u003e","manuscriptTitle":"Targeted Stimulation of the Sensory Afferents Improves Motoneuron Function in Humans With Spinal Muscular Atrophy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-15 05:59:37","doi":"10.21203/rs.3.rs-3970994/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-medicine","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nm","sideBox":"Learn more about [Nature Medicine](http://www.nature.com/nm/)","snPcode":"","submissionUrl":"","title":"Nature Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"5a347c2b-f30b-4fb3-b6a6-195021e392ec","owner":[],"postedDate":"March 15th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":29473828,"name":"Biological sciences/Neuroscience/Diseases of the nervous system/Neurodegeneration"},{"id":29473829,"name":"Biological sciences/Neuroscience/Motor control/Motor neuron"},{"id":29473830,"name":"Biological sciences/Neuroscience/Motor control/Spinal cord"},{"id":29473831,"name":"Biological sciences/Neuroscience/Motor control/Brain\u0026#x2013;machine interface"}],"tags":[],"updatedAt":"2025-02-06T08:07:57+00:00","versionOfRecord":{"articleIdentity":"rs-3970994","link":"https://doi.org/10.1038/s41591-024-03484-8","journal":{"identity":"nature-medicine","isVorOnly":false,"title":"Nature Medicine"},"publishedOn":"2025-02-05 05:00:00","publishedOnDateReadable":"February 5th, 2025"},"versionCreatedAt":"2024-03-15 05:59:37","video":"","vorDoi":"10.1038/s41591-024-03484-8","vorDoiUrl":"https://doi.org/10.1038/s41591-024-03484-8","workflowStages":[]},"version":"v1","identity":"rs-3970994","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3970994","identity":"rs-3970994","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}