Spinal neuromodulation targeting synergistically acting locomotor networks facilitates walking recovery after spinal cord injury

Spinal neuromodulation targeting synergistically acting locomotor networks facilitates walking recovery after spinal cord injury | 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 Spinal neuromodulation targeting synergistically acting locomotor networks facilitates walking recovery after spinal cord injury Pawan Sharma, Andrea M. Willhite, Ricardo Siu, Nicholas A. Stanis, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8563891/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 9 You are reading this latest preprint version Abstract Background: Non-invasive spinal cord transcutaneous stimulation (scTS) to the lumbosacral cord, combined with activity-based locomotor training (ABLT) and pharmacological intervention, enhances residual motor activity of the lower extremity muscles in individuals with chronic spinal cord injury (SCI). However, improvements in locomotor function remain limited. Recent findings suggest that locomotor and stepping ability post-SCI can be better regulated by the simultaneous delivery of scTS to synergistically acting locomotor-related neural networks along the spinal cord. We developed a novel multimodal neuromodulation that combines continuous scTS delivery to the spinal cord with alternating stimulation of the posterior nerve roots during ABLT to increasefunctional coupling between multilevelintegrated locomotor neural circuitries. Additionally, pharmacological neuromodulation was incorporated to increase spinal cord excitability and motor output further, thereby promoting locomotor recovery after SCI. Methods: We tested the developed neuromodulatory approach in two individuals, one with complete SCI and the other with motor-incomplete SCI. ScTS was delivered to the cervical, lumbosacral, and coccygeal spinal segments. Simultaneously, gait phase-dependent scTS was used to activate flexor-extensor motor pools in a spatiotemporally appropriate manner. ScTS delivery was coupled with ABLT to progressively increase body weight loading in incrementally challenging environments, transitioning from a non-weight-bearing position to body-weight-supported treadmill training and finally to overground walking. Both participants received periodic buspirone administration to further enhance spinal plasticity. Results: Within the first session, both participants generated electromyography activity in inactive or hypoactive muscles. Post-intervention, robust improvements in stepping and locomotor capabilities were observed across multiple testing environments. Notably, independent step initiation was observed for the first time in the participant with complete SCI, and the participant with motor-incomplete SCI progressed from AIS C to D. Kinematic, electromyography, and neurophysiological assessments revealed more symmetrical, task-appropriate muscle activation and increased spinal–supraspinal connectivity. Conclusion: This is the first report of improved locomotor function in humans with complete and incomplete SCI via the combination of coordinated activation of distinct locomotor networks, ABLT, and pharmacological intervention. This novel multimodal neuromodulation strategy offers a compelling rehabilitation approach to restore walking capabilities post-SCI. Trial Registration: The study was prospectively registered atClinicalTrials.gov (NCT04105114) on 26 September 2019. Spinal Cord Injury Neurorehabilitation Multimodal Neuromodulation Locomotion Spinal Cord Transcutaneous Stimulation Full Text Additional Declarations Competing interest reported. Y.P.G. holds shared interest in Cosyma Inc. and Onward. V.R.E. holds shared interest in Onward and SpineX, Inc. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest. Supplementary Files SupplementaryMaterial.docx SupplementaryVideo1.mp4 SupplementaryVideo2.mp4 SupplementaryVideo3.mp4 SupplementaryVideo4.mp4 Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 27 Jan, 2026 Reviews received at journal 27 Jan, 2026 Reviews received at journal 21 Jan, 2026 Reviewers agreed at journal 15 Jan, 2026 Reviewers agreed at journal 12 Jan, 2026 Reviewers invited by journal 12 Jan, 2026 Editor assigned by journal 12 Jan, 2026 Submission checks completed at journal 12 Jan, 2026 First submitted to journal 09 Jan, 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. 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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-8563891","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":574104132,"identity":"cf748f4f-f1c5-45e4-8283-4ebd4f6e3249","order_by":0,"name":"Pawan Sharma","email":"","orcid":"","institution":"Good Shepherd Rehabilitation","correspondingAuthor":false,"prefix":"","firstName":"Pawan","middleName":"","lastName":"Sharma","suffix":""},{"id":574104137,"identity":"e93ff8c2-de8d-47d6-8d5c-c260b37dc199","order_by":1,"name":"Andrea M. 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Y.P.G. holds shared interest in Cosyma Inc. and Onward. V.R.E. holds shared interest in Onward and SpineX, Inc. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.","formattedTitle":"Spinal neuromodulation targeting synergistically acting locomotor networks facilitates walking recovery after spinal cord injury","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":"journal-of-neuroengineering-and-rehabilitation","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jner","sideBox":"Learn more about [Journal of NeuroEngineering and Rehabilitation](http://jneuroengrehab.biomedcentral.com/)","snPcode":"12984","submissionUrl":"https://submission.nature.com/new-submission/12984/3","title":"Journal of NeuroEngineering and Rehabilitation","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Spinal Cord Injury, Neurorehabilitation, Multimodal Neuromodulation, Locomotion, Spinal Cord Transcutaneous Stimulation","lastPublishedDoi":"10.21203/rs.3.rs-8563891/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8563891/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNon-invasive spinal cord transcutaneous stimulation (scTS) to the lumbosacral cord, combined with activity-based locomotor training (ABLT) and pharmacological intervention, enhances residual motor activity of the lower extremity muscles in individuals with chronic spinal cord injury (SCI). However, improvements in locomotor function remain limited. Recent findings suggest that locomotor and stepping ability post-SCI can be better regulated by the simultaneous delivery of scTS to synergistically acting locomotor-related neural networks along the spinal cord. We developed a novel multimodal neuromodulation that combines continuous scTS delivery to the spinal cord with alternating stimulation of the posterior nerve roots during ABLT to increasefunctional coupling between multilevelintegrated locomotor neural circuitries. Additionally, pharmacological neuromodulation was incorporated to increase spinal cord excitability and motor output further, thereby promoting locomotor recovery after SCI.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe tested the developed neuromodulatory approach in two individuals, one with complete SCI and the other with motor-incomplete SCI. ScTS was delivered to the cervical, lumbosacral, and coccygeal spinal segments. Simultaneously, gait phase-dependent scTS was used to activate flexor-extensor motor pools in a spatiotemporally appropriate manner. ScTS delivery was coupled with ABLT to progressively increase body weight loading in incrementally challenging environments, transitioning from a non-weight-bearing position to body-weight-supported treadmill training and finally to overground walking. Both participants received periodic buspirone administration to further enhance spinal plasticity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWithin the first session, both participants generated electromyography activity in inactive or hypoactive muscles. Post-intervention, robust improvements in stepping and locomotor capabilities were observed across multiple testing environments. Notably, independent step initiation was observed for the first time in the participant with complete SCI, and the participant with motor-incomplete SCI progressed from AIS C to D. Kinematic, electromyography, and neurophysiological assessments revealed more symmetrical, task-appropriate muscle activation and increased spinal–supraspinal connectivity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is the first report of improved locomotor function in humans with complete and incomplete SCI via the combination of coordinated activation of distinct locomotor networks, ABLT, and pharmacological intervention. 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