Fundamental limitations of kilohertz-frequency carriers in afferent fiber recruitment with transcutaneous spinal cord stimulation

Fundamental limitations of kilohertz-frequency carriers in afferent fiber recruitment with transcutaneous spinal cord stimulation | 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 Fundamental limitations of kilohertz-frequency carriers in afferent fiber recruitment with transcutaneous spinal cord stimulation Ismael Seáñez, Rodolfo Keesey, Ursula Hofstoetter, Zhaoshun Hu, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4810374/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 May, 2026 Read the published version in Nature Biomedical Engineering → Version 1 posted You are reading this latest preprint version Abstract The use of kilohertz-frequency (KHF) waveforms has rapidly gained momentum in transcutaneous spinal cord stimulation (tSCS) to restore motor function after paralysis. However, the mechanisms by which these fast-alternating currents depolarize efferent and afferent fibers remain unknown. Our study fills this research gap by providing a hypothesis- and evidence-based investigation using peripheral nerve stimulation, lumbar tSCS, and cervical tSCS in 25 unimpaired participants together with computational modeling. Peripheral nerve stimulation experiments and computational modeling showed that KHF waveforms negatively impact the processes required to elicit action potentials, thereby increasing response thresholds and biasing the recruitment towards efferent fibers. While these results translate to tSCS, we also demonstrate that lumbar tSCS results in the preferential recruitment of afferent fibers, while cervical tSCS favors recruitment of efferent fibers. Given the assumed importance of proprioceptive afferents in motor recovery, our work suggests that the use of KHF waveforms should be reconsidered to maximize neurorehabilitation outcomes, particularly for cervical tSCS. We posit that careful analysis of the mechanisms that mediate responses elicited by novel approaches in tSCS is crucial to understanding their potential to restore motor function after paralysis. Biological sciences/Neuroscience/Motor control/Spinal cord Biological sciences/Neuroscience/Regeneration and repair in the nervous system/Spinal cord injury Full Text Additional Declarations Yes there is potential Competing Interest. A.R., and K.M. hold several patents related to spinal cord stimulation. Supplementary Files IsmaelSeanez2024KeeseyHofstoettereditorialpolicychecklist.pdf Editorial policy checklist Cite Share Download PDF Status: Published Journal Publication published 12 May, 2026 Read the published version in Nature Biomedical Engineering → 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-4810374","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":343060220,"identity":"bc467de3-3846-407a-af0a-15637e64b9ce","order_by":0,"name":"Ismael Seáñez","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9klEQVRIiWNgGAWjYBACNjBZAOV9ABHsQMxDUIsBhMM4A6SamYAWBmQtzDzEaOHjP5344YNBnRz/7ObDn23bDtvbMzMwPnjbhsdhErmbJWcYHDaWuHMswTi37XBiDzMDs+FcvFp4N0jzGBxIbLiRY5Ccu+1wAtBhbNK8+LTwn938+49BXf38G/kfDltuO2wP1ML+G68Whtxt0gwGzAkGN3IYmxm3HWYEOoyNGa8Widxtlj0Ghw033kgzZuz9l57Yc5ixWXLOOdxa5PvPbr7xo6JOXu5G8uMPP85Y27O3Nx/88KYMtxZsgLGBNPWjYBSMglEwCjAAACY2S3dN7JzSAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-0068-7124","institution":"Washington University in St. Louis","correspondingAuthor":true,"prefix":"","firstName":"Ismael","middleName":"","lastName":"Seáñez","suffix":""},{"id":343060221,"identity":"41e4e0e6-9110-44dc-a676-2a99c0b12448","order_by":1,"name":"Rodolfo Keesey","email":"","orcid":"","institution":"Washington University in St. Louis","correspondingAuthor":false,"prefix":"","firstName":"Rodolfo","middleName":"","lastName":"Keesey","suffix":""},{"id":343060222,"identity":"c4f3cea0-2592-4f8d-ae10-1cc4dc800c29","order_by":2,"name":"Ursula Hofstoetter","email":"","orcid":"","institution":"Medical University of Vienna","correspondingAuthor":false,"prefix":"","firstName":"Ursula","middleName":"","lastName":"Hofstoetter","suffix":""},{"id":343060223,"identity":"52e6e83e-75e6-47f6-8b8e-e38bbf5c7d8b","order_by":3,"name":"Zhaoshun Hu","email":"","orcid":"","institution":"University of Erlangen-Nuremberg","correspondingAuthor":false,"prefix":"","firstName":"Zhaoshun","middleName":"","lastName":"Hu","suffix":""},{"id":343060224,"identity":"4f1e0aba-176a-475a-9a31-3fa758ab0814","order_by":4,"name":"Lorenzo Lombardi","email":"","orcid":"","institution":"Washington University in St. Louis","correspondingAuthor":false,"prefix":"","firstName":"Lorenzo","middleName":"","lastName":"Lombardi","suffix":""},{"id":343060225,"identity":"48147010-c03c-40ab-a014-af97a5292a71","order_by":5,"name":"Rachel Hawthorn","email":"","orcid":"","institution":"Washington University in St. Louis","correspondingAuthor":false,"prefix":"","firstName":"Rachel","middleName":"","lastName":"Hawthorn","suffix":""},{"id":343060226,"identity":"18ccd9f2-88f3-435e-844e-91cb7bdff449","order_by":6,"name":"Noah Bryson","email":"","orcid":"","institution":"Washington University in St. Louis","correspondingAuthor":false,"prefix":"","firstName":"Noah","middleName":"","lastName":"Bryson","suffix":""},{"id":343060227,"identity":"5f84fe8b-626f-4bd6-b4d8-113f8a26567f","order_by":7,"name":"Andreas Rowald","email":"","orcid":"","institution":"University of Erlangen-Nuremberg","correspondingAuthor":false,"prefix":"","firstName":"Andreas","middleName":"","lastName":"Rowald","suffix":""},{"id":343060228,"identity":"ea6afa8e-6a34-4fa4-9824-d8c9a6904478","order_by":8,"name":"Karen Minassian","email":"","orcid":"","institution":"Medical University of Vienna","correspondingAuthor":false,"prefix":"","firstName":"Karen","middleName":"","lastName":"Minassian","suffix":""}],"badges":[],"createdAt":"2024-07-26 22:55:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4810374/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4810374/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41551-026-01684-w","type":"published","date":"2026-05-12T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":109158920,"identity":"88d86b0c-9177-4626-bd43-e79a73037e51","added_by":"auto","created_at":"2026-05-13 07:16:16","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":18485302,"visible":true,"origin":"","legend":"","description":"","filename":"2024KeeseyHofstoetterNatureBME.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4810374/v1_covered_a4084994-b814-4401-8882-1f9fbe9681d8.pdf"},{"id":62995424,"identity":"332eeb0b-3114-4de9-96c0-ec25b2f34655","added_by":"auto","created_at":"2024-08-22 01:13:47","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1682464,"visible":true,"origin":"","legend":"Editorial policy checklist","description":"","filename":"IsmaelSeanez2024KeeseyHofstoettereditorialpolicychecklist.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4810374/v1/437b9c61e2ad81e32bcc939e.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nA.R., and K.M. hold several patents related to spinal cord stimulation.","formattedTitle":"Fundamental limitations of kilohertz-frequency carriers in afferent fiber recruitment with transcutaneous spinal cord stimulation","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"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":"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-4810374/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4810374/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"The use of kilohertz-frequency (KHF) waveforms has rapidly gained momentum in transcutaneous spinal cord stimulation (tSCS) to restore motor function after paralysis. However, the mechanisms by which these fast-alternating currents depolarize efferent and afferent fibers remain unknown. Our study fills this research gap by providing a hypothesis- and evidence-based investigation using peripheral nerve stimulation, lumbar tSCS, and cervical tSCS in 25 unimpaired participants together with computational modeling. Peripheral nerve stimulation experiments and computational modeling showed that KHF waveforms negatively impact the processes required to elicit action potentials, thereby increasing response thresholds and biasing the recruitment towards efferent fibers. While these results translate to tSCS, we also demonstrate that lumbar tSCS results in the preferential recruitment of afferent fibers, while cervical tSCS favors recruitment of efferent fibers. Given the assumed importance of proprioceptive afferents in motor recovery, our work suggests that the use of KHF waveforms should be reconsidered to maximize neurorehabilitation outcomes, particularly for cervical tSCS. We posit that careful analysis of the mechanisms that mediate responses elicited by novel approaches in tSCS is crucial to understanding their potential to restore motor function after paralysis.","manuscriptTitle":"Fundamental limitations of kilohertz-frequency carriers in afferent fiber recruitment with transcutaneous spinal cord stimulation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-22 01:13:42","doi":"10.21203/rs.3.rs-4810374/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-biomedical-engineering","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"natbiomedeng","sideBox":"Learn more about [Nature Biomedical Engineering](http://www.nature.com/natbiomedeng/)","snPcode":"41551","submissionUrl":"https://mts-natbiomedeng.nature.com/cgi-bin/main.plex","title":"Nature Biomedical Engineering","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"e001c714-db3c-479d-845f-9b1f79daafb6","owner":[],"postedDate":"August 22nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":36346365,"name":"Biological sciences/Neuroscience/Motor control/Spinal cord"},{"id":36346366,"name":"Biological sciences/Neuroscience/Regeneration and repair in the nervous system/Spinal cord injury"}],"tags":[],"updatedAt":"2026-05-13T07:15:37+00:00","versionOfRecord":{"articleIdentity":"rs-4810374","link":"https://doi.org/10.1038/s41551-026-01684-w","journal":{"identity":"nature-biomedical-engineering","isVorOnly":false,"title":"Nature Biomedical Engineering"},"publishedOn":"2026-05-12 04:00:00","publishedOnDateReadable":"May 12th, 2026"},"versionCreatedAt":"2024-08-22 01:13:42","video":"","vorDoi":"10.1038/s41551-026-01684-w","vorDoiUrl":"https://doi.org/10.1038/s41551-026-01684-w","workflowStages":[]},"version":"v1","identity":"rs-4810374","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4810374","identity":"rs-4810374","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}