{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T03:00:49Z","timestamp":1784775649596,"version":"3.55.0"},"posted":{"date-parts":[[2025,8,13]]},"group-title":"Neurology","reference-count":130,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T00:00:00Z","timestamp":1755043200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,8,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Multiple sclerosis (MS) is a progressive inflammatory neurodegenerative disease that degrades neural transmission between the brain and spinal \u03b1-motoneurons. These voluntary motor commands contain excitatory, inhibitory, and neuromodulatory components that must be appropriately balanced for skilled motor control. Unlike other clinical populations, in MS we have no knowledge about how voluntary motor commands are disrupted. MS is a clinically heterogeneous population, with sensorimotor impairments that vary widely and unpredictably across patients. Our overall scientific hypothesis is that the voluntary motor command in the MS population varies accordingly, with multiple \u201cphenotypes\u201d evident. Here, we explore this idea by identifying pathological aspects of the voluntary motor command in 59 participants with MS with a range of sensorimotor symptoms and disability, compared with 38 age-\/sex-matched controls. We recorded motor unit discharge from the tibialis anterior and soleus muscles during isometric dorsiflexion\/plantarflexion contractions. We then calculated geometric and temporal features in their firing patterns to characterize their excitatory, inhibitory, and neuromodulatory inputs according to a recently developed \u201creverse engineering\u201d paradigm. MS values for many of our parameters were highly variable, with some participants with abnormally values and others with abnormally low values. In addition to this variability, MS group means for most parameters reflecting the balance of neuromodulation and inhibition were significantly lower than those of controls. These initial findings support the idea that there may be different phenotypes of voluntary motor command pathology among patients with MS, indicating the potential need to personalize the selection of mechanistically targeted rehabilitation therapies.<\/jats:p>","DOI":"10.1101\/2025.08.12.25333527","type":"posted-content","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T00:05:32Z","timestamp":1755129932000},"source":"Crossref","is-referenced-by-count":1,"title":["Pathophysiology of voluntary motor commands at the level of the spinal motoneuron in patients with multiple sclerosis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8228-0525","authenticated-orcid":false,"given":"Laura M.","family":"McPherson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7643-3887","authenticated-orcid":false,"given":"Keith R.","family":"Lohse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Skyler M.","family":"Simon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2288-8672","authenticated-orcid":false,"given":"James A.","family":"Beauchamp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9094-8932","authenticated-orcid":false,"given":"Francesco","family":"Negro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0520-4283","authenticated-orcid":false,"given":"Robert T.","family":"Naismith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0829-7569","authenticated-orcid":false,"given":"Anne H.","family":"Cross","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025081602201084000_2025.08.12.25333527v1.1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00598.2017"},{"key":"2025081602201084000_2025.08.12.25333527v1.2","first-page":"247","article-title":"Monoamine metabolites in successive samples of spinal fluid: A comparison between healthy volunteers and patients with multiple sclerosis","volume":"63","year":"1981","journal-title":"Acta Neurologica Scandinavica"},{"key":"2025081602201084000_2025.08.12.25333527v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-022-01196-1"},{"key":"2025081602201084000_2025.08.12.25333527v1.4","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2021.791824"},{"key":"2025081602201084000_2025.08.12.25333527v1.5","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2011.215160"},{"key":"2025081602201084000_2025.08.12.25333527v1.6","doi-asserted-by":"crossref","unstructured":"Baker SN , Zaaimi B , Fisher KM , Edgley SA & Soteropoulos DS (2015). 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