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The integration of epidural electrical stimulation (EES) of the spinal cord with rehabilitation has substantial potential to improve recovery of motor functions; however, abnormal muscle cocontraction and spasticity may limit the benefit of these interventions and hinder the effectiveness of EES in promoting functional movements. High-frequency excitation block introduced in peripheral nerve stimulation could reduce abnormal activity and lead to more physiological activation patterns. Here, we evaluated the application of high-frequency EES (HF-EES) in alleviating undesired muscular cocontraction and spasticity in two patients with motor incomplete SCI implanted with a commercial 32-channel EES paddle commonly used for pain therapy. To design custom HF-EES protocols, we first mapped the muscles targeted by different EES configurations. Our results showed that HF-EES substantially reduced patellar reflex in one participant and eliminated both patellar reflex and ankle clonus in the other participant. By combining HF-EES and low-frequency EES (LF-EES) to enhance functional movements with intensive rehabilitation, we observed notable improvements in lower limb kinematics, muscle strength, and clinical lower limb motor assessments over the trial period. This study suggests that HF-EES could be an important supplementary tool in SCI treatment, emphasizing the importance of personalized rehabilitation approaches and advanced tools to optimize EES treatments and offering hope for individuals with SCI-related motor deficits.<\/jats:p>","DOI":"10.1126\/scitranslmed.adp9607","type":"journal-article","created":{"date-parts":[[2025,1,8]],"date-time":"2025-01-08T13:58:20Z","timestamp":1736344700000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":48,"title":["High-frequency epidural electrical stimulation reduces spasticity and facilitates walking recovery in patients with spinal cord injury"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0903-9441","authenticated-orcid":true,"given":"Simone","family":"Romeni","sequence":"first","affiliation":[{"name":"Modular Implantable Neuroprostheses (MINE) Laboratory, Universit\u00e0 Vita-Salute San Raffaele &amp; 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