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While speed dependent treadmill training (SDTT) is clinically effective, the specific biomechanical and neurophysiological mechanisms driving these improvements remain unclear. The \u201cStepuP\u201d multicenter randomized controlled trial aims to elucidate these mechanisms and determine whether training enriched with virtual reality or mechanical perturbations (SDTT+) enhances gait efficacy and transfer to daily life.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We will recruit 126 individuals with Parkinson\u2019s disease across four clinical sites and 21 healthy older adults as a reference group. Participants will be randomized to receive either standard SDTT or SDTT+ for 12 sessions. To capture the trajectory of recovery and retention, assessments will occur at three distinct timepoints: baseline, post-intervention, and a 12-week follow-up, each assessment including synchronized 64-channel electroencephalography (EEG), electromyography (EMG), and 3D kinematics. This multimodal setup allows for the quantification of cortical beta-band activity, corticomuscular coherence, and stability-related foot placement control. Furthermore, we will assess participant\u2019s satisfaction, usability, and engagement through questionnaires and interviews to understand individual adherence and barriers to training.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>The primary clinical endpoint is comfortable overground walking speed. We hypothesize that gait improvements are mediated by improved stability-related foot placement and cortical sensorimotor integration. By correlating lab-based mechanistic changes with real-world mobility patterns and participant experiences, this study seeks to identify specific pathophysiological mechanisms engaged during the treadmill training. These insights will help distinguish responders from non-responders, facilitating the development of personalized, acceptable, and effective rehabilitation strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0348957","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T17:29:12Z","timestamp":1782408552000},"page":"e0348957","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Steps against the burden of Parkinson\u2019s disease (StepuP): Protocol of a randomized controlled trial elucidating the biomechanical and neurophysiological mechanisms of a speed dependent treadmill training intervention"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9620-2990","authenticated-orcid":true,"given":"Anina Moira","family":"van Leeuwen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julius","family":"Welzel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1568-7149","authenticated-orcid":true,"given":"Ilaria","family":"D\u2019Ascanio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Lang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2951-2208","authenticated-orcid":true,"given":"Vaishali","family":"Vinod","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pia","family":"G\u00f6rrisen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Geritz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clint","family":"Hansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eran","family":"Gazit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahar Siman","family":"Tov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Revital","family":"Prusak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Casadei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6057-6816","authenticated-orcid":true,"given":"Angela","family":"Contri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Tampellini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"Pellicciari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Lopane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna Calandra","family":"Buonaura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Palmerini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noman","family":"Zahid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehwish","family":"Mehwish","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayna","family":"Ratanapongleka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Husna","family":"Razee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederic","family":"von Wegner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6129-0801","authenticated-orcid":true,"given":"Bernadette C. 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