{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T17:36:01Z","timestamp":1785000961460,"version":"3.55.0"},"reference-count":135,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Fatigue is a common and disabling symptom in multiple sclerosis (MS), quantifiable by patient reported outcome instruments such as the Fatigue Scale for Motor and Cognitive Functions (FSMC). The pathophysiology of fatigue remains poorly understood, and effective treatments are limited. Emerging evidence implicates disrupted excitation\u2013inhibition balance in the premotor cortex as a potential culprit of fatigue in MS. Converging evidence now show that such network imbalance can be modulated with repetitive transcranial magnetic stimulation (TMS). The efficacy of premotor rTMS retuning excitation-inhibition balance, thus improving MS-related fatigue, has yet to be examined in a clinical trial.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This randomized, double-blinded, sham-controlled, parallel-group trial investigates the efficacy of premotor TMS in treating fatigue in MS. Fifty-eight patients with MS will receive either active or sham TMS targeting the left dorsal premotor cortex (PMd). On five consecutive days, participants will undergo 30-min sessions using a novel low-frequency (0.72\u202fHz) paired-pulse repetitive TMS protocol with an interstimulus interval of 33\u202fms. The primary endpoint is the change in FSMC score 6 days post-intervention. Secondary outcomes include additional fatigue assessments and quantification of regional \u03b3-aminobutyric acid (GABA) and glutamate concentrations of the targeted PMd, via ultra-high-field (7T) magnetic resonance spectroscopy. We hypothesize that active treatment will result in greater fatigue reduction than sham treatment and correlate positively with an increase in regional GABA in the stimulated premotor region. Exploratory endpoints include structural and functional connectivity changes assessed with 7T resonance imaging and motor cortical excitability changes measured with TMS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>This study will assess the feasibility and efficacy of a novel low-frequency paired-pulse TMS protocol for fatigue in MS. Repeated neurophysiological measurements of cortical excitation\u2013inhibition balance will yield mechanistic insights and guide future repetitive TMS trials targeting MS-related fatigue.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical Trial Registration<\/jats:title>\n                    <jats:p>\n                      <jats:uri>http:\/\/www.clinicaltrials.gov<\/jats:uri>\n                      , NCT06569550.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fneur.2026.1759679","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T05:29:13Z","timestamp":1772083753000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Repetitive transcranial magnetic stimulation to alleviate fatigue in multiple sclerosis\u2014study protocol for a randomized sham-controlled double-blinded clinical trial"],"prefix":"10.3389","volume":"17","author":[{"given":"Sofus","family":"Nygaard","sequence":"first","affiliation":[{"name":"Danish Research Centre for Magnetic Resonance, Department of Radiology and Nuclear Medicine, Copenhagen University Hospital\u2014Amager and Hvidovre","place":["Hvidovre, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mads Alexander Just","family":"Madsen","sequence":"additional","affiliation":[{"name":"Danish Research Centre for Magnetic Resonance, Department of Radiology and Nuclear Medicine, Copenhagen University Hospital\u2014Amager and Hvidovre","place":["Hvidovre, Denmark"]},{"name":"MS Center Amsterdam, Anatomy and Neurosciences, Amsterdam Neuroscience, Amsterdam University Medical Center, location VUmc, Vrije Universiteit Amsterdam","place":["Amsterdam, Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Wiggermann","sequence":"additional","affiliation":[{"name":"Danish Research Centre for Magnetic Resonance, Department of Radiology and Nuclear Medicine, Copenhagen University Hospital\u2014Amager and Hvidovre","place":["Hvidovre, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Cabras","sequence":"additional","affiliation":[{"name":"Danish Research Centre for Magnetic Resonance, Department of Radiology and Nuclear Medicine, Copenhagen University Hospital\u2014Amager and Hvidovre","place":["Hvidovre, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lasse","family":"Christiansen","sequence":"additional","affiliation":[{"name":"Danish Research Centre for Magnetic Resonance, Department of Radiology and Nuclear Medicine, Copenhagen University Hospital\u2014Amager and Hvidovre","place":["Hvidovre, Denmark"]},{"name":"Department of Nutrition, Exercise and Sports, University of Copenhagen","place":["Copenhagen, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alena","family":"Svatkova","sequence":"additional","affiliation":[{"name":"Danish Research Centre for Magnetic Resonance, Department of Radiology and Nuclear Medicine, Copenhagen University Hospital\u2014Amager and Hvidovre","place":["Hvidovre, Denmark"]},{"name":"Department of Radiology and Nuclear Medicine, Copenhagen University Hospital\u2014Amager and Hvidovre","place":["Hvidovre, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Lundell","sequence":"additional","affiliation":[{"name":"Danish Research Centre for Magnetic Resonance, Department of Radiology and Nuclear Medicine, Copenhagen University Hospital\u2014Amager and Hvidovre","place":["Hvidovre, Denmark"]},{"name":"MR Section, DTU Health Tech, Technical University of Denmark","place":["Lyngby, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helene","family":"H\u00f8jsgaard Chow","sequence":"additional","affiliation":[{"name":"Department of Neurology, Danish Multiple Sclerosis Center, Copenhagen University Hospital\u2014Rigshospitalet","place":["Glostrup, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeppe","family":"Romme Christensen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Danish Multiple Sclerosis Center, Copenhagen University Hospital\u2014Rigshospitalet","place":["Glostrup, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morten","family":"Blinkenberg","sequence":"additional","affiliation":[{"name":"Department of Neurology, Danish Multiple Sclerosis Center, Copenhagen University Hospital\u2014Rigshospitalet","place":["Glostrup, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Finn","family":"Sellebjerg","sequence":"additional","affiliation":[{"name":"Department of Neurology, Danish Multiple Sclerosis Center, Copenhagen University Hospital\u2014Rigshospitalet","place":["Glostrup, Denmark"]},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen","place":["Copenhagen, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hartwig","family":"Siebner","sequence":"additional","affiliation":[{"name":"Danish Research Centre for Magnetic Resonance, Department of Radiology and Nuclear Medicine, Copenhagen University Hospital\u2014Amager and Hvidovre","place":["Hvidovre, Denmark"]},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen","place":["Copenhagen, Denmark"]},{"name":"Department of Neurology, Copenhagen University Hospital\u2014Bispebjerg and Frederiksberg","place":["Copenhagen, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,26]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1016\/j.smim.2009.08.003","article-title":"Genetics and pathogenesis of multiple sclerosis","volume":"21","author":"Zuvich","year":"2009","journal-title":"Semin Immunol"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1016\/s1474-4422(18)30443-5","article-title":"Global, regional, and national burden of multiple sclerosis 1990\u20132016: a systematic analysis for the global burden of disease study 2016","volume":"18","author":"Wallin","year":"2019","journal-title":"Lancet Neurol"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"3","DOI":"10.2217\/nmt.15.55","article-title":"Prevalence of multiple sclerosis symptoms across lifespan: data from the NARCOMS registry","volume":"5","author":"Fox","year":"2015","journal-title":"Neurodegener Dis 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