{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T16:11:47Z","timestamp":1778256707229,"version":"3.51.4"},"reference-count":83,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000},"content-version":"vor","delay-in-days":105,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007366","name":"Fondazione Italiana Sclerosi Multipla","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007366","id-type":"DOI","asserted-by":"publisher"}]},{"name":"\u2018Detecting, Understanding and Treating Central Fatigue in Multiple Sclerosis (DUT-CF-MS): from Neurophysiological and Structural Hallmarks to Non-Invasive Brain Stimulation Treatment\u2019","award":["DOD W81XWH-19-1-0810"],"award-info":[{"award-number":["DOD W81XWH-19-1-0810"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,5,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Central fatigue affects 80% of patients with multiple sclerosis, with 60% of them claiming it as the most disabling symptom. Current research often independently explores neurophysiological, structural, or functional imaging and biological underpinnings of fatigue, thus lacking a multidimensional perspective. Here, we used a multidimensional approach to investigate the functional, structural and biological underpinnings of fatigue in MS and to assess the relative contribution of each factor. A cross-sectional study was conducted with 41 patients with relapsing\u2013remitting multiple sclerosis and 21 healthy controls (female 14) (HC). MS patients were recruited by including only those with an Expanded Disability Status Scale score &amp;lt; 4, and were categorized as fatigued (MS-F: 19, Female 13, FSS \u2265 4) or non-fatigued (MS-NF: 22, Female 11, FSS &amp;lt; 4). Over five phases, participants underwent Transcranial Magnetic Stimulation, resting-state Electroencephalography, structural and functional Magnetic Resonance, clinical assessments, and blood tests for neurofilament light chain, serum glial fibrillary acidic protein and cytokine levels. Data were analysed using both non-parametric and parametric tests, based on the data distribution. Finally, a decision-tree model was applied to predict patient group assignment. Neurophysiologically, the two patient groups differed in several domains. Those with fatigue had increased \u03b8-band EEG power in frontocentral regions with eyes open. Transcranial Magnetic Stimulation findings indicated significantly lower intracortical facilitation in the MS-F group. Neuroimaging revealed stronger functional connectivity between nodes of the Default Mode Network, between the left temporal node and the right prefrontal node, in the MS-F group. Furthermore, fractional anisotropy via Diffusion Tensor Imaging showed reduced white matter integrity in the corticospinal tracts and corpus callosum in these patients. No significant differences were observed in lesion load, brain volumes, clinical\/psychological measures, or blood sample findings linked with neurodegeneration or inflammation; the only psychological variable that differed between the two groups was the depression scale score, with MS-F patients reporting higher scores than MS-NF patients. The decision tree analysis identified both ICF and significantly lower fractional anisotropy values as the most accurate predictors of fatigue, with a classification accuracy of 84.2%. Results highlight the importance of a multidisciplinary approach in defining central fatigue in multiple sclerosis, which would emerge through subtle, subclinical, regional abnormalities of myelin integrity and clearly manifest neurophysiological evidence of impaired glutamatergic activity in motor areas. They also suggest possible biomarkers for the diagnosis of fatigue, possibly useful for eventual targeting novel neuromodulatory treatments.<\/jats:p>","DOI":"10.1093\/braincomms\/fcag134","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T11:42:16Z","timestamp":1776339736000},"source":"Crossref","is-referenced-by-count":0,"title":["Neurophysiological, imaging and neurobiological markers of central fatigue in multiple sclerosis"],"prefix":"10.1093","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1483-4650","authenticated-orcid":false,"given":"Alberto","family":"Benelli","sequence":"first","affiliation":[{"name":"Siena Brain Investigation & Neuromodulation Lab (Si-BIN Lab), Department of Medicine, Surgery and Neuroscience, University of Siena , Siena, 53100 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisa","family":"Tatti","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cellular and Biomedical Sciences, City University of NewYork, School of Medicine , New York, NY, 10031 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9803-7914","authenticated-orcid":false,"given":"Rosa","family":"Cortese","sequence":"additional","affiliation":[{"name":"UOC Neurologia, Department of Medicine, Surgery and Neuroscience, University of Siena , Siena, 53100 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisa","family":"Massucco","sequence":"additional","affiliation":[{"name":"Siena Brain Investigation & Neuromodulation Lab (Si-BIN Lab), Department of Medicine, Surgery and Neuroscience, University of Siena , Siena, 53100 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ludovico","family":"Luchetti","sequence":"additional","affiliation":[{"name":"UOC Neurologia, Department of Medicine, Surgery and Neuroscience, University of Siena , Siena, 53100 ,","place":["Italy"]},{"name":"Siena Imaging SRL , Siena, 53100 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Battaglini","sequence":"additional","affiliation":[{"name":"UOC Neurologia, Department of Medicine, Surgery and Neuroscience, University of Siena , Siena, 53100 ,","place":["Italy"]},{"name":"Siena Imaging SRL , Siena, 53100 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Javier","family":"Cudeiro","sequence":"additional","affiliation":[{"name":"Department of Physiotherapy, Medicine, and Biomedical Sciences, NEUROcom (Neuroscience and Motor Control Group), CICA (Interdisciplinary Center for Chemistry and Biology), and Galician Brain Stimulation Centre, Universidade da Coru\u00f1a , A Coru\u00f1a, 15001 ,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"de Mauro","sequence":"additional","affiliation":[{"name":"UOC Neurologia, Department of Medicine, Surgery and Neuroscience, University of Siena , Siena, 53100 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8820-3248","authenticated-orcid":false,"given":"Jian","family":"Zhang","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, Guangxi Medical University , Nanning, 530000 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Domenico","family":"Plantone","sequence":"additional","affiliation":[{"name":"UOC Neurologia, Department of Medicine, Surgery and Neuroscience, University of Siena , Siena, 53100 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrizio","family":"Pasqualetti","sequence":"additional","affiliation":[{"name":"Health Statistics, University La Sapienza , Roma, 00185 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Delia","family":"Righi","sequence":"additional","affiliation":[{"name":"UOC Neurologia, Department of Medicine, Surgery and Neuroscience, University of Siena , Siena, 53100 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Neri","sequence":"additional","affiliation":[{"name":"Siena Brain Investigation & Neuromodulation Lab (Si-BIN Lab), Department of Medicine, Surgery and Neuroscience, University of Siena , Siena, 53100 ,","place":["Italy"]},{"name":"Oto-Neuro-Tech Conjoined Lab, Policlinico Le Scotte, University of Siena , Siena, 53100 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Laura","family":"Stromillo","sequence":"additional","affiliation":[{"name":"UOC Neurologia, Department of Medicine, Surgery and Neuroscience, University of Siena , Siena, 53100 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandra","family":"Cinti","sequence":"additional","affiliation":[{"name":"Siena Brain Investigation & Neuromodulation Lab (Si-BIN Lab), Department of Medicine, Surgery and Neuroscience, University of Siena , Siena, 53100 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandro","family":"Giannotta","sequence":"additional","affiliation":[{"name":"Siena Brain Investigation & Neuromodulation Lab (Si-BIN Lab), Department of Medicine, Surgery and Neuroscience, University of Siena , Siena, 53100 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Lomi","sequence":"additional","affiliation":[{"name":"Siena Brain Investigation & Neuromodulation Lab (Si-BIN Lab), Department of Medicine, Surgery and Neuroscience, University of Siena , Siena, 53100 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adriano","family":"Scoccia","sequence":"additional","affiliation":[{"name":"Siena Brain Investigation & Neuromodulation Lab (Si-BIN Lab), Department of Medicine, Surgery and Neuroscience, University of Siena , Siena, 53100 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4499-212X","authenticated-orcid":false,"given":"Giuseppe","family":"Lai","sequence":"additional","affiliation":[{"name":"Goldsmiths, UK Department of Psychology, University of London , London, WC1E 7HU ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4930-7639","authenticated-orcid":false,"given":"Nicola","family":"De Stefano","sequence":"additional","affiliation":[{"name":"UOC Neurologia, Department of Medicine, Surgery and Neuroscience, University of Siena , Siena, 53100 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica","family":"Ulivelli","sequence":"additional","affiliation":[{"name":"UOC Neurologia, Department of Medicine, Surgery and Neuroscience, University of Siena , Siena, 53100 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6697-9459","authenticated-orcid":false,"given":"Simone","family":"Rossi","sequence":"additional","affiliation":[{"name":"Siena Brain Investigation & Neuromodulation Lab (Si-BIN Lab), Department of Medicine, Surgery and Neuroscience, University of Siena , Siena, 53100 ,","place":["Italy"]},{"name":"UOC Neurologia, Department of Medicine, Surgery and Neuroscience, University of Siena , Siena, 53100 ,","place":["Italy"]},{"name":"Oto-Neuro-Tech Conjoined Lab, Policlinico Le Scotte, University of Siena , Siena, 53100 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,4,16]]},"reference":[{"issue":"6","key":"2026050811380749500_fcag134-B1","first-page":"752","article-title":"Multiple sclerosis: Clinical aspects","volume":"31","author":"Oh","year":"2018","journal-title":"Curr Opin Neurol"},{"issue":"4","key":"2026050811380749500_fcag134-B2","first-page":"386","article-title":"Central fatigue in multiple sclerosis: A review of the literature","volume":"39","author":"Newland","year":"2016","journal-title":"J Spinal Cord Med"},{"issue":"4","key":"2026050811380749500_fcag134-B3","first-page":"409","article-title":"Fatigue and fatigability in neurologic illnesses: Proposal for a unified taxonomy","volume":"80","author":"Kluger","year":"2013","journal-title":"Neurology"},{"issue":"2","key":"2026050811380749500_fcag134-B4","first-page":"165","article-title":"Cytokine mRNA expression in patients with multiple sclerosis and fatigue","volume":"10","author":"Flachenecker","year":"2004","journal-title":"Mult Scler"},{"issue":"1","key":"2026050811380749500_fcag134-B5","first-page":"34","article-title":"Fatigue in multiple sclerosis: An example of cytokine mediated sickness behaviour?","volume":"77","author":"Heesen","year":"2006","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"2026050811380749500_fcag134-B6","first-page":"1","article-title":"Fatigue in patients with multiple sclerosis: Is it related to pro- and anti-inflammatory cytokines?","volume":"2015","author":"Malekzadeh","year":"2015","journal-title":"Dis Markers"},{"issue":"4","key":"2026050811380749500_fcag134-B7","first-page":"322","article-title":"Review: Cytokines and the pathogenesis of multiple sclerosis","volume":"45","author":"Navikas","year":"1996","journal-title":"J Neurosci Res"},{"key":"2026050811380749500_fcag134-B8","first-page":"67","article-title":"On the role of the amygdala for experiencing fatigue in patients with multiple sclerosis","volume":"20","author":"Hanken","year":"2018","journal-title":"Mult Scler Relat Disord"},{"issue":"2","key":"2026050811380749500_fcag134-B9","first-page":"128","article-title":"Anxiety levels are independently associated with cognitive performance in an Australian multiple sclerosis patient cohort","volume":"29","author":"Ribbons","year":"2017","journal-title":"JNP"},{"issue":"8","key":"2026050811380749500_fcag134-B10","first-page":"102","article-title":"Structural and neuronal integrity measures of fatigue severity in multiple sclerosis","volume":"7","author":"Bernitsas","year":"2017","journal-title":"Brain Sci"},{"issue":"1","key":"2026050811380749500_fcag134-B11","first-page":"6","article-title":"Fatigue in multiple sclerosis: The role of thalamus","volume":"26","author":"Capone","year":"2020","journal-title":"Mult Scler"},{"issue":"7","key":"2026050811380749500_fcag134-B12","first-page":"751","article-title":"Brain anatomical correlates of fatigue in multiple sclerosis","volume":"26","author":"Palotai","year":"2020","journal-title":"Mult Scler"},{"key":"2026050811380749500_fcag134-B13","first-page":"47","article-title":"Inter-hemispheric functional connectivity changes with corpus callosum morphology in multiple sclerosis","volume":"266","author":"Zito","year":"2014","journal-title":"Neuroscience"},{"issue":"13","key":"2026050811380749500_fcag134-B14","first-page":"1696","article-title":"Fatigue in multiple sclerosis: The contribution of resting-state functional connectivity reorganization","volume":"24","author":"Bisecco","year":"2018","journal-title":"Mult Scler"},{"issue":"8","key":"2026050811380749500_fcag134-B15","first-page":"2372","article-title":"Neural mechanisms underlying state mental fatigue in multiple sclerosis: A pilot study","volume":"267","author":"Chen","year":"2020","journal-title":"J Neurol"},{"issue":"14","key":"2026050811380749500_fcag134-B16","first-page":"1809","article-title":"Fatigue in multiple sclerosis: Does the functional or structural damage prevail?","volume":"26","author":"Bertoli","year":"2020","journal-title":"Mult Scler"},{"issue":"8","key":"2026050811380749500_fcag134-B17","first-page":"1398","article-title":"Functional MRI during the execution of a motor task in patients with multiple sclerosis and fatigue","volume":"117","author":"Specogna","year":"2012","journal-title":"Radiol Med"},{"issue":"4","key":"2026050811380749500_fcag134-B18","first-page":"554","article-title":"Multiple sclerosis\u2013related fatigue: Altered resting-state functional connectivity of the ventral striatum and dorsolateral prefrontal cortex","volume":"25","author":"Jaeger","year":"2019","journal-title":"Mult Scler"},{"issue":"1-2","key":"2026050811380749500_fcag134-B19","first-page":"34","article-title":"Fatigue and basal ganglia","volume":"179","author":"Chaudhuri","year":"2000","journal-title":"J Neurol Sci"},{"key":"2026050811380749500_fcag134-B20","first-page":"52","article-title":"Evaluation of MS related central fatigue using MR neuroimaging methods: Scoping review","volume":"400","author":"Arm","year":"2019","journal-title":"J Neurol Sci"},{"issue":"1","key":"2026050811380749500_fcag134-B21","first-page":"21927","article-title":"Using functional connectivity changes associated with cognitive fatigue to delineate a fatigue network","volume":"10","author":"Wylie","year":"2020","journal-title":"Sci Rep"},{"issue":"1","key":"2026050811380749500_fcag134-B22","first-page":"101","article-title":"Quantifying fatigue using electrophysiological techniques and non-invasive brain stimulation in people with multiple sclerosis- A review and discussion","volume":"26","author":"Hamilton","year":"2024","journal-title":"Biol Res Nurs"},{"issue":"4","key":"2026050811380749500_fcag134-B23","first-page":"474","article-title":"Prolonged cortical silent period is related to poor fitness and fatigue, but not tumor necrosis factor, in multiple sclerosis","volume":"130","author":"Chaves","year":"2019","journal-title":"Clinical Neurophysiology"},{"issue":"3","key":"2026050811380749500_fcag134-B24","first-page":"316","article-title":"Motor cortex excitability and fatigue in multiple sclerosis: A transcranial magnetic stimulation study","volume":"11","author":"Liepert","year":"2005","journal-title":"Mult Scler"},{"key":"2026050811380749500_fcag134-B25","first-page":"460","article-title":"Fatigue in multiple sclerosis: Neural correlates and the role of non-invasive brain stimulation","volume":"9","author":"Chalah","year":"2015","journal-title":"Front Cell Neurosci"},{"key":"2026050811380749500_fcag134-B26","first-page":"566","article-title":"Inflammation and corticospinal functioning in multiple sclerosis: A TMS perspective","volume":"11","author":"Stampanoni Bassi","year":"2020","journal-title":"Front Neurol"},{"issue":"7","key":"2026050811380749500_fcag134-B27","first-page":"1020","article-title":"Fatigue, depression, and pain 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