{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T10:47:32Z","timestamp":1787741252922,"version":"build-2784847793"},"reference-count":46,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,20]],"date-time":"2025-04-20T00:00:00Z","timestamp":1745107200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Fatigue is a prevalent and debilitating symptom in people with multiple sclerosis (pwMS), significantly impairing quality of life. While the cerebellum is traditionally associated with motor control, emerging evidence suggests its involvement in cognitive, emotional, and integrative functions. This study aimed to explore the relationship between fatigue components (physical, cognitive, and psychosocial), clinical disability, and cerebellar structural changes in pwMS acquired via magnetic resonance imaging (MRI). Methods: Participants of this cross-sectional study underwent clinical assessments for fatigue (Modified Fatigue Impact Scale) and disability (Expanded Disability Status Scale). Cerebellar volumes were measured using high-resolution MRI and voxel-based morphometry (VBM) to identify correlations between fatigue subdomains and specific cerebellar subregions. Statistical analyses included group comparisons and correlation tests. Results: Forty-four pwMS were included. Fatigued MS patients exhibited reduced sensorimotor cerebellar volumes compared to non-fatigued counterparts. Physical fatigue correlated negatively with sensorimotor cerebellum volume, while cognitive fatigue showed an inverse relationship with limbic cerebellum regions. Interestingly, psychosocial fatigue was positively associated with limbic cerebellum volume, contrary to initial hypotheses. Higher disability scores were linked to atrophy in cognitive and limbic cerebellar regions. Conclusions: The findings highlight the cerebellum\u2019s multifaceted role in MS-related fatigue, with distinct subregions contributing to physical, cognitive, and psychosocial fatigue components. These results underscore the cerebellum\u2019s critical function as a hub for motor, cognitive, and emotional integration. Future longitudinal studies incorporating objective measures and advanced imaging are essential to elucidate these relationships further and inform targeted therapeutic strategies for pwMS.<\/jats:p>","DOI":"10.3390\/jcm14082840","type":"journal-article","created":{"date-parts":[[2025,4,20]],"date-time":"2025-04-20T20:24:16Z","timestamp":1745180656000},"page":"2840","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Role of the Cerebellum in Multiple Sclerosis-Related Fatigue and Disability"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-9900-4725","authenticated-orcid":false,"given":"Nicola","family":"Manocchio","sequence":"first","affiliation":[{"name":"Physical and Rehabilitation Medicine, Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ornella","family":"Argento","sequence":"additional","affiliation":[{"name":"Behavioural Neuropsychology, IRCCS \u201cSanta Lucia\u201d Foundation, 00179 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Bossa","sequence":"additional","affiliation":[{"name":"Physical and Rehabilitation Medicine, Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, 00133 Rome, Italy"},{"name":"Behavioural Neuropsychology, IRCCS \u201cSanta Lucia\u201d Foundation, 00179 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5291-0984","authenticated-orcid":false,"given":"Barbara","family":"Span\u00f2","sequence":"additional","affiliation":[{"name":"Neuroimaging Unit, IRCCS \u201cSanta Lucia\u201d Foundation, 00179 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9521-3759","authenticated-orcid":false,"given":"Leonardo","family":"Pellicciari","sequence":"additional","affiliation":[{"name":"IRCCS Istituto delle Scienze Neurologiche di Bologna, 40139 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2246-348X","authenticated-orcid":false,"given":"Calogero","family":"Foti","sequence":"additional","affiliation":[{"name":"Physical and Rehabilitation Medicine, Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7445-4441","authenticated-orcid":false,"given":"Ugo","family":"Nocentini","sequence":"additional","affiliation":[{"name":"Physical and Rehabilitation Medicine, Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, 00133 Rome, Italy"},{"name":"Behavioural Neuropsychology, IRCCS \u201cSanta Lucia\u201d Foundation, 00179 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,20]]},"reference":[{"key":"ref_1","first-page":"220","article-title":"Principles of Neurology","volume":"10","author":"Adams","year":"1997","journal-title":"Neuropsychiatry Neuropsychol. Behav. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/S0022-510X(00)00411-1","article-title":"Fatigue and Basal Ganglia","volume":"179","author":"Chaudhuri","year":"2000","journal-title":"J. Neurol. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Khan, F., Amatya, B., and Galea, M. (2014). Management of Fatigue in Persons with Multiple Sclerosis. Front. Neurol., 5.","DOI":"10.3389\/fneur.2014.00177"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/j.pmr.2013.06.006","article-title":"Multiple Sclerosis and Fatigue: Understanding the Patient\u2019s Needs","volume":"24","author":"Cook","year":"2013","journal-title":"Phys. Med. Rehabil. Clin. N. Am."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"476","DOI":"10.3390\/neurosci3030034","article-title":"Non-Pharmacological Treatments of Cognitive Impairment in Multiple Sclerosis: A Review","volume":"3","author":"Bossa","year":"2022","journal-title":"NeuroSci"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2707","DOI":"10.1152\/jn.00245.2018","article-title":"Cerebellum and Cognition in Multiple Sclerosis","volume":"120","author":"Schreck","year":"2018","journal-title":"J. Neurophysiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1093\/brain\/121.4.561","article-title":"The Cerebellar Cognitive Affective Syndrome","volume":"121","author":"Schmahmann","year":"1998","journal-title":"Brain"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/j.neuroscience.2009.02.001","article-title":"Quantification of Gray Matter Changes in the Cerebral Cortex after Isolated Cerebellar Damage: A Voxel-Based Morphometry Study","volume":"162","author":"Clausi","year":"2009","journal-title":"Neuroscience"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3672","DOI":"10.1093\/brain\/awr266","article-title":"The Cerebellar Cognitive Profile","volume":"134","author":"Tedesco","year":"2011","journal-title":"Brain"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/j.neubiorev.2017.01.010","article-title":"Cognitive-Motor Dual-Task Interference: A Systematic Review of Neural Correlates","volume":"75","author":"Leone","year":"2017","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Tramontano, M., Argento, O., Manocchio, N., Piacentini, C., Orejel Bustos, A.S., De Angelis, S., Bossa, M., and Nocentini, U. (2024). Dynamic Cognitive\u2013Motor Training versus Cognitive Computer-Based Training in People with Multiple Sclerosis: A Preliminary Randomized Controlled Trial with 2-Month Follow-Up. JCM, 13.","DOI":"10.3390\/jcm13092664"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.cortex.2009.11.008","article-title":"Evidence for Topographic Organization in the Cerebellum of Motor Control versus Cognitive and Affective Processing","volume":"46","author":"Stoodley","year":"2010","journal-title":"Cortex"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1592","DOI":"10.1016\/j.apmr.2021.12.010","article-title":"Cerebellar Contributions to Motor and Cognitive Control in Multiple Sclerosis","volume":"103","author":"Fritz","year":"2022","journal-title":"Arch. Phys. Med. Rehabil."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1093\/arclin\/acaa089","article-title":"Dual-Task Performance in Multiple Sclerosis\u2019 Patients: Cerebellum Matters?","volume":"36","author":"Argento","year":"2021","journal-title":"Arch. Clin. Neuropsychol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1007\/s12311-014-0634-8","article-title":"The Role of the Cerebellum in Multiple Sclerosis","volume":"14","author":"Weier","year":"2015","journal-title":"Cerebellum"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"105","DOI":"10.2174\/1573405054038726","article-title":"Voxel-Based Morphometry of the Human Brain: Methods and Applications","volume":"1","author":"Mechelli","year":"2005","journal-title":"Curr. Med. Imaging"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.neuroimage.2008.08.039","article-title":"Functional Topography in the Human Cerebellum: A Meta-Analysis of Neuroimaging Studies","volume":"44","author":"Stoodley","year":"2009","journal-title":"NeuroImage"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.neulet.2018.07.005","article-title":"The Cerebellum and Cognition","volume":"688","author":"Schmahmann","year":"2019","journal-title":"Neurosci. Lett."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"(2013). World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. JAMA, 310, 2191.","DOI":"10.1001\/jama.2013.281053"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1002\/ana.22366","article-title":"Diagnostic Criteria for Multiple Sclerosis: 2010 Revisions to the McDonald Criteria","volume":"69","author":"Polman","year":"2011","journal-title":"Ann. Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1212\/WNL.33.11.1444","article-title":"Rating Neurologic Impairment in Multiple Sclerosis: An Expanded Disability Status Scale (EDSS)","volume":"33","author":"Kurtzke","year":"1983","journal-title":"Neurology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"S79","DOI":"10.1093\/clinids\/18.Supplement_1.S79","article-title":"Measuring the Functional Impact of Fatigue: Initial Validation of the Fatigue Impact Scale","volume":"18","author":"Fisk","year":"1994","journal-title":"Clin. Infect. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5366","DOI":"10.1080\/09638288.2024.2302878","article-title":"Italian Adaptation and Psychometric Validation of the Fatigue Impact Scale (FIS) and Its Modified Versions in Adults with Multiple Sclerosis: A Rasch Analysis Study","volume":"46","author":"Piscitelli","year":"2024","journal-title":"Disabil. Rehabil."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.neuroimage.2009.01.045","article-title":"A Probabilistic MR Atlas of the Human Cerebellum","volume":"46","author":"Diedrichsen","year":"2009","journal-title":"NeuroImage"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.neuroimage.2006.05.056","article-title":"A Spatially Unbiased Atlas Template of the Human Cerebellum","volume":"33","author":"Diedrichsen","year":"2006","journal-title":"NeuroImage"},{"key":"ref_26","unstructured":"Munro, B.H. (2005). Statistical Methods for Health Care Research, Lippincott Williams & Wilkins."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.jns.2019.03.007","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."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1177\/1352458515614407","article-title":"Abnormal Adaptation over Time of Motor Network Recruitment in Multiple Sclerosis Patients with Fatigue","volume":"22","author":"Rocca","year":"2016","journal-title":"Mult. Scler."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Genova, H.M., Rajagopalan, V., Deluca, J., Das, A., Binder, A., Arjunan, A., Chiaravalloti, N., and Wylie, G. (2013). Examination of Cognitive Fatigue in Multiple Sclerosis Using Functional Magnetic Resonance Imaging and Diffusion Tensor Imaging. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0078811"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1006\/nimg.2001.1011","article-title":"Functional Magnetic Resonance Imaging Correlates of Fatigue in Multiple Sclerosis","volume":"15","author":"Filippi","year":"2002","journal-title":"Neuroimage"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1177\/1352458517717807","article-title":"Abnormal Functional Connectivity of Thalamic Sub-Regions Contributes to Fatigue in Multiple Sclerosis","volume":"24","author":"Valsasina","year":"2018","journal-title":"Mult. Scler."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1080\/01616412.2018.1547813","article-title":"Structural and Cognitive Correlates of Fatigue in Progressive Multiple Sclerosis","volume":"41","author":"Andreasen","year":"2019","journal-title":"Neurol. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"136082","DOI":"10.1016\/j.neulet.2021.136082","article-title":"Resting-State Functional Magnetic Resonance Imaging of the Cerebellar Vermis in Patients with Parkinson\u2019s Disease and Visuospatial Disorder","volume":"760","author":"Yin","year":"2021","journal-title":"Neurosci. Lett."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"McIsaac, T.L., Fritz, N.E., Quinn, L., and Muratori, L.M. (2018). Cognitive-Motor Interference in Neurodegenerative Disease: A Narrative Review and Implications for Clinical Management. Front. Psychol., 9.","DOI":"10.3389\/fpsyg.2018.02061"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.1016\/j.cub.2019.04.012","article-title":"Topographic Maps of Visual Space in the Human Cerebellum","volume":"29","author":"Knapen","year":"2019","journal-title":"Curr. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Marafioti, G., Cardile, D., Culicetto, L., Quartarone, A., and Lo Buono, V. (2024). The Impact of Social Cognition Deficits on Quality of Life in Multiple Sclerosis: A Scoping Review. Brain Sci., 14.","DOI":"10.3390\/brainsci14070691"},{"key":"ref_37","first-page":"81","article-title":"Fatigue Syndrome, Depression and the Quality of Life in Patients with Multiple Sclerosis","volume":"6","author":"Halicka","year":"2017","journal-title":"Piel\u0119gniarstwo Neurol. Neurochir."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1007\/s12311-019-01096-4","article-title":"Selective Cerebellar Atrophy Associates with Depression and Fatigue in the Early Phases of Relapse-Onset Multiple Sclerosis","volume":"19","author":"Lazzarotto","year":"2020","journal-title":"Cerebellum"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1007\/s10865-017-9840-4","article-title":"Tracking Daily Fatigue Fluctuations in Multiple Sclerosis: Ecological Momentary Assessment Provides Unique Insights","volume":"40","author":"Powell","year":"2017","journal-title":"J. Behav. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1177\/1352458514546791","article-title":"Cingulum Bundle Alterations Underlie Subjective Fatigue in Multiple Sclerosis","volume":"21","author":"Pardini","year":"2015","journal-title":"Mult. Scler."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Redlicka, J., Zieli\u0144ska-Nowak, E., Lipert, A., and Miller, E. (2021). Impact of Moderate Individually Tailored Physical Activity in Multiple Sclerosis Patients with Fatigue on Functional, Cognitive, Emotional State, and Postural Stability. Brain Sci., 11.","DOI":"10.3390\/brainsci11091214"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e31020","DOI":"10.2196\/31020","article-title":"Immersive Virtual Reality and Vestibular Rehabilitation in Multiple Sclerosis: Case Report","volume":"10","year":"2022","journal-title":"JMIR Serious Games"},{"key":"ref_43","first-page":"8624986","article-title":"Effects of Vestibular Rehabilitation on Fatigue and Activities of Daily Living in People with Parkinson\u2019s Disease: A Pilot Randomized Controlled Trial Study","volume":"2020","author":"Abasi","year":"2020","journal-title":"Park. Dis."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1002\/jnr.25235","article-title":"Rehabilitation on Cerebellar Ataxic Patients with Multiple Sclerosis: A Systematic Review","volume":"101","author":"Chasiotis","year":"2023","journal-title":"J. Neurosci. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"102799","DOI":"10.1016\/j.msard.2021.102799","article-title":"Associations between Fatigue Impact and Lifestyle Factors in People with Multiple Sclerosis\u2014The Danish MS Hospitals Rehabilitation Study","volume":"50","author":"Johansson","year":"2021","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1186\/s13063-019-3825-2","article-title":"Testing Non-Inferiority of Blended versus Face-to-Face Cognitive Behavioural Therapy for Severe Fatigue in Patients with Multiple Sclerosis and the Effectiveness of Blended Booster Sessions Aimed at Improving Long-Term Outcome Following Both Therapies: Study Protocol for Two Observer-Blinded Randomized Clinical Trials","volume":"21","author":"Beckerman","year":"2020","journal-title":"Trials"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/8\/2840\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:18:20Z","timestamp":1760030300000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/8\/2840"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,20]]},"references-count":46,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["jcm14082840"],"URL":"https:\/\/doi.org\/10.3390\/jcm14082840","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,20]]}}}