{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T02:57:32Z","timestamp":1793933852613,"version":"4.8.0"},"reference-count":263,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2024,3,29]],"date-time":"2024-03-29T00:00:00Z","timestamp":1711670400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"MS Society Edinburgh Centre for MS Research","award":["133"],"award-info":[{"award-number":["133"]}]},{"name":"Chief Scientist Office \u2013 SPRINT MND\/MS program","award":["MMPP\/01"],"award-info":[{"award-number":["MMPP\/01"]}]},{"name":"Anne Rowling Regenerative Neurology Clinic"},{"name":"UK Dementia Research Institute which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council"},{"name":"Alzheimer\u2019s Society and Alzheimer\u2019s Research UK"},{"name":"MS Society Edinburgh Centre for MS Research"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>\n                    Multiple Sclerosis (MS) is an autoimmune disease affecting the central nervous system, characterised by neuroinflammation and neurodegeneration. Fatigue and depression are common, debilitating, and intertwined symptoms in people with relapsing-remitting MS (pwRRMS). An increased understanding of brain changes and mechanisms underlying fatigue and depression in RRMS could lead to more effective interventions and enhancement of quality of life. To elucidate the relationship between depression and fatigue and brain connectivity in pwRRMS we conducted a systematic review. Searched databases were PubMed, Web-of-Science and Scopus. Inclusion criteria were: studied participants with RRMS (\n                    <jats:italic>n<\/jats:italic>\n                    \u2265 20; \u2265 18 years old) and differentiated between MS subtypes; published between 2001-01-01 and 2023-01-18; used fatigue and depression assessments validated for MS; included brain structural, functional magnetic resonance imaging (fMRI) or diffusion MRI (dMRI). Sixty studies met the criteria: 18 dMRI (15 fatigue, 5 depression) and 22 fMRI (20 fatigue, 5 depression) studies. The literature was heterogeneous; half of studies reported no correlation between brain connectivity measures and fatigue or depression. Positive findings showed that abnormal cortico-limbic structural and functional connectivity was associated with depression. Fatigue was linked to connectivity measures in cortico-thalamic-basal-ganglial networks. Additionally, both depression and fatigue were related to altered cingulum structural connectivity, and functional connectivity involving thalamus, cerebellum, frontal lobe, ventral tegmental area, striatum, default mode and attention networks, and supramarginal, precentral, and postcentral gyri. Qualitative analysis suggests structural and functional connectivity changes, possibly due to axonal and\/or myelin loss, in the cortico-thalamic-basal-ganglial and cortico-limbic network may underlie fatigue and depression in pwRRMS, respectively, but the overall results were inconclusive, possibly explained by heterogeneity and limited number of studies. This highlights the need for further studies including advanced MRI to detect more subtle brain changes in association with depression and fatigue. Future studies using optimised imaging protocols and validated depression and fatigue measures are required to clarify the substrates underlying these symptoms in pwRRMS.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0299634","type":"journal-article","created":{"date-parts":[[2024,3,29]],"date-time":"2024-03-29T13:31:43Z","timestamp":1711719103000},"page":"e0299634","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":28,"title":["Brain connectivity changes underlying depression and fatigue in relapsing-remitting multiple sclerosis: A systematic review"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7266-002X","authenticated-orcid":true,"given":"Agniete","family":"Kampaite","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecka","family":"Gustafsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4310-8607","authenticated-orcid":true,"given":"Elizabeth N.","family":"York","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Foley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4195-5538","authenticated-orcid":true,"given":"Niall J. J.","family":"MacDougall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark E.","family":"Bastin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siddharthan","family":"Chandran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam D.","family":"Waldman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3346-260X","authenticated-orcid":true,"given":"Rozanna","family":"Meijboom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,3,29]]},"reference":[{"issue":"2","key":"pone.0299634.ref001","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1055\/s-0038-1649502","article-title":"Multiple Sclerosis.","volume":"38","author":"BI Yamout","year":"2018","journal-title":"Semin Neurol"},{"key":"pone.0299634.ref002","volume-title":"Committee on Multiple Sclerosis: Current Status and Strategies for the Future, Board on Neuroscience and Behavioral Health, Institute of Medicine","author":"National Academy Press","year":"2001"},{"issue":"9","key":"pone.0299634.ref003","doi-asserted-by":"crossref","first-page":"a028928","DOI":"10.1101\/cshperspect.a028928","article-title":"Clinical Course of Multiple Sclerosis.","volume":"8","author":"S Klineova","year":"2018","journal-title":"Cold Spring Harb Perspect Med."},{"issue":"2","key":"pone.0299634.ref004","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/S1474-4422(17)30470-2","article-title":"Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria","volume":"17","author":"AJ Thompson","year":"2018","journal-title":"The Lancet Neurology"},{"issue":"2","key":"pone.0299634.ref005","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/s40263-018-0489-5","article-title":"Depression in Multiple Sclerosis: Epidemiology, Aetiology, Diagnosis and Treatment.","volume":"32","author":"C Solaro","year":"2018","journal-title":"CNS Drugs"},{"issue":"4","key":"pone.0299634.ref006","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1097\/01.PSY.0000074757.11682.96","article-title":"Effects of treatment for depression on fatigue in multiple sclerosis.","volume":"65","author":"DC Mohr","year":"2003","journal-title":"Psychosom Med."},{"issue":"S200","key":"pone.0299634.ref007","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1111\/ane.12648","article-title":"Fatigue and depression in multiple sclerosis: pharmacological and non-pharmacological interventions.","volume":"134","author":"P Brenner","year":"2016","journal-title":"Acta Neurologica Scandinavica"},{"key":"pone.0299634.ref008","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.jns.2016.11.067","article-title":"Prevalence of depression and anxiety in Multiple Sclerosis: A systematic review and meta-analysis","volume":"372","author":"RE Boeschoten","year":"2017","journal-title":"J Neurol Sci"},{"issue":"8","key":"pone.0299634.ref009","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1093\/sleep\/33.8.1061","article-title":"Fatigue in multiple sclerosis: mechanisms, evaluation, and treatment.","volume":"33","author":"TJ Braley","year":"2010","journal-title":"Sleep."},{"key":"pone.0299634.ref010","unstructured":"Heiser K. 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