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Aberrant monoaminergic functional connectivity is presumably involved in MS-related fatigue, but mechanisms remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>To investigate how static and dynamic functional connectivity of monoaminergic circuits relate to fatigue in MS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      60 healthy controls (HC) and 217 people with MS (pwMS) completed the Fatigue Scale for Motor and Cognitive Functions (FSMC) and underwent functional brain MRI. Brain regions were assigned to resting-state networks. Additionally, PET-derived receptor\/transporter density atlases determined assignment to monoaminergic circuits (5-HT\n                      <jats:sub>1a<\/jats:sub>\n                      \/5-HT\n                      <jats:sub>2a<\/jats:sub>\n                      \/5-HTT\/ D\n                      <jats:sub>1<\/jats:sub>\n                      \/D\n                      <jats:sub>2<\/jats:sub>\n                      \/DAT\/NAT). Per monoaminergic circuit, we compared the frequency of switching between networks (flexibility) and the total number of networks switched to (promiscuity), between HC and pwMS with no fatigue (FSMC\u2009&lt;\u200943), mild\/moderate fatigue (43\u2009\u2264\u2009FSMC\u2009&lt;\u200963), or severe fatigue (FSMC\u2009\u2265\u200963). For circuits showing flexibility differences, we also compared rates of synchronous (cohesion) and independent switches (disjointedness).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Global flexibility was higher in severely fatigued pwMS compared to non-fatigued pwMS (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.025) and HC (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.016). In line, global cohesion was higher in severely fatigued pwMS compared to non-fatigued pwMS (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.022) and HC (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.017). Compared to HC, 5-HT\n                      <jats:sub>1a<\/jats:sub>\n                      circuit flexibility (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.048) and cohesion (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.031) were higher in severely fatigued pwMS. Static FC showed significant group differences for the 5-HTT, D\n                      <jats:sub>1<\/jats:sub>\n                      , and D\n                      <jats:sub>2\/<\/jats:sub>\n                      DAT circuits, but no significant pairwise contrasts.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Fatigued pwMS show more dynamic functional connectivity, both globally and in the inhibitory serotonergic receptor circuit. Unstable global and serotonergic dynamics likely raise energy expenditure in pwMS and therefore may underlie MS-related fatigue.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00415-026-13876-0","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T14:26:41Z","timestamp":1780410401000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Functional connectivity dynamics of monoaminergic circuits related to fatigue in multiple sclerosis"],"prefix":"10.1007","volume":"273","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5582-5411","authenticated-orcid":false,"given":"Marloes D. A.","family":"Bet","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"Helmlinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommy A. 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Bet: nothing to disclose. B. Helmlinger received speaker honoraria from Roche, Bristol-Myers Squibb, and Sanofi, and travel funding from Janssen. S.M.C. Hechenberger received speaking honoraria from Roche, Bristol-Myers Squibb, and Merck. T.A.A. Broeders received research support from Dutch MS Research Foundation. C.G. Tinauer: nothing to disclose. S. Ropele: nothing to disclose. F. Barkhof serves on the steering committee and is an iDMC member for Biogen, Merck, Roche, EISAI, acts as a consultant for Roche, Biogen, Merck, IXICO, Jansen, Combinostics, has research agreements with Novartis, Merck, Biogen, GE, Roche and is co-founder and shareholder of Queen Square Analytics LTD. M. Khalil received travel funding and speaker honoraria from Bayer, Novartis, Merck, Biogen, Sanofi and Teva Pharmaceutical Industries Ltd. and serves on scientific advisory boards for Biogen, Merck, Roche, Novartis, Bristol-Myers Squibb and Gilead. He received research grants from Teva Pharmaceutical Industries, Ltd., Biogen and Novartis. C. Enzinger received travel funding and speaker honoraria from Biogen Idec, Bayer Schering Pharma, Merck Serono, Novartis, Genzyme and Teva Pharmaceutical Industries Ltd.\/Sanofi-Aventis, Shire; received research support from Merck Serono, Biogen Idec, and Teva Pharmaceutical Industries Ltd.\/Sanofi-Aventis; and serves on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, Genzyme, Roche, and Teva Pharmaceutical Industries Ltd.\/Sanofi-Aventis. L. Douw is supported by the Dutch Research Council (NWO, Vidi 198.015). M.M. Schoonheim serves on the editorial board of Neurology, Multiple Sclerosis Journal and Frontiers in Neurology, receives research support from the Dutch MS Research Foundation, Eurostars-EUREKA, ARSEP, Amsterdam Neuroscience and ZonMW (Vidi grant, project number 09150172010056) and has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Celgene\/Bristol Meyers Squibb, EIP, Sanofi, MedDay and Merck.\u00a0D.T. Pinter is a member of the advisory board for \"Cognition and MS\" for Novartis and received speaking honoraria from Biogen, Novartis, MedAhead and Bristol-Meyers Squibb. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and\/or publication of this article.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of interest"}},{"value":"This study was conducted in accordance with the Declaration of Helsinki. Study procedures were approved by the ethical review board of the Medical University of Graz (31\u2013432 ex 18\/19 1264\u20132019). All participants provided written informed consent prior to inclusion.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}],"article-number":"354"}}