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However, the role of neuromodulatory networks in multiple sclerosis (MS) has not been assessed. We applied resting-state functional connectivity and graph theory to investigate the changes in the functional connectivity within neuromodulatory networks including the serotonergic, noradrenergic, cholinergic, and dopaminergic systems in MS. Twenty-nine MS patients and twenty-four age- and gender-matched healthy controls performed clinical and cognitive assessments including the expanded disability status score, symbol digit modalities test, and Hamilton Depression rating scale. We demonstrated a diffuse reorganization of network topography (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.01) in serotonergic, cholinergic, noradrenergic, and dopaminergic networks in patients with MS. Serotonergic, noradrenergic, and cholinergic network functional connectivity derangement was associated with disease duration, EDSS, and depressive symptoms (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.01). Derangements in serotonergic, noradrenergic, cholinergic, and dopaminergic network impairment were associated with cognitive abilities (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.01). Our results indicate that functional connectivity changes within neuromodulatory networks might be a useful tool in predicting disability burden over time, and could serve as a surrogate endpoint to assess efficacy for symptomatic treatments.<\/jats:p>","DOI":"10.1007\/s00415-020-09806-3","type":"journal-article","created":{"date-parts":[[2020,3,26]],"date-time":"2020-03-26T10:02:31Z","timestamp":1585216951000},"page":"2042-2053","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Impaired connectivity within neuromodulatory networks in multiple sclerosis and clinical implications"],"prefix":"10.1007","volume":"267","author":[{"given":"Antonio","family":"Carotenuto","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beniamino","family":"Giordano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia P.","family":"Caminiti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary","family":"Chappell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven C. 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Caminiti, Zachary Chappell, Steven C.R. Williams, and Alexander Hammers declare no potential conflicts of interest with respect to the research, authorship, and\/or publication of this abstract. Dr Eli Silber and Peter Brex received funding to attend lectures, advisory board, and for lecturing from Biogen, Merck, Teva, Genzyme, and Roche. Professor Marios Politis research is supported by Parkinson\u2019s UK, Lily and Edmond J. Safra Foundation, Michael J Fox Foundation (MJFF) for Parkinson\u2019s research, and CHDI Foundation.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of interest"}},{"value":"The study was approved by the London-South East Research Ethics Committee.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Written informed consent was obtained from all study\u2019s subjects prior to inclusion in the study in accordance to the Declaration of Helsinki.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}]}}