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Original research
Monoaminergic network abnormalities: a marker for multiple sclerosis-related fatigue and depression
  1. Antonio Carotenuto1,
  2. Paola Valsasina1,
  3. Paolo Preziosa1,2,3,
  4. Damiano Mistri1,
  5. Massimo Filippi1,2,3,4,5,
  6. Maria A Rocca1,2,3
  1. 1 Neuroimaging Research Unit, Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy
  2. 2 Neurology Unit, IRCCS Ospedale San Raffaele, Milan, Italy
  3. 3 Vita-Salute San Raffaele University, Milan, Italy
  4. 4 Neurorehabilitation Unit, IRCCS Ospedale San Raffaele, Milan, Italy
  5. 5 Neurophysiology Service, IRCCS Ospedale San Raffaele, Milan, Italy
  1. Correspondence to Professor Maria A Rocca, Neuroimaging Research Unit, Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan 20132, Italy; rocca.mara{at}


Objective To investigate monoaminergic network abnormalities in patients with multiple sclerosis (MS) according to their fatigue and depressive status through a positron emission tomography (PET)-based constrained independent component analysis (ICA) on resting state (RS) functional MRI (fMRI).

Methods In this prospective study, 213 patients with MS (mean age=40.6±12.5 years; 94/119 men/women; 153 relapsing-remitting; 60 progressive) and 62 healthy controls (HCs, mean age=39.0±10.4 years; 30/32 men/women) underwent neurological, fatigue, depression and RS fMRI assessment. Patterns of dopamine, norepinephrine-related and serotonin-related RS functional connectivity (FC) were derived by ICA, constrained to PET atlases for dopamine, norepinephrine and serotonin transporters, obtained in HCs’ brain.

Results Compared with HCs, patients with MS showed abnormalities in all three explored monoaminergic networks, mostly with decreased RS FC within PET-guided monoaminergic networks in frontal regions and subcortical areas including the cerebellum and thalamus, and increased RS FC in temporo-parieto-occipital cortical areas, including bilateral precunei.

MS-related fatigue was associated with decreased RS FC within the PET-guided dopamine network in the left thalamus and left cerebellum, and with increased RS FC within the PET-guided serotonin network in the left middle occipital gyrus. MS-related depression was associated with more distributed abnormalities involving the three explored monoaminergic networks, resulting in overall reduced RS FC in the frontal lobe, limbic areas and the precuneus.

Conclusions Patients with MS present diffuse dysregulation in the monoaminergic networks. Specific alterations in these networks were associated with fatigue and depression, providing a pathological marker for these bothersome symptoms and putative targets for their treatment.

  • MRI

Data availability statement

Data are available upon reasonable request. The anonymised dataset used and analysed during the current study is available from the corresponding author upon reasonable request.

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Data availability statement

Data are available upon reasonable request. The anonymised dataset used and analysed during the current study is available from the corresponding author upon reasonable request.

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  • Presented at Abstracts reporting this study were presented at the following conferences: the American Academy of Neurology (AAN) 2022 Annual Meeting (2–7 April, Seattle, USA); and the 8th European Academy of Neurology (EAN) congress (25–28 June 2022, Vienna, Austria).

  • Contributors AC, PV and MAR contributed to the study conception and design. Material preparation was performed by AC, PV and MAR. Data collection was performed by PP, DM, MF and MAR. Data analysis was performed by AC, PV and MAR. The first draft of the manuscript was written by AC and PV, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. MAR acts as guarantor.

  • Funding AC was supported by a MAGNIMS/ECTRIMS research fellowship programme.

  • Competing interests AC has received research grants from Almirall, and served on advisory boards for: Merk, Novartis, Roche and Almirall. PV received speaker honoraria from Biogen Idec. PP received speaker honoraria from Biogen, Novartis, Merck Serono, Bristol Myers Squibb and ExceMED. DM has nothing to declare. MF is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Associate Editor of Radiology and Associate Editor of Neurological Sciences; received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche and Sanofi; speaking activities from Bayer, Biogen, Celgene, Chiesi Italia, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda and Teva; participation in Advisory Boards for Alexion, Biogen, Bristol Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme and Takeda; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol Myers Squibb, Lilly, Novartis, Sanofi-Genzyme; receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla and ARiSLA (Fondazione Italiana di Ricerca per la SLA). MAR received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen and Roche; and speaker honoraria from Bayer, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Merck Healthcare Germany, Merck Serono, Novartis, Roche and Teva. She receives research support from the MS Society of Canada and Fondazione Italiana Sclerosi Multipla. She is Associate Editor for Multiple Sclerosis and Related Disorders.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.