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Resting state functional connectivity modifications in monoaminergic circuits underpin fatigue development in patients with multiple sclerosis

Molecular Psychiatry (2024)Cite this article

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Abstract

Dysregulation of monoaminergic networks might have a role in the pathogenesis of fatigue in multiple sclerosis (MS). We investigated longitudinal changes of resting state (RS) functional connectivity (FC) in monoaminergic networks and their association with the development of fatigue in MS. Eighty-nine MS patients and 49 age- and sex-matched healthy controls (HC) underwent neurological, fatigue, and RS functional MRI assessment at baseline and after a median follow-up of 1.3 years (interquartile range = 1.01–2.01 years). Monoaminergic-related RS FC was estimated with an independent component analysis constrained to PET atlases for dopamine (DA), noradrenaline (NA), and serotonin (5-HT) transporters. At baseline, 24 (27%) MS patients were fatigued (F) and 65 were not fatigued (NF). Of these, 22 (34%) developed fatigue (DEV-FAT) at follow-up and 43 remained not fatigued (NO-FAT). At baseline, F-MS patients showed increased monoaminergic-related RS FC in the caudate nucleus vs NF-MS and in the hippocampal, postcentral, temporal, and occipital cortices vs NF-MS and HC. Moreover, F-MS patients exhibited decreased RS FC in the frontal cortex vs NF-MS and HC, and in the thalamus vs NF-MS. During the follow-up, no RS FC changes were observed in HC. NO-FAT patients showed limited DA-related RS FC modifications, whereas DEV-FAT MS patients showed increased DA-related RS FC in the left hippocampus, significant at time-by-group interaction analysis. In the NA-related network, NO-FAT patients showed decreased RS FC over time in the left superior frontal gyrus. This region showed increased RS FC in both DEV-FAT and F-MS patients; this divergent behavior was significant at time-by-group interaction analysis. Finally, DEV-FAT MS patients presented increased 5-HT-related RS FC in the angular and middle occipital gyri, while this latter region showed decreased 5-HT-related RS FC during the follow-up in F-MS patients. In MS patients, distinct patterns of alterations were observed in monoaminergic networks based on their fatigue status. Fatigue was closely linked to specific changes in the basal ganglia and hippocampal, superior frontal, and middle occipital cortices.

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Fig. 1: Resting state functional connectivity abnormalities at baseline within PET-guided monoaminergic networks in patients with multiple sclerosis according to the presence of fatigue compared with healthy controls.
Fig. 2: Resting state functional connectivity abnormalities within PET-guided monoaminergic networks in multiple sclerosis patients who remained not fatigued (NO-FAT), fatigued (FAT), and developed fatigue (DEV-FAT) at follow-up vs baseline.

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Data availability

The anonymized dataset used and analyzed during the current study is available from the corresponding author upon reasonable request.

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Funding

The study described in the present manuscript received no funding.

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Authors and Affiliations

  1. Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Monica Margoni, Paola Valsasina, Anna Bacchetti, Damiano Mistri, Paolo Preziosa, Maria A. Rocca & Massimo Filippi

  2. Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Monica Margoni, Anna Bacchetti, Paolo Preziosa, Maria A. Rocca & Massimo Filippi

  3. Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Monica Margoni & Massimo Filippi

  4. Vita-Salute San Raffaele University, Milan, Italy

    Paolo Preziosa, Maria A. Rocca & Massimo Filippi

  5. Neurophysiology Service, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Massimo Filippi

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Contributions

MM, PV, and AB contributed to the acquisition, analysis, and interpretation of MRI data, drafting and revising the text, and preparing the figures. DM and PP contributed to the acquisition, analysis, and interpretation of clinical and MRI data and revising the text. MAR and MF contributed to the conception of the study, drafting and revising the text, acting as the study supervisors. All the authors gave their approval to the current version of the manuscript.

Corresponding author

Correspondence to Massimo Filippi.

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Competing interests

MM reports grants and personal fees from Sanofi Genzyme, Merck Serono, Novartis, and Almiral. She was awarded a MAGNIMS-ECTRIMS fellowship in 2020. PV received speakers’ honoraria from Biogen Idec. AB and DM have nothing to disclose. PP received speaker honoraria from Roche, Biogen, Novartis, Merck Serono, Bristol Myers Squibb, Genzyme, Horizon, and Sanofi. He has received research support from Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla. MAR received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche; and speaker honoraria from Almirall, Bayer, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Merck Healthcare Germany, Merck Serono SpA, Novartis, Roche, and Teva. She receives research support from the MS Society of Canada, the Italian Ministry of Health, The Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla. She is Associate Editor for Multiple Sclerosis and Related Disorders. 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, Sanofi; speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, 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, Takeda; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol Myers Squibb, Lilly, Novartis, Sanofi Genzyme; he receives research support from Biogen Idec, Merck Serono, Novartis, Roche, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla.

Ethical approval

Approval was received from the institutional ethical standards committee on human experimentation of IRCCS Ospedale San Raffaele for any experiments using human subjects (Protocol N° 2015-33). Written informed consent was obtained from all subjects prior to study participation according to the Declaration of Helsinki.

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Margoni, M., Valsasina, P., Bacchetti, A. et al. Resting state functional connectivity modifications in monoaminergic circuits underpin fatigue development in patients with multiple sclerosis. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02532-6

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  • DOI: https://doi.org/10.1038/s41380-024-02532-6

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