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Functional connectivity modifications in monoaminergic circuits occur in fatigued MS patients treated with fampridine and amantadine

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Abstract

Background

Monoaminergic network dysfunction may have a role in multiple sclerosis (MS) fatigue pathogenesis.

Objective

To investigate modifications of fatigue severity and resting state (RS) functional connectivity (FC) in monoaminergic networks of 45 fatigued MS patients after different symptomatic treatments.

Methods

Patients were randomly, blindly assigned to fampridine (n = 15), amantadine (n = 15) or placebo (n = 15) treatment and underwent clinical and 3T-MRI evaluations at baseline (t0) and week 4 (w4), i.e. after four weeks of treatment. Fifteen healthy controls (HC) were enrolled. Dopamine-, noradrenaline- and serotonin-related RS FC was assessed by PET-guided constrained independent component analysis.

Results

At t0, MS patients showed widespread monoamine-related RS FC abnormalities. At w4, fatigue scores decreased in all groups (p = range < 0.001–0.002). Concomitantly, fampridine and amantadine patients showed increased insular RS FC in dopamine-related and noradrenaline-related networks (p < 0.001, uncorrected). Amantadine patients also showed increased RS FC of anterior cingulate cortex in dopamine-related and noradrenaline-related networks (p < 0.001, uncorrected). Placebo patients showed increased precuneus/middle cingulate RS FC in the noradrenaline-related network (p < 0.001, uncorrected). In fampridine and placebo patients, just tendencies towards correlations between RS FC and fatigue modifications were found.

Conclusions

In MS patients, specific RS FC modifications in PET-guided monoaminergic networks were observed, concomitantly with fatigue improvements following treatment.

Trial registration number

EudraCT 2010-023678-38.

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Data availability

The dataset used and analysed during the current study is available from the corresponding author on reasonable request.

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Funding

This work has been partially supported by grants from Italian Ministry of Healthy (grant GR-2008-1138784).

Author information

Authors and Affiliations

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

    Maria A. Rocca, Paola Valsasina, Maria Teresa Lamanna & Massimo Filippi

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

    Maria A. Rocca, Maria Teresa Lamanna, Bruno Colombo, Vittorio Martinelli & Massimo Filippi

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

    Massimo Filippi

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

    Massimo Filippi

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

    Maria A. Rocca & Massimo Filippi

Authors
  1. Maria A. Rocca
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  2. Paola Valsasina
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  3. Maria Teresa Lamanna
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  4. Bruno Colombo
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  5. Vittorio Martinelli
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Corresponding author

Correspondence to Maria A. Rocca.

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Conflicts of interest

M.A. Rocca received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche; and speaker honoraria from 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 and Fondazione Italiana Sclerosi Multipla. She is Associate Editor for Multiple Sclerosis and Related Disorders. P. Valsasina received speaker honoraria from Biogen Idec. M.T. Lamanna and B. Colombo have nothing to disclose. V. Martinelli received travel support and speaker’s honoraria for activities with Biogen Idec, Merck Serono, Bayer, Teva Pharma, Novartis, Almirall and Genzyme. Prof. Filippi is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology; 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, Italian Ministry of Health, and Fondazione Italiana Sclerosi Multipla.

Ethical approval

Approval was received from the local ethical standards committee on human experimentation of IRCCS Ospedale San Raffaele (registration number: GR-2008-1138784); all subjects signed written informed consent before study participation.

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Rocca, M.A., Valsasina, P., Lamanna, M.T. et al. Functional connectivity modifications in monoaminergic circuits occur in fatigued MS patients treated with fampridine and amantadine. J Neurol 270, 4697–4706 (2023). https://doi.org/10.1007/s00415-023-11858-0

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  • DOI: https://doi.org/10.1007/s00415-023-11858-0

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