Monoaminergic network abnormalities are associated with fatigue in pediatric multiple sclerosis.

Background: Fatigue is commonly observed in pediatric multiple sclerosis (pedMS) patients, but its underlying mechanisms remain largely unexplored. We evaluated whether resting-state (RS) functional connectivity (FC) abnormalities in monoaminergic networks contributed to explain fatigue in pedMS.
Methods: Fifty-five pedMS and twenty-three matched healthy controls (HC) underwent clinical and RS functional MRI assessment. Patients with Fatigue Severity Scale (FSS) score ≥ 4 were classified as fatigued (F). Patterns of dopamine-, noradrenaline- and serotonin-related RS FC were derived by constrained independent component analysis, using PET atlases for dopamine, noradrenaline, and serotonin transporters obtained in HCs' brain.
Results: Compared to non-fatigued (NF)-pedMS patients and HC, F-pedMS patients (15/55, 27.3%) showed decreased dopamine-related RS FC in the right postcentral gyrus. They also showed decreased dopamine-related RS FC in the left insula vs. HC and increased dopamine-related RS FC in the left middle temporal gyrus and cerebellum (lobule VI) vs. NF patients. In the noradrenaline-related network, F-pedMS patients showed decreased RS FC in the left superior parietal lobule and increased RS FC in the right thalamus vs. HC and NF-pedMS. Compared to HC, F-pedMS patients also showed decreased RS FC in the right calcarine cortex and increased RS FC in the right middle frontal gyrus. In the serotonin-related network, F-pedMS patients showed decreased RS FC in the right angular gyrus and increased RS FC in the right postcentral gyrus vs. NF-pedMS patients.
Discussion: In pedMS, fatigue is associated with specific monoaminergic network abnormalities, providing pathological markers for this bothersome symptom and putative targets for its treatment.
Competing Interests: Declarations. Conflict of interest: M. Margoni reports grants and personal fees from Sanofi Genzyme, Merck Serono, Novartis and Almiral. She was awarded a MAGNIMS-ECTRIMS fellowship in 2020. P. Valsasina and D. Mistri have nothing to disclose. L. Moiola received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Sanofi Genzyme, Novartis, Teva, Merck Serono, Biogen, Roche, and Excemed. Prof. M. 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, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla. Prof. M.A. Rocca received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche; and speaker honoraria from AstraZaneca, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Horizon Therapeutics Italy, Merck Serono SpA, Novartis, Roche, Sanofi 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. Ethical standards: Approval was received from the local ethical standards committee on human experimentation (Protocol ID: 25/2007). Written informed consent was obtained from all subjects prior to study participation according to the Declaration of Helsinki.
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