Monoaminergic network abnormalities are associated with fatigue in pediatric multiple sclerosis

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.

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.

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.

In pedMS, fatigue is associated with specific monoaminergic network abnormalities, providing pathological markers for this bothersome symptom and putative targets for its treatment.