Monoaminergic network abnormalities: a marker for multiple sclerosis-related fatigue and depression

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.