Brainstem monoaminergic functional and structural connectivity was investigated in a cohort of patients with multiple sclerosis (MS) and healthy controls. RS-fMRI analysis revealed in MS patients reduced functional connectivity between monoaminergic nuclei and central brain networks that are critically involved in the pathophysiology of MS. Functional alterations were associated to structural disconnections between these nuclei and cortical/subcortical efferent targets in MS patients. Axonal loss in the mesocorticolimbic tracts and in the noradrenergic projections to prefrontal cortex was associated with central fatigue in MS patients, whereas brainstem functional connectivity did not correlate with fatigue.
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