Associations between fatigue and functional connectivity of dopamine and noradrenaline circuits in Parkinson's disease

Patients with Parkinson's disease are often afflicted by non-motor symptoms including fatigue. Alterations of multiple neurotransmitter systems, including dopamine and noradrenaline, have been hypothesized to play a role in the pathogenesis of fatigue. However, whether and how dysfunction in their underlying neurocircuitries contribute to fatigue remains elusive. Here, we used resting-state functional MRI data of 29 patients with Parkinson's disease to investigate associations between clinical ratings of fatigue and functional connectivity within dopamine and noradrenaline transporter-defined functional networks by applying a recently developed multimodal framework “Receptor-Enriched Analysis of functional Connectivity by Targets”. We found a negative linear relation between fatigue and noradrenaline-enriched functional connectivity in regions of the sensorimotor and salience networks, and a positive linear trend between fatigue and dopamine-enriched functional connectivity in regions of the default mode network. These findings provide empirical support to the hypothesised dysfunctions in the brain's monoaminergic circuits in Parkinson's patients with fatigue.