Multiple sclerosis-related fatigue: Altered resting-state functional connectivity of the ventral striatum and dorsolateral prefrontal cortex

Objective: Since recent studies suggested a role of the striatum and prefrontal cortex for multiple sclerosis (MS)-related fatigue, we investigated resting-state functional connectivity alterations of striatal subdivisions and the dorsolateral prefrontal cortex (dlPFC). Methods: Resting-state functional magnetic resonance imaging was acquired in 77 relapsing-remitting MS patients (38 fatigued (F-MS), 39 non-fatigued (NF-MS)) and 41 matched healthy controls (HC). Fatigue severity was assessed using the fatigue severity scale. Seed-based connectivity analyses were performed using subregions of the striatum and the dlPFC as regions of interest applying non-parametric permutation testing. Results: Compared to HC and NF-MS patients, F-MS patients showed reduced caudate nucleus and ventral striatum functional connectivity with the sensorimotor cortex (SMC) and frontal, parietal, and temporal cortex regions. Fatigue severity correlated negatively with functional connectivity of the caudate nucleus and ventral striatum with the SMC and positively with functional connectivity of the dlPFC with the rostral inferior parietal gyrus and SMC. Conclusion: MS-related fatigue is associated with reduced functional connectivity between the striatum and sensorimotor as well as attention and reward networks, in which the ventral striatum might be a key integration hub. Together with increased connectivity between the dlPFC and sensory cortical areas, these connectivity alterations shed light on the mechanisms of MS-related fatigue.