Supplementary motor area functional connectivity in “drug-naïve” Parkinson’s disease patients with fatigue

Fatigue is a common and disabling nonmotor manifestation in patients with Parkinson’s disease (PD), and the supplementary motor area (SMA) has been implicated in its pathophysiology. SMA is usually divided in its rostro-caudal axis, with the rostral (pre-) SMA playing a major role in motor planning, and the caudal (proper) SMA related to movement execution. To investigate brain functional connectivity of SMA subregions in de novo, drug-naive PD patients affected by fatigue, 17 patients with fatigue, 18 without fatigue, and 16 matched healthy controls were recruited. All the participants were not depressed and did not suffer from daytime sleepiness. Parkinson Fatigue Scale (PFS) was used for fatigue screening (cut-off > 3.3 points) and severity rating. Seed-based resting-state functional MRI was used to compare the functional connectivity from bilateral SMA subregions to the whole brain. Voxel-based morphometry analysis was employed to test whether functional connectivity results were related to brain structural differences. PD-related fatigue was associated with an increased connectivity between the left pre-SMA and the left postcentral gyrus as well as a decreased connectivity between the left SMA proper and the left middle frontal gyrus (ps < 0.01). These patterns of functional connectivity were tightly correlated with PFS scores (Pearson’s rs < 0.01). No structural brain changes were observed. In early PD, altered functional connectivity of both SMA subregions might play a crucial role in fatigue pathophysiology. These results offer new insights into the mechanisms responsible for fatigue in PD, suggesting possible targets for neuromodulation strategies oriented to modulate the SMA activity.