Motor cerebro‐cerebellar network breakdown among different subtypes of Parkinson’s disease

Abstract Background To investigate functional alterations in the cerebro‐cerebellar system in two Parkinson’s disease (PD) clinical phenotypes (tremor‐dominant [TD] and postural instability and gait disorder [PIGD]using stepwise functional connectivity (SFC). Method 58 PD patients performed clinical and cognitive evaluations and resting‐state functional MRI (fMRI). PD cohort was divided into two groups: 32 patients with TD (PD‐TD) and 26 with PIGD (PD‐PIGD). 60 age‐ and sex‐matched healthy controls were also enrolled. SFC analysis aims to characterize regions that connect to specific seed brain areas at different levels of link‐step distances. The cerebellar seed‐region was identified using motor task‐based fMRI in 23 controls. For each of the SFC maps, whole‐brain two‐sample t‐test comparisons between groups were performed. Result The performance of the motor task during fMRI was associated with activation of the lobule VI and vermis of the cerebellum. SFC analysis at one‐link step distance showed, in both PD subtypes, a decreased regional–local connectivity between seed region and thalamus and parietal lobe relative to controls; across intermediate link‐steps, a reduced connectivity was observed with frontal, parietal and occipital lobes. Only PD‐PIGD patients showed lower connectivity at intermediate link‐step distances between the seed‐cerebellar region and sensorimotor areas. In addition, SFC pattern identified different localization of functional over‐connectivity in frontal lobe in both PD groups: in inferior frontal gyrus and insula in PD‐PIGD, and in orbitofrontal gyrus in PD‐TD. Conclusion These findings highlight subtype‐specific PD changes in cerebellar functional connectivity, providing novel insights into the pathophysiological mechanism potentially underlying different motor phenotypes. Ministry of Education and Science Republic of Serbia (Grant #175090), Italian Ministry of Health (Grant #RF‐2018‐12366746).