Alterations of functional connectivity between hyperdirect pathway regions and outside regions in Parkinson's disease patients with freezing of gait.

Emerging neuroimaging evidence has propelled the formulation of the hypothesis that freezing of gait (FOG) in Parkinson's disease (PD) arises from dysfunction within the locomotor network. However, to date, there has been a lack of functional connectivity analyses targeting the hyperdirect pathway (HDP) to explore this hypothesis. In this study, we investigate impaired communication within the HDP neural circuitry in FOG patients. Fifty-nine PD patients (33 PD-nFOG and 26 PD-FOG) and thirty matched healthy controls underwent resting-state functional magnetic resonance imaging. Both ROI-wise and voxel-wise based resting-state functional connectivity were calculated in this study. No group differences were observed in the ROI-wise functional connectivity among the regions within the HDP. However, significant reduced functional connectivity based on voxel-wise analysis were observed between the HDP and several brain regions, including the default mode network (DMN), sensorimotor cortex, limbic system and cerebellum in PD, which were associated with psychiatric symptoms, emotional decline, and motor dysfunction. Of note, compared to PD-nFOG, PD-FOG showed increased functional connectivity between the HDP and the cerebellum and the middle occipital gyrus, which was associated with motor impairment in the contralateral limbs. These data extend neuroimaging evidence on that compensatory increased functional connectivity in HDP in FOG patients may indicate a failure compensate for clinical manifestations of limb akinesia, and may represent a loss of low-level automatic control of gait regulation by the basal ganglia.