Objective: To investigate the neural mechanisms underlying gait initiation failure in Parkinson’s disease patients with Freezing of Gait.

Background: Freezing of Gait (FOG) is a debilitating symptom of Parkinson’s disease (PD), causing regular falls. Patients with FOG often experience gait initiation failure, which is a delay or complete inability to initiate their first step. Unfortunately, gait initiation failure has a complex and poorly understood pathophysiological basis, which challenges clinical management.

Methods: Twenty PD patients with FOG (PD+FOG) and 17 PD patients without FOG (PD-NF) performed a virtual reality paradigm off their dopaminergic medication, while blood oxygen level dependent (BOLD) responses were recorded. Subjects used foot pedals to navigate a virtual corridor that presented a series of Stop and Walk cues. Step initiation (i.e. the time between a walk cue and the first pedal depression) was used as proxy for gait initiation. Although step initiation does not model all features of gait initiation, such as balance, it does require the initiation and execution of a selective lower limb motor plan, similar to gait initiation. Step initiation failure (SIF) was defined as any delayed initiation response relative to that subject’s modal footstep initiation time. Behavioral responses were recorded and BOLD data was analyzed using a mixed-effects analysis in SPM12.

Results: More PD+FOG patients experienced SIF as compared to PD-NF (p<0.05), while their modal step initiation times were similar (p>0.10). Successful step initiation in PD+FOG patients was associated with increased BOLD across the striatum, cerebellum and visual cortex and a decreased BOLD in the right inferior frontal gyrus compared to PD-NF. Interestingly, when contrasting SIF with successful initiations within PD+FOG patients that experienced SIF (n=11), an increased BOLD was found in the right inferior frontal gyrus and subthalamic nucleus, which are part of the hyper-direct stopping network and the anterior cingulate, which is associated with error monitoring.

Conclusions: PD+FOG require compensatory BOLD responses across multiple cortical and cerebellar regions to successfully initiate a step. However, a malfunctioning interplay between competing neural networks associated with motor execution and termination led to significantly delayed footstep initiations and potential monitoring of the erroneous initiation.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/neural-mechanisms-underlying-step-initiation-failure-in-patients-with-parkinsons-disease-and-freezing-of-gait/