Hitting the brakes: pathological subthalamic nucleus activity in Parkinson's disease gait freezing.

Gait freezing is a complex and devastating paroxysmal motor arrest commonly suffered in Parkinson's disease that causes significant impairment to mobility, commonly resulting in falls and subsequent injury. The neurobiological basis of gait freezing in Parkinson's disease is poorly understood and thus, currently available therapies are partially effective at best. We used a validated virtual reality gait paradigm to elicit freezing behaviour intraoperatively in eight patients undergoing subthalamic nucleus deep brain stimulation surgery while microelectrode recordings were obtained. This allowed us to directly test the hypothesis that increases in pathological multi-unit activity in the subthalamic nucleus are associated with freezing onset in real time, manifest as dysfunctional firing of lower limb muscles typical of freezing that were detected by EMG. We present evidence that freezing is related to transient increases in pathological subthalamic nucleus activity. We performed time-frequency analysis to characterize the oscillatory dynamics of subthalamic nucleus activity coincident with freezing onset, demonstrating an increase in pathological beta and theta rhythms that are followed by a temporal chain of activity culminating in characteristically abnormal lower limb muscle firing detected by EMG. Finally, we interrogate the potential clinical utility of our findings by contrasting the subthalamic nucleus activity signature during pathological freezing against purposeful stopping. These results advance our understanding of the neurobiological basis of gait freezing in Parkinson's disease, highlighting the role of the subthalamic nucleus and emergent synchronous activity in basal ganglia circuits in driving non-purposeful motor arrests in individuals with Parkinson's disease. Pathological subthalamic nucleus activity identified in association with freezing is discernible from that of volitional stopping, paving the way towards more effective therapeutics such as adaptive closed-loop deep brain stimulation protocols.

Antisaccade errors reveal cognitive control deficits in Parkinson's disease with freezing of gait.

Freezing of gait is a poorly understood symptom of Parkinson's disease (PD) that is commonly accompanied by executive dysfunction. This study employed an antisaccade task to measure deficits in inhibitory control in patients with freezing, and to determine if these are associated with a specific pattern of grey matter loss using voxel-based morphometry. PD patients with (n = 15) and without (n = 11) freezing along with 10 age-matched controls were included. A simple prosaccade task was administered, followed by a second antisaccade task that required subjects to either look towards or away from a peripheral target. Behavioral results from the antisaccade task were entered as covariates in the voxel-based morphometry analysis. Patient and control groups performed equally well on the first task. However, patients with freezing were significantly worse on the second, which was driven by a specific impairment in suppressing their responses toward the target on the antisaccade trials. Impaired antisaccade performance was associated with grey matter loss across bilateral visual and fronto-parietal regions. These results suggest that patients with freezing have a significant deficit of inhibitory control that is associated with volume reductions in regions crucial for orchestrating both complex motor behaviors and cognitive control. These findings highlight the inter-relationship between freezing of gait and cognition and confirm that dysfunction along common neural pathways is likely to mediate the widespread cognitive dysfunction that emerges with this symptom.