Parkinson's disease (PD) is the fastest-growing neurological disease, outpacing even Alzheimer's disease. Aerobic exercise is accepted as an integral part of PD treatment, and stationary cycling, in particular, has been suggested to be an ideal exercise modality to treat the motor symptoms of PD. Our seminal tandem cycling study was the first to utilize forced exercise (FE) in human PD patients and demonstrate a 30% improvement in clinical ratings compared to voluntary exercise (VE) at a self-selected rate. FE is a mode of high-intensity aerobic exercise originating in animal models of PD in which the voluntary pedaling rate (cadence) of exercise is augmented, but not replaced. The precise effects of exercise, VE or FE, on cognitive function and dual-task performance has not been systematically evaluated, thus leaving a major gap in the potential optimization and utilization of exercise in addressing the well-known cognitive declines associated with PD. Hypersynchrony of motor circuits within the basal ganglia and specifically the subthalamic nucleus (STN) is associated with cardinal motor and non-motor signs of PD. The STN occupies a zone of important cortical input via the hyperdirect pathway receiving projections from the primary motor cortex, supplementary motor area, premotor cortices, and prefrontal cortices; all of which are implicated in various executive functions. Until recently, neural recordings of basal ganglia activity, specifically from the STN, were only possible during DBS surgery or in patients whose electrode was temporarily externalized immediately post-surgery. Recently, the U.S. Food and Drug Administration approved the Medtronic Percept DBS platform, which has the functionality to simultaneously stream and record, bilaterally, neural activity from the DBS electrode within the STN. The proposed project will, for the first time, simultaneously gather neural activity from the STN using the Percept DBS platform and cortical activity from electroencephalography (EEG) while PD patients perform cognitive and dual-task paradigms and while completing a VE and FE session. The resultant data will provide a neural signature underlying PD-related cognitive and dual-task declines and the neural signature of two modes of aerobic exercise.

Our underlying hypothesis is that high-intensity exercise, in particular FE, reduces STN hypersynchrony which facilitates cortico-basal ganglia thalamocortical circuit functionality thereby improving cognitive function following exercise. Twenty-five participants with PD who have previously undergone DBS surgery utilizing the Percept system will be enrolled in the project and complete a single FE and VE exercise session on a stationary cycle while OFF antiparkinsonian medication and Off-DBS stimulation. The 150-minute experimental session will be completed in the OFF antiparkinsonian medication and Off-DBS and will be divided into six epochs: (1) resting state Off-DBS, (2) cognitive and dual-task testing Off-DBS, (3) Off-DBS + Exercise, (4) cognitive and dual-task testing Post-exercise, (5) rest Post-exercise and (6) cognitive and dual-task testing Post-exercise. Cognitive assessments include Reaction Time, Trail Making Test A & B, and n-back test; an upper extremity dual-task (force tracking + n-back) will challenge the motor/cognitive interaction.

The aim of the study is to identify the neural signature underlying PD-related cognitive and dual-task impairments and to determine the role of FE and VE on the pattern of STN output and its effect on cognitive and dual-task performance. Our previous data indicate exercising at a higher cadence increases in cortico-subcortical connectivity and improves motor function slower pedaling rates. While we expect improvements in performance and attenuation in beta band activity following a single bout of both FE and VE, it is hypothesized that FE will result in superior outcomes in cognitive and dual-task performance as a result of greater theta and beta attenuation.

The proposed project is poised to benefit the PD population by unlocking the mechanism underlying cognitive dysfunction and for the first time detailing the neural interaction between exercise and cognitive and dual-task function. The proposed mechanistic project is a necessary precursor to improving treatment paradigms. It is anticipated that data from this project inform medication regimens, DBS parameter selection and optimization and refine aerobic exercise recommendations.