The Impact of Exercise on Subthalamic Nucleus Neural Activity in Parkinson's Disease

Study Overview
=================
Brief Summary
-----------------
Fifteen PwPD who have undergone DBS surgery and utilize the Percept system will complete a FE and VE exercise session on a stationary cycle while Off antiparkinsonian medication. Bilateral neural activity of the STN will be continuously recorded for 130 minutes (pre-, during FE or VE and post-exercise). The Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III Motor Exam and upper extremity force-tracking task will be used to determine motor response to exercise.

Detailed Description
-----------------
Parkinson's disease (PD) is a progressive neurological disease, most prevalent in older adults, estimated to affect over 12 million people world-wide by 2040. While antiparkinsonian medication and deep brain simulation (DBS) are effective in managing disease symptoms, disease modification has remained elusive. Exercise has been proposed as the Universal Prescription for PD capable of slowing disease progression; stationary cycling in particular has been suggested as an ideal exercise modality for people with PD (PwPD).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). Briefly, FE is a mode of high intensity exercise originating in animal models of PD in which voluntary exercise rate is augmented, but not replaced. Thus, PwPD were assisted in pedaling at a higher rate (cadence) on the tandem cycle compared to those on a standard stationary cycle performing voluntary exercise (VE). This work resulted in a paradigm shift in terms of recommending high intensity exercise for PwPD. Currently, we are involved in two multi-site clinical trials aimed at identifying the potential of high intensity exercise to slow PD (2R01NS073717 & 1U01NS113851). Despite the potential of exercise to alter disease progression, its mechanism of action and effects on basal ganglia function are not understood. The loss of dopamine producing neurons associated with PD results in hypersynchrony of basal ganglia motor circuits that underlies PD symptoms. Recent animal studies using FE evaluated neural activity, local field potentials (LFPs), from the primary motor cortex (M1) to estimate the impact of exercise on basal ganglia function. Following FE, neural hypersynchrony in the beta (13-35Hz) frequency band was reduced in M1, which was proposed to underlie improved motor function. M1 activity is impacted by the activity in the subthalamic nucleus (STN), a structure in the basal ganglia, via the direct and indirect pathways. The impact of high intensity exercise, VE or FE, on STN hypersynchrony in humans is unknown. Recording of STN neural activity, until recently, was only possible during DBS surgery or in patients whose electrode was temporarily externalized immediately post-surgery. Neither approach is feasible or safe to systematically evaluate the effects of exercise on basal ganglia function. Recently, the Medtronic Percept DBS platform received FDA approval. The Percept platform records and streams neural activity from the DBS electrode within the STN. This project, for the first time, will record neural activity from the STN during two modes of high intensity exercise, FE and VE, in PwPD to identify the potential mechanism underlying the beneficial effects of exercise on PD. Our underlying hypothesis is that high intensity exercise reduces STN hypersynchrony which facilitates cortico-basal ganglia-thalamocortical circuit functionality thereby improving motor function following exercise.

Official Title
-----------------
The Impact of Exercise on Subthalamic Nucleus Neural Activity in Parkinson's Disease

Conditions
-----------------
Parkinson Disease, Deep Brain Stimulation

Intervention / Treatment
-----------------
* Other: Forced and Voluntary Exercise


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adult with a diagnosis of PD by a movement disorders neurologist Previous placement, at least six months, of bilateral Medtronic Precept DBS as standard of care treatment for their PD. Stable and clinically optimized DBS parameters for three months prior to enrollment. Demonstrate the ability to safely mount and dismount a recumbent exercise cycle with an upright back. Willingness to withhold antiparkinsonian medication and DBS stimulation. Exercise clearance using the American College of Sports Medicine (ACSM) Pre-participation Health Screen: a. If the ACSM screen recommends medical clearance, the subject must obtain medical clearance by their health care provider prior to participation; b. Those who choose not to obtain physician clearance will not be eligible for participation. Exclusion Criteria: Diagnosis of dementia or any neurocognitive impairment that compromises the ability to provide informed consent. A musculoskeletal issue that limits one's ability to cycle Neurological disease other than Parkinson's disease (i.e. multiple sclerosis, stroke) that impacts motor or cognitive function Uncontrolled cardiovascular risk factor such as a current cardiac arrhythmia, uncontrolled hypertension, untreated deep vein thrombosis, etc.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Interventional Model Description: Fifteen Parkinson's disease patients who have undergone DBS surgery and utilize the Percept system will complete a FE and VE exercise session on a stationary cycle while OFF antiparkinsonian medication. Bilateral neural activity of the STN will be continuously recorded.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental Arm<br>Two modes of high intensity exercise | Other: Forced and Voluntary Exercise<br>* Participants will complete a forced exercise (FE) and voluntary exercise (VE) session. Forced exercise is a mode of high intensity exercise in which voluntary exercise rate is augmented, but not replaced. Voluntary exercise is standard stationary cycling. FE and VE exercise sessions will be Off antiparkinsonian medication. The order in which exercise session is conducted first will be randomized. Bilateral neural activity of the STN will be continuously recorded for 130 minutes (pre, during FE or VE and post-exercise).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Finger Tapping | Finger tapping portion of the MDS-UPDRS III | Data collection days two and three | 
| Force Tracking | Force-tracking time within range | Data collection days two and three | 
| Local Field Potential | Power in frequency bands of interest | Data collection days two and three |