The Impact of Exercise on Subthalamic Nucleus Neural Activity in Parkinson's Disease
Phase: NA
Conditions: Parkinson Disease, Deep Brain Stimulation
Sponsor: Jay Alberts

 
 
The Impact of Exercise on Subthalamic Nucleus Neural 
Activity in Parkinson’s Disease 
 
Study Protocol 
 
NCT05905302 
 
Document Date 2/14/2023 
 
Posted 9/16/2025 
 
 
 

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Project Title: The impact of exercise on subthalamic nucleus neural activity in Parkinson’s disease 
PI: Jay Alberts, PhD 
Version Date: 2/14/2023 
 
APPROACH 
Fifteen PwPD utilizing the Percept PC DBS system will be enrolled for this project. Briefly, all patients will be at 
least six-months post bilateral DBS surgery with DBS parameters clinically optimized for at least three months 
prior to enrollment. To reduce possibility of a cardiac adverse event during the proposed exercise sessions, the 
American College of Sports Medicine (ACSM) Pre-exercise Screen1 will be performed prior to exercise (see 
Protection of Human Subjects for details).  We anticipate an ample population of PwPD eligible for recruitment 
as neurosurgeons within the Center for Neurological Restoration (CNR) perform 200 bilateral STN DBS 
surgeries annually. The Percept platform is rapidly becoming the system of choice due to ease of 
programming. 
Following all pre-screening, 
participants will complete three visits on 
3 separate days. For Visit 1, participants 
will complete the informed consent 
process, establish resting heart rate 
(HR; supine x5 min), be fitted to the 
cycle to ensure proper mechanics, 
complete ~5-10 minutes of FE and VE to 
ensure safety and understand cycle 
operation, complete 5-10 familiarization 
force-tracking trials,2 and have order of 
FE or VE assigned for Visit 2 and 3 via a 
computerized randomization scheme. 
Target HR will be calculated using the 
Karvonen method3 [(Max HR-Resting 
HR) x (60%-80%) + Resting HR]; max 
HR will be estimated as (220-age).4 
Figure 1 provides an overview of the 
experimental paradigm for Visit 2 and 3.  
For Visit 2 and 3, PwPD will 
arrive OFF antiparkinsonian medication 
and On-DBS. The 130-minute 
experimental session will be divided into 
four epochs: 1) On-DBS, 2) Off-DBS, 3) 
Off-DBS + Exercise and 4) Post-
exercise. Neural activity from the STN 
will be continuously recorded from both 
DBS electrodes for the entire 130-
minute session.   
 
To ensure proper autonomic and hemodynamic response to exercise, BP will be taken before, during (minute 
20), and following cool-down.  During exercise sessions, pedaling torque, cadence and HR will be continuously 
recorded at 60Hz and rate of perceived exertion (RPE) will be recorded every 10 minutes using our previous 
methods.5 The main exercise set (40 min) and HR (60-80% of HHR)6 will be identical across FE and VE. The 
single manipulated independent variable is pedaling cadence. For the VE group, maximum cadence will be 
limited to 60rpms.  During FE, with assistance of the motor, cadence will be maintained between 80-90rpms.6 
This approach replicates previous human and animal exercise paradigms and will lead to clear interpretation of 
the effect of cadence on STN neural activity and upper extremity motor function.  
 
Forced-exercise (FE) Cycle and Session: To deliver the FE intervention, a suite of sensors is integrated into 
a standard stationary cycle to monitor system and rider status. The inertia wheel, brake and brake controller 
Figure 1: Illustration of experimental protocol and equipment utilized to obtain 
LFPs from STN-DBS implanted in PD patients during exercise. (A) Percept PC 
system is integrated into the implantable pulse generator (IPG) shown in circle 
insert and continuously transmits LFPs in real time wirelessly to a storage device 
(tablet) (B) Illustration of the DBS lead implanted in the subthalamic nucleus (STN) 
and surrounding basal ganglia nuclei  (C)Assessments, MDS-UPDRS-III and force-
tracking, will be performed at 3 time points during an experimental session.  

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were replaced with three core components: servomotor, motor-drive, and programmable controller. While the 
motor augments pedaling rate in the FE mode, participants actively contribute to pedaling as they must 
exercise within their specified target HR range. The control algorithm automatically adjusts assistance or 
resistance during FE based on the user’s continuously-monitored torque production and heart rate thus 
allowing the system to maintain an effective therapeutic cadence while the user maintains their target heart 
rate.   
 
Voluntary Exercise (VE) Session: During the VE session, individuals will complete the main exercise set at a 
cadence of no greater than 60rpms6 on the same stationary cycle while in its standard voluntary mode. In the 
event that a participant’s voluntary rate is >60rpms, resistance will be applied to ensure cadence is maintained 
and target HR is reached. In standard voluntary mode the motor control assistance algorithm is disabled and 
the cycle functions as a typical resistance based stationary cycle. During the VE exercise session, pedaling 
torque, cadence and HR will be continuously recorded at 60Hz and RPE will be recorded as in the FE session.  
 
DATA COLLECTION 
Local Field Potentials (LFP) Recordings: Neural activity of the STN will be gathered bilaterally for the 
duration of each 130-minute visit. Medtronic’s BrainSense Indefinite Streaming platform will provide LFP data 
from Medtronic 3389 electrode model or SenSight directional leads. For the On-DBS epoch, LFPs from 
contact pairs surrounding the stimulating contact  (0-2, 0-3, 1-3) for each hemisphere will be recorded (2 
channels total).7 In the Off DBS, Exercise and Post-exercise epochs, LFPs will be recorded between contact 
pairs 0-2, 0-3, 1-3 bilaterally resulting in simultaneous recordings of 3 channels per hemisphere (6 channels 
total). All LFP recording will be sampled at 250Hz and low-pass filtered (0-100Hz) and streamed via Bluetooth 
to the Medtronic tablet (Figure 1A&B). While in the Off DBS epoch, the bipolar channel with highest peak 
power in the beta band (13–35 Hz) during rest in each hemisphere will be selected for further analyses. This 
selection is based on previous studies demonstrating a significant correlation between contact-pair location in 
the sensorimotor portion of the STN and beta power.8 LFP outcomes: Prior to calculation of outcomes, 
windows containing movement artifacts will be visually identified by large fluctuations in the time series and 
high amplitude broadband activity in the spectrogram and removed from further analysis. Triggered 
spectrograms will be calculated for each trial using the multitaper method with a 500 ms, 250 ms overlap 
moving window, 2.0 Hz frequency resolution, and 1 taper. Relative power will be obtained for each subject and 
frequency by normalizing the absolute power by its average across time for each channel. This approach will 
facilitate comparison across subjects, whose absolute signal magnitude can vary by one or two orders of 
magnitude.  The relationship of synchronization and desynchronization changes in oscillatory activity within the 
frequency bands of interest, delta, theta, alpha, beta and gamma bands, will be calculated across each of the 
four epochs within an experimental session. Along with average power, moment-to-moment dynamics of the 
band power, e.g., beta bursts, will be assessed in each condition as previous data indicate beta burst activity 
during continuous movement is related to PD bradykinesia.9 Dr. Miller Koop will lead the collection and 
analysis of LFP data.  
 
Force-tracking:  Upper extremity motor control will be assessed during the performance of a force-tracking 
task used previously with older adults10,11 and PwPD.2,12 Patients will use a precision grip (thumb and index 
finger) with the dominant hand to exert an isometric force against a six-degree of freedom force transducer 
(Figure 1C) affixed to an adjustable experimental table. The greatest force produced in the FZ axis (grip force) 
during a five second trial will be considered their maximum voluntary contraction (MVC).  To ensure consistent 
motor task demands across the four data collection timepoints, target tracking force will be 20% of their MVC 
for a given session. During the force-tracking task, participants match their grip force to the target force as 
accurately as possible; a monitor simultaneously displays target force and patient produced grip force.  
 
Force-tracking Outcomes: Force data will be filtered with a phase-symmetric low-pass filter employing 
Woltring's algorithm using existing Matlab analysis programs.13,14 The primary outcomes will be time within the 
target range (TWR) and relative root mean square error (RRMSE). The TWR is calculated by determining the 
time the patient’s force trace is within ±2.5% of the target line. The TWR provides an overall accuracy measure 
of force-tracking. To account for differences in the amplitude of the target force (e.g. inter-patient and intra-
patient variability due to stimulation or exercise status), the RRMSE will be used as a method of normalizing 

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performance relative to force amplitude.  Where, FT(t) is the target force provided to the patient, F0(t) is the 
force produced by the patient, T trial time. 
 
Aim 1: To determine the effects of two modes of high intensity exercise, FE and VE, on the pattern of 
neural activity within the STN.   
Statistical Analysis: Average band powers (delta, theta, alpha, beta and gamma) will be calculated at rest for 
90 seconds in the Off DBS session immediately prior to exercise and immediately following FE and VE 
sessions. Mixed effect models will be utilized for each band power to determine if band powers at rest while Off 
DBS are significantly reduced following high intensity exercise (primary outcome), and to determine if the FE 
reduces band power significantly more than VE (secondary outcome).  
 
Aim 2: To determine the relationship between changes in STN neural activity associated with FE and 
VE on upper extremity motor function and clinical symptoms of PD.  
Statistical Analysis: The force-tracking outcomes, including TWR, will be calculated for all trials. Data from 
the Off DBS and Off DBS + Post Exercise sessions will be used for the primary analysis.  Mixed effects models 
will be utilized to determine if force tracking performance improves following either exercise mode compared to 
Off-DBS and secondary analysis will be conducted to determine if FE improves force tracking more than VE.  
Clinical data from the same time points will be evaluated to determine the overall clinical response to high 
intensity exercise and any differential effects of exercise mode (FE vs. VE).  Mixed models will be adjusted for 
confounding characteristics determined a priori, including sex, education, and PD severity. Model assumptions 
and model fit will be assessed, and variables will be transformed, as needed. 
 
Inclusion Criteria: 
a) Adult with a diagnosis of PD by a movement disorders neurologist 
b) Previous placement, at least six months, of bilateral Medtronic Precept DBS as standard of care 
treatment for their PD. 
c) Stable and clinically optimized DBS parameters for three months prior to enrollment. 
d) Demonstrate the ability to safely mount and dismount a recumbent exercise cycle with an upright back.  
e) Willingness to withhold antiparkinsonian medication and DBS stimulation. 
f) 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:  
a) Diagnosis of dementia or any neurocognitive impairment that compromises the ability to provide 
informed consent. 
b) A musculoskeletal issue that limits one’s ability to cycle 
c) Neurological disease other than Parkinson’s disease (i.e. multiple sclerosis, stroke) that impacts motor 
or cognitive function 
d) Uncontrolled cardiovascular risk factor such as a current cardiac arrhythmia, uncontrolled hypertension, 
untreated deep vein thrombosis, etc.  
 
 
 
 
 

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REFERENCES  
 
1. 
Riebe D, Franklin BA, Thompson PD, et al. Updating ACSM's recommendations for exercise 
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2. 
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disease patients using a computational modelling approach to deep brain stimulation programming. Brain. Mar 
2010;133(Pt 3):746-61. doi:10.1093/brain/awp315 
3. 
Karvonen MJ, Kentala E, Mustala O. The effects of training on heart rate; a longitudinal study. Ann Med 
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doi:10.1002/hbm.23594 
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Syrkin-Nikolau J, Koop MM, Prieto T, et al. Subthalamic neural entropy is a feature of freezing of gait in 
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