Priming Upper Extremity Motor Practice With Aerobic Exercise: A Feasibility and Pilot Study
Phase: NA
Conditions: Stroke
Sponsor: Medical University of South Carolina

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Priming Upper Extremity Motor Practice with Aerobic Exercise (Pump-Ex):  A feasibility and 
pilot study 
NCT # 04259424 
02/18/2021 
 
 
 

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PROTOCOL TITLE: 
Priming Upper Extremity Motor Practice with Aerobic Exercise (Pump-Ex):  A feasibility and 
pilot study 
 
PRINCIPAL INVESTIGATOR: 
 
 
Ryan Ross 
 
 
 
 
 

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1.0 
Objectives / Specific Aims 
 
The purpose of this project is to establish initial feasibility and tolerability of a combined aerobic 
exercise (AEx) and upper extremity motor practice intervention on upper extremity (UE) function 
in chronic stroke survivors.  This novel intervention pairs AEx with a virtual reality-based upper 
extremity rehabilitation game, Duck Duck Punch (DDP).   While response to UE rehabilitation 
interventions, such as DDP, involves a multitude of factors, neuroplastic changes are a primary 
mechanism underlying functional recovery. 1 AEx has been shown to improve overall brain 
function 2and promote a neuroplastic environment 3,4; thus it may serve as an effective ‘primer’ 
and enhance the effects of DDP.  Movement-based priming for neurorehabilitation involves 
performing movement or exercise before, or concurrent to, a therapeutic intervention with the goal 
of improving the efficacy of the therapeutic intervention. 5 Emerging evidence supports AEx as a 
potential priming tool for UE stroke rehabilitation.  AEx combined with UE task training can 
improve UE function and self-reported health status in chronic stroke survivors. 6-8 Despite the 
promising results, there are gaps in the literature involving: 1) the clinical applicability of an AEx 
priming session; and 2) mechanisms contributing to changes in UE functions in response to AEx-
primed UE rehabilitation. Addressing these gaps will be necessary to develop an AEx primer that 
is potent and time efficient, with respect to current clinical models. Therefore, the purpose of this 
pilot proposal will be to establish initial feasibility and tolerability benchmarks for the AEx + DDP 
intervention. 
 
Aim 1: Demonstrate the feasibility of pairing AEx + DDP in stroke survivors with UE hemiparesis. 
Outcomes for Aim 1: The primary objective of this project is to demonstrate feasibility and 
tolerability of this novel intervention. Metrics including recruitment, adherence, 
acceptability, retention, and adverse events will be examined to assess the feasibility and 
tolerability of AEx +DDP. Recently Valkenborghs and colleagues (2019) reported rates of 
93% adherence, 95% retention, and 100% acceptability among 9 stroke survivors 
participating in a similar dual intervention. 8 We will use these benchmarks to determine 
the feasibility and tolerability of AEx+DDP.   
Aim 2: Quantify the magnitude of the effect of AEx + DDP intervention on UE impairment and 
function. 
Outcomes for Aim 2: Two objective outcome measures, Fugl-Meyer Upper Extremity 
Assessment (FMA-UE) and Wolf Motor Function Test (WMFT), will be used to assess 
upper extremity impairment and function. This data will compared to historical controls 
from previous DDP trials from Dr. Woodbury’s (Co-I) lab.   
Aim 3: Examine the relationship of biomarkers of neuroplasticity (BDNF and corticomotor 
excitability) and response to AEx + DDP. 
Outcomes for Aim 3: We have selected transcranial magnetic stimulation (TMS)-based and 
blood-based measures to assess the neuroplastic potential of each subject as well as the 
acute effects of AEx+DDP on biomarkers of plasticity. These assessments will provide 
important data describing the neuroplastic potential of each subject (potential responders 
vs. non-responders) and the acute effect of AEx and DDP on indices of neuroplasticity. 
2.0 
Background 
With a surviving cohort of nearly 7 million individuals, stroke is the leading cause of long-term 
disability in the United States. 9 Of the ~795,000 new strokes occurring annually, approximately 

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2/3rds of survivors will have some degree of long term disability. 9,10 The prevalence of post-stroke 
disability coupled with the fact that more people are surviving stroke reflects an increasing need 
to develop effective rehabilitation strategies aimed at reducing disability and improving quality of 
life for the millions of stroke survivors, their families and caregivers. 
The overwhelming majority of stroke survivors, >75%, exhibit upper extremity (UE) hemiparesis, 
and only 15% will recover fully. 11,12 Furthermore, residual UE impairment is closely linked to 
long-term disability 13 and reduced quality of life. 14 Current meta-analytic evidence supports 
virtual reality stroke rehabilitation interventions for improving UE function suggesting that this is 
a promising area for further therapeutic development. 15 Our team (Co-I: Woodbury) has developed 
an innovative virtual reality stroke rehabilitation game, Duck Duck Punch (DDP). DDP is an 
interactive computer game deliberately designed to enhance UE movement quality via 
individualized progressive movement practice along with an array of performance metrics 
allowing for within-session feedback on movement performance.  Although response to UE virtual 
reality rehabilitation interventions, such as DDP, involves a multitude of factors, neuroplastic 
changes are a primary mechanism underlying functional recovery. 1 Thus, pairing DDP with a 
priming intervention to facilitate a ‘neuroplastic-friendly’ environment may make the CNS more 
amenable, and enhance response to DDP rehabilitation and ultimately improve outcomes. 
Aerobic exercise (AEx) training has positive benefits on overall brain function including enhanced 
global cognition, executive function, and processing speed and attention in healthy, older adults. 2 
Additionally, a single session of AEx acutely improves motor memory and learning in younger, 
healthy adults. 3,16 Although AEx has been used to improve cardiovascular function following 
stroke, 17 its neurofacilitatory effects in stroke have yet to be tested empirically. Candidate 
mechanisms through which AEx enhances brain function and motor learning include changes in 
circulating brain-derived neurotrophic factor (BDNF) and corticomotor excitability.  BDNF is 
believed to play an integral role in several neuroplastic processes and promotes the strengthening 
of synaptic connections, i.e. long-term potentiation (LTP) and current research indicates that AEx 
can acutely 4,18 and chronically 19 increase circulating BDNF. Corticomotor excitability (CME) is 
often used as an indicator of LTP-like neuroplasticity and may underlie improvements in motor 
memory and learning. 20 Similarly to BDNF, AEx can acutely enhance corticomotor excitability 
in control and chronic stroke subjects. 3,21,22 Facilitating central nervous system function provides 
rationale to determine the role of AEx in ‘priming’ the brain for a subsequent intervention to 
maximize neuroplastic potential. 
Preliminary Data:  
Aerobic exercise enhances indices of neuroplastic potential.  Single sessions of AEx can 
enhance neuroplastic potential 3,21 and serum BDNF 4,23,24 suggesting that it may ‘prime’ the brain 
for a subsequent rehabilitation intervention.  Work from our lab indicates that, in neurologically 
intact subjects, AEx increases neuroplastic potential (Figure 1.a) and serum BDNF 4 in an intensity 
dependent manner. Currently, we have an ongoing project investigating the acute effect of AEx on 
neuroplastic potential in chronic stroke survivors (Fig 1.b).     
Exploring a bout of priming AEx that fits into current clinical model.  Current AEx priming 
models in UE stroke rehabilitation have incorporated priming bouts that have exceeded 30 
minutes. 6,8 This could be problematic for stroke survivors lacking endurance to complete a 30-
minute bout of AEx before rehabilitation.  Additionally, extended priming bouts may be clinically 
burdensome if resources or staff is limited or if it incurs greater cost to the stroke survivor.  Thus 
we are seeking to find a potent, yet time efficient, priming bout of AEx.  Our previous work 
indicates that 15 minutes of AEx was sufficient in enhancing neuroplastic potential (Figures 1.a 
and 1.b) for up to 60 minutes post-AEx.      

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3.0 
Intervention to be studied  
This project involves the study of the effects of the 
combination of AEx and an UE motor practice 
intervention (DDP) on UE function in chronic stroke 
survivors.  A preceding 15-minute bout of AEx will serve 
as a ‘primer’ to enhance the effects of the DDP 
intervention on UE function. Duck Duck Punch (DDP) is 
an interactive game with an old time carnival theme. In 
2015 DDP received FDA clearance for use as a 
rehabilitation device for post-stroke upper extremity 
rehabilitation.  The patient sits (we prioritized safety so that the player sits vs. stands) in front of 
the Microsoft Kinect and controls a virtual arm with his/her physical arm; reaching forward to 
“punch” virtual ducks (Figure 2). The game can be customized, i.e., made easier or harder, so that 
patients with all levels of impairment can play. Success motivates continued play, so that the user 
engages in high-repetition UE movement practice. Importantly, DDP was deliberately designed 
by therapists so that all aspects of the game elicit beneficial therapeutic arm and postural 
movements. These beneficial movements are ensured via:  
Trunk Constraint: Trunk motions will be constrained by fixing the shoulder avatar in space 
meaning that the avatar arm does not respond to attempts to use compensatory trunk motion 
to “punch” the target rather than reach forward with the arm. As shown in the photos, the 
avatar hand moves forward only when the patient reaches forward using shoulder flexion-
elbow extension not when he/she leans the trunk forward. Therefore, when a therapeutically 
beneficial (i.e., “therapist approved”) strategy is used, the patient experiences the reward of 
successful game play to reinforce the movement strategy. 
Avatar Elbow Extension Scaling:  During set-up, the Kinect maps the patient’s actual 
hemiparetic arm movement abilities and displays it on the screen. The user (therapist or 
patient) can scale, i.e., exaggerate, the patient’s actual arm motion so that the avatar arm has 
more movement than the hemiparetic arm.  This enables patients who have limited range of 
motion in the real-world, to have full range of motion in the virtual world which allows them 
to successfully play the games. The importance of this feature is that it enables the difficulty 
of game play sessions to match the patients’ levels of ability. A task-difficulty to patient-
ability match is required to facilitate post-stroke motor skill (re)learning that underlies 
recovery. 25 If game play is too difficult, i.e., if the patient does not have enough skill to 
achieve the task goal, compensatory trunk and/or arm movement strategies will be used. 26 
Atypical, poor quality motions (learned bad-use 27) may inhibit overall recovery. Matching 
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Normalized$MEP$amplitude$(mean$±$SEM)$$$$$
Time$point$
NeuroplasCc$changes$in$response$to$AEx$+$PAS$$
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LTD-likeresponse|LTP-likeresponse
Figure 1. The acute effects of AEx on neuroplastic potential in control subjects (1a, n=38) and stroke subject 
(1b, n=1). Note that AEx (red and blue lines) enhances neuroplastic potential compared to sitting (black line). 
1.a 
1.b 
Figure 2. A subject playing Duck Duck Punch 

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game difficulty to players’ ability allows a combination of both errors and success during 
repetitive practice 28 thereby providing implicit and explicit feedback to challenge the 
nervous system and promote learning of good quality motions.   
4.0 
Inclusion and Exclusion Criteria/ Study Population 
 
Eligibility screening: Subjects (male and female), ages 21-90, will be screened and recruited for 
the study six months to ten years post-stroke, allowing for natural recovery during the first 6 
months post-stroke. The pool of candidates for the study will be recruited from the database 
registry supported by the Clinical and Translation Tools and Resources (CTTR) Core of the NIH-
funded Center of Biomedical Research Excellence (COBRE) in Stroke Recovery at MUSC.. 
Eligible participants will be screened for participation and if appropriate will be accepted into the 
study. 
 
Inclusion criteria: 1) experienced unilateral stroke at least 6 months, but no more than 120 months 
prior; 2) voluntary shoulder flexion of the affected arm ≥20° with simultaneous elbow extension 
≥10°; 3) moderate arm movement impairment (UE Fugl-Meyer Assessment > 21 but < 52 points; 
4) passive range of motion in paretic shoulder, elbow, wrist, thumb and fingers within 20 degrees 
of normal; 5) 21-90 years of age; 6) ability to communicate as per the therapists’ judgement at 
baseline testing; 7) ability to complete and pass an exercise tolerance test.   
 
Exclusion criteria: 1) lesion in brainstem/cerebellum as these may interfere with visual-
perceptual/cognitive skills needed for motor re-learning; 2) presence of other neurological disease 
that may impair motor learning skills; 3) orthopedic condition or impaired corrected vision that 
alters reaching ability (e.g., prior rotator cuff tear without full recovery); 4) paretic arm pain that 
interferes with reaching; 5) unable to understand or follow 3-step directions; 6) severe cognitive 
impairment (Montreal Cognitive Assessment score <22); 7) severe aphasia; 8) inability to read 
English, 9) history of congestive heart failure, unstable cardiac arrhythmias, hypertrophic 
cardiomyopathy, severe aortic stenosis, angina or dyspnea at rest or during ADL’s; 10) Severe 
hypertension with systolic >200 mmHg and diastolic >110 mmHg at rest; 11) history of, or current, 
depression; and for brain stimulation procedures only: 12) women of child-bearing potential;  
13) electronic or metallic implants; 14) history of seizures. 
 
5.0 
Number of Subjects 
A total of 10 chronic stroke survivors will be accrued locally. 
6.0 
Setting 
All study procedures will take place at MUSC. 
Functional Neurostimulation Laboratory (FNL): This laboratory provides state-of-the-art brain 
stimulation resources to support research activities. The bulk of research procedures for this 
proposal will take place in this laboratory. The FNL is physically located in the College of Health 
Professions Research building although researchers from various disciplines, including neurology, 
psychiatry, and rehabilitation, regularly collaborate in this lab. This lab offers state-of-the-art brain 
stimulation equipment that can be utilized for a multitude of research protocols. The primary brain 
stimulation tools are a MagStim BiStim2 and MagStim Rapid2 transcranial magnetic stimulator 
modules (The Magstim Company Limited; Whitland, UK). The stimulators can be outfitted with 
a figure-of-eight, double-cone, or air-cooled coil. The combination of these brain stimulation tools 
allow researchers to perform a variety of protocols including single pulse, paired pulse, and 
repetitive pulse to assess either upper or lower extremity neurophysiology. The lab is also equipped 

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with a stereotaxic passive marker and camera system as well as neuro-navigation software. 
Magnetic resonance images can be uploaded to the neuro-navigation software, which allows 
researchers to identify and accurately stimulate brain structures of interest. Neurophysiological 
data is collected using a multi-channel data acquisition and analysis package consisting of Spike2 
v7.12 software (Cambridge Electronic Design; Cambridge, UK), a CED 1902 amplifier 
(Cambridge Electronic Design; Cambridge, UK), and a CED Micro 1401-3 data acquisition unit 
(Cambridge Electronic Design; Cambridge, UK). Additionally, the lab is equipped with a constant 
current stimulator and train/delay generator for paired peripheral nerve and brain stimulation 
protocols (i.e. paired associative stimulation). The myriad of tools available in this lab allows 
researchers to perform and analyze mostly all brain stimulation protocols. Specific to this proposal, 
there is ample space to perform the aerobic exercise protocol within the laboratory. Additionally 
there is a laboratory space adjacent to the FNL, which provides ample space for pre-participation 
screening. This reduces travel time between laboratories, and provides convenience for both study 
personnel and participants. 
Upper Extremity Motor Function Laboratory:  This MUSC supported laboratory features 
resources directed to generating and implementing innovative and scientifically-based 
rehabilitation interventions to improve recovery of UE motor function after neurological 
injury/disease. This lab features a virtual environment (enabling DDP intervention) and a multitude 
of assessment tools used in UE rehabilitation trials.  
Locomotor Rehabilitation Laboratory: This 800 ft2 laboratory is a shared resource supported in 
part by the Department of Health Sciences and Research, and features equipment capable of 
collecting kinematic, and electromyographic data during walking. Additionally, a COSMED 
Quark Cardio-Pulmonary Exercise Metabolic Analyzer is housed in this lab and provides the 
ability to assess respiratory gas exchange and electrocardiographic activity during exercise. 
Various exercise equipment (3 recumbent bikes, 2 treadmills, 1 recumbent step trainer) with 
appropriate safety apparatuses (overhead support system) are available in this lab. 
 
7.0 
Recruitment Methods 
 
Subject recruitment:  
 
Since the proposed research investigates stroke recovery it will be supported by the Clinical and 
Translation Tools and Resources (CTTR) Core of the NIH-funded Center of Biomedical Research 
Excellence (COBRE) in Stroke Recovery at MUSC. The CTTR Core provides subject recruitment 
resources through a bioinformatics-enabled database registry. Currently there are more than 900 
post-stroke subjects in our database registry and ongoing recruitment is expected to add 1-3 more 
subjects each week. Additionally, Co-I’s on this project have successfully recruited subjects for 
trials as part of the South Carolina Center for Stroke Recovery Research. Thus, we are confident 
that recruitment goals will be met without difficulty. 
 
8.0 
Consent Process 
Informed consent will be obtained from participants prior to participation. Participants will first 
be informed of the purpose of the experiments and possible risks. The PI or an authorized study 
team member will then review the Informed Consent form with the potential participant, ensuring 
they are given adequate time to review the document. The potential participant will be asked if 
they have any questions about the study, and asked if they agree to participate. The Informed 
Consent and HIPAA forms will be signed by the participant. Copies of the signed forms will be 
given to the participant. The consent process will take place in a private room in the MUSC College 

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of Health Professions Research Building. There will be no set period between informing the 
prospective participant and obtaining the consent. In every session, participants will be reminded 
that they may end their participation in the study at any point. 
 
9.0 
Study Design / Methods 
 Project Overview. Subjects will attend 3 initial visits consisting of informed consent, screening, 
and assessments.  All assessments and AEx + DDP sessions will take place in the College of Health 
Professions Research Building.  The AEx + DDP intervention will consist of 18 sessions to be 
completed within 7 weeks. Subjects will complete 15 minutes of AEx prior to DDP. Sessions will 
be scheduled up to three times weekly separated by at least 24 hours to allow for adequate rest.  
After 18 sessions have been completed, post-testing will be scheduled. Any sessions that are not 
completed within 7 weeks of the first session will be considered missed visits.  After completion 
of the intervention subjects will complete 2 assessment visits.  It is expected that the entirety of 
the 
study 
will 
take 
approximately 8 weeks to complete (See Figure 3 for study timeline).  
 
Screening and assessment visits 
 
Screening Assessments:  Following informed consent procedures we will perform screening 
assessments.  Participants will be screened for cognitive function and depression with the Montreal 
Cognitive Assessment and Patient Health Questionnaire.  
• Montreal Cognitive Assessment (MoCA): The MoCA is 30-point test used for 
assessing cognitive impairment.  It assesses short-term memory recall, attention and 
concentration, executive function, language, visuoconstructional skills, orientation, and 
calculations.  Subjects demonstrating cognitive impairment, indicated by a MoCA 
score < 22 will be excluded. 29     
• Patient Health Questionnaire (PHQ-9): The PHQ-9 is a 9-item instrument used for 
screening and monitoring depression. 30 Since depression has been shown to impact 
neuroplastic potential, 31 subjects with depression (PHQ-9 > 4) will be excluded. 
• Transcranial Magentic Stimulation (TMS) Screen:  The TMS Screen has been 
developed from safety guidelines 32 to ensure patients and study participants are safe to 
receive TMS.  If the TMS screen identifies one or more contraindications to TMS 
subjects will be excluded from receiving TMS assessments.  
Clinical Assessments: We will perform clinical assessments of UE impairment (FMA-UE), UE 
function (WMFT), and ‘real world’ arm use (SIS).  This assessment battery is standard to most 
post-stroke rehabilitation trials. These data will help describe the functional status of participants.  
A licensed physical therapist, exercise physiologist, or trained study personnel through the South 
Informed Consent 
FMA-UE 
WMFT 
MoCA 
SIS 
PHQ-9 


Pre 
Visit 1 
Exercise Tolerance Test 


Pre 
Visit 2 
PAS Testing 


Pre 
Visit 3 
Week 1 
AEx - BDNF 
DDP - CME 


AEx + DDP 
18 sessions 
3x/week x 6 weeks 
FMA-UE 
WMFT 
SIS 


Post 
Visit 1 
PAS Testing 


Post 
Visit 2 
Mid 
AEx - BDNF 
DDP - CME 


Week 6 
AEx - BDNF 
DDP - CME 


+
Figure 3. Study timeline 

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Carolina Center for Stroke Recovery Research will perform all assessments.  These assessments 
will be performed pre- and post-intervention (Pre Visit 1 and Post Visit 1). 
 
• Fugl Meyer Upper Extremity Assessment (FMA-UE): The FMA-UE is a 33-item 
measure of UE impairment; 33 however, the 3 items testing reflex response will not be 
administered because they do not measure a voluntary movement construct.  
Assessments will be video recorded and scored from the videos by trained, blinded 
raters. Each item will be scored on a 3-point rating scale (0=unable, 1=partial 2=near 
normal performance), item ratings will be summed and reported out of 60 points so that 
larger numbers indicate greater UE motor ability. The FMA-UE will be video recorded 
to allow for scoring by a blinded reviewer. 
• Wolf Motor Function Test (WMFT):  The WMFT is a 15-item measure of UE 
functional ability. 34 The WMFT will be administered in a standardized manner 
according to lab specific procedures. Assessments will be video recorded and scored 
from the videos by trained, blinded raters.  Performance of each item will be timed 
(seconds) and the average time to perform items will be reported so that lower values 
indicate greater UE function.   
• Stroke Impact Scale (SIS): The SIS assesses physical function as well as other 
dimension of health-related quality of life: emotion, communication, memory & 
thinking, and social role function. 35 Specifically, the Hand and Perceived Recovery 
subsets of the SIS 35 will be used to assess the effect of the intervention on ‘real world’ 
arm use. The SIS-hand consists of 5-items regarding difficulty of paretic hand use 
during everyday tasks during the previous two weeks. Items will be rated on a 5-point 
scale (5=not difficult, 1=cannot do) and reported as an average item rating. The SIS-
recovery subtest is a single-item in which the participant rates his/her perceived post-
stroke recovery from 0%-100% recovered.   
• International Physical Activity Questionnaire (IPAQ): The IPAQ  is a 5-part self-
administered physical activity seven-day recall.  The IPAQ assesses physical activity 
frequency, duration, and intensity over the previous seven days in four domains: (1) 
job-related, (2) transportation, (3) housework and family caring, recreation, (4) sport 
and leisure.  In addition, the fifth domain assesses time spent sitting at work, at home, 
and during leisure time.  The IPAQ has been shown to produce reliable results and 
validity has been established against accelerometer measurement of physical activity. 
36 It is also easily implemented and appropriate for broadly defining physical activity 
habits.   
• NeuroCom Balance Master Test:  Participants will take part in a balance 
assessment using the NeuroCom Balance Master Sensory Organization Test. This test 
is able to identify whether balance deficits are due to vestibular, visual, or 
somatosensory dysfunction. Participants will stand on a force plate, connected to a 
harness to prevent falls, and participate in several conditions. Participants will be asked 
to keep their eyes open or closed, depending on the condition, while the force plate they 
are standing on and/or the walls surrounding them move according to their movements. 
If participants stay standing still, nothing will move. However, if participants sway, the 
force plate and/or walls, depending on the condition, will move accordingly. There are 
6 conditions: 1) eyes open, everything stable. 2) eyes closed, everything stable. 3) eyes 
open, force plate moving. 4) eyes closed, force plate moving. 5) eyes open, walls 
moving. 6) eyes open, force plate and walls moving. All 6 conditions are completed 3 
times. In total, the 6 conditions completed 3 times each will take approximately 15-20 
minutes.  

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Exercise Tolerance Testing: Prior to experimental visits, a bicycle ergometry protocol modified 
from the LEAPS trial 37 will be used to assess exercise tolerance prior to study inclusion. The 
protocol will be overseen by a physician and will commence with the subject seated quietly for 
two minutes. Exercise will begin with the subject pedaling at ~60 revolutions per minute (RPM) 
and 0 Watts (W) of workload, with workload will be increased by ~15 W every 3 minutes. If the 
pedal cadence drops below 50 RPM, additional reminders will be given. Testing continues until 
maximal effort is achieved. The test will be terminated prior to achieving maximum effort for 
predefined symptomatic, clinical, and electrocardiographic criteria. Symptom-related reasons for 
termination include angina, dyspnea, and fatigue. Fatigue is defined as either voluntary exhaustion 
or inability to maintain a minimum cycling cadence of 40 RPM. Clinical criteria for termination 
include: 1) Hypertension: ≥ 220/120 mmHg, or 2) Hypotension: a drop in diastolic blood pressure 
>20 mmHg, and O2 saturation <85%. Electrocardiogram criteria include: 1) ≥ 1 mm horizontal or 
down sloping ST segment depression, 2) sustained paroxysmal ventricular tachycardia (>30 beats), 
and 3) sustained paroxysmal supraventricular tachycardia (>30 beats). If the test is terminated 
because of electrocardiographic findings, the subject will be managed medically as needed, 
referred for care, and disapproved for participation. Resting blood pressure and heart rate will be 
obtained prior to initiation of exercise as well as after the subject has been sitting on the stationary 
bicycle for 1 minute. During the exercise test, blood pressure readings will be obtained every 3 
minutes. Heart rate will be obtained from the 12-lead EKG. Maximal heart rate will be recorded 
as the highest heart rate achieved during the exercise tolerance test. 
 
Neurophysiological Assessments 
• Assessment of neuroplastic potential:  Participants’ neuroplastic potential will be 
assessed with a plasticity-inducing paradigm called Paired Associative Stimulation 
(PAS).  Briefly, PAS utilizes a repeated and timed peripheral nerve stimulation 
combined with transcranial magnetic stimulation (TMS) of the contralateral motor 
cortex to induce motor cortex plasticity.  Prior to- and after PAS, corticomotor 
excitability (CME) is assessed via motor evoked potentials (MEP) which are obtained 
by single pulse TMS and electromyography (EMG) of a contralateral peripheral 
muscle.  PAS will be assessed pre- and post-intervention (Pre Visit 3, Post Visit 2).  
PAS will be assessed in the ipsilesional motor cortex and paretic UE.       
 
• Paired Associative Stimulation:  Prior to PAS, all participants will be assessed for 
potential contraindications to TMS using a safety-screening questionnaire.  First, we 
will use a combination of on-line surface electromyography (sEMG) recordings to view 
peak-to-peak motor evoked potential (MEP) amplitude and a neuro-navigation system 
to identify the optimal coil position for stimulation of the abductor pollicus brevis 
(APB) muscle (APB ‘hotspot’). The area on the hand knob of the motor cortex that 
produces the largest and most consistent MEP’s of the APB muscle will be marked as 
the ‘hotspot’ using the neuro- navigation system.  We will then assess baseline cortical 
excitability by collecting a ‘bin’ of twenty test MEP’s and a standardized stimulation 
intensity.  This stimulation intensity will remain the same throughout the experimental 
session in order to allow for comparisons of MEP amplitude before and after PAS.  
After assessment of cortical excitability participants will receive PAS.  For PAS, 
participants will receive a combination of simultaneous peripheral nerve stimulation 
and brain stimulation.  Stimulation of the median nerve will be delivered via constant 
current stimulator (DS7A; Digitimer, Hertfordshire, UK) just proximal to the wrist.  
Bipolar electrodes will deliver a 200μs square wave pulse at an intensity equal to 300% 

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sensory threshold. Single pulse TMS will be applied to the APB muscle representation 
on the contralateral motor cortex 25ms (ISI25) after the delivery of median nerve 
stimulation. A train/delay generator (DG2A; Digitimer, Hertfordshire, UK) will trigger 
paired peripheral nerve stimulation and brain stimulation.  A total of 200 paired stimuli 
will be delivered at rate of .25 Hz, resulting in a total stimulation time of approximately 
14 minutes.  Bins of twenty test MEP’s will then be collected immediately, fifteen, and 
thirty minutes post-PAS.  
 
• Electromyographic assessment:  Surface electromyography (sEMG) will be collected 
using 2cm by 2cm surface recording electrodes (Natus, Pleasanton, CA, USA) and will 
be placed perpendicular to the orientation of the fibers of the APB muscle belly.  Prior 
to sEMG placement the site of the APB muscle will be lightly abraded and cleaned 
with pre-packaged alcohol swabs.  All EMG signals will be collected using Spike2 
v7.12 software (Cambridge Electronic Design; Cambridge, UK), amplified (x1000), 
bandpass-filtered (100-2000 Hz) using a CED 1902 amplifier (Cambridge Electronic 
Design; Cambridge, UK), and sampled at 5000 Hz using CED Micro 1401-3 data 
acquisition unit (Cambridge Electronic Design; Cambridge, UK).  Data will be saved 
directly to a network drive for offline analysis.  During all stimulation protocols sEMG 
activity will be continuously monitored in order to ensure that the APB muscle is not 
voluntarily active.  
 
• Assessment of DDP-induced CME:  The effect of DDP on CME will be assessed in 
the paretic UE.   Before and after DDP on 3 occasions (DDP sessions 2, 10, and 17) a 
bin of twenty test MEP’s will be collected.  If reductions in impairments and 
improvements in function are mediated by a strengthening of the corticomotor pathway 
(eg. long-term potential-like response) we would expect DDP to increase CME.  While 
PAS testing will provide information regarding the neuroplastic potential of each 
subject, this assessment will provide data describing the direct effect of a single and 
multiple sessions of DDP on the corticomotor pathway of the paretic UE.      
 
Blood specimen collection  
• BDNF assessment: Blood specimens will be obtained immediately before and after 
AEx on three separate occasions (sessions 1, 9, and 18).  A nurse from the South 
Carolina Clinical and Translational Research Institute (SCTR) will conduct all blood 
specimen collections. Briefly, an intravenous catheter will be placed in a superficial 
forearm vein at the beginning of the experimental session and will be maintained patent 
using an isotonic saline solution. Baseline blood samples will be drawn after a 30-
minute equilibration period and will be drawn immediately before exercise 
commences.  Immediate post-exercise blood samples will be taken within sixty seconds 
of exercise completion while the participant remains seated in the cycle ergometer. 
Blood samples will be collected into serum-separating tubes (SST) containing gel and 
clot activator and Ethylenediametetraacetic acid (EDTA) tubes and will be processed 
by The South Carolina Clinical and Translational Research Institute’s Laboratory and 
Bio-repository.    The purpose of collecting samples into SST and EDTA tubes will be 
to allow for assays for serum and plasma BDNF to be performed. Samples will be 
processed 
according 
to 
manufacturers 
recommendations. 
Enzyme-linked 
immunosorbent assays (Quantikine, R&D Systems, Minneapolis, MN) will be 
performed, in duplicate, to determine the concentration of serum and plasma BDNF.  
Serum and plasma BDNF will be assayed so that we may more completely describe 

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exercise-induced changes in BDNF.  Recent work suggests reporting both serum and 
plasma to account for the potential of platelet activation to overestimate the effect of 
exercise on serum BDNF. 38,39 
 
Intervention visits 
The AEx + DDP intervention will be a total of 18 sessions to be completed within 7 weeks.  Each 
week, subjects will attend up to 3 sessions of AEx + DDP on non-consecutive days (M, W, F).  It 
is expected that AEx + DDP sessions will last approximately 90 minutes.  Post assessment visits 
will occur after the completion of 18 AEx + DDP session or 7 weeks, whichever occurs first. 
 
AEx: Aerobic exercise will be performed on a recumbent stationary cycle (Monark 837e).  During 
AEx, heart rate, blood pressure, and rate of perceived exertion (RPE) 40 will be assessed at baseline, 
every 5 minutes during exercise (or sitting), immediately post-exercise, and then 5 minutes post-
exercise.  Exercise intensity will be determined using the Karvonen equation. 41 The Karvonen 
equation uses an individual’s maximum heart rate (MHR) and resting heart rate (RHR) to calculate 
heart rate reserve (HRR) using the equation: HRR = (MHR) – RHR.  The MHR for each subject 
will be determined during his/her exercise tolerance test.  An exercise physiologist will oversee 
each AEx session.  The target intensity of each AEx session will be 70% HRR and will remain 
constant throughout the intervention.  This intensity was selected for the ‘priming’ bout of AEx as 
preliminary results from our lab have shown it is has a substantial impact on neuroplastic potential 
(See Figure 1.a) and serum BDNF 4 in control subjects.      
DDP: A therapist will oversee the patient’s safety and progress during DDP by: (1) monitoring 
patient compliance and performance via metrics provided by the Microsoft Kinect system, (2) 
determining session parameters for all DDP sessions, and (3) continuously monitoring the patient 
to assess fatigue/pain, answer questions, and problem solve any issues. DDP will be dosed based 
on the number of repetitions performed.  A repetition is recorded when the player moves his/her 
arm so that the avatar leaves a start position. The goal dose for subjects will be 200 repetitions per 
DDP session. The number of repetitions was selected because subjects enrolled in our previous 
studies have averaged 200 self-selected repetitions per day, achieved in ~1 hours without adverse 
event. Birkenmeir et al (2010) demonstrated that subjects with chronic stroke could safely obtain 
200-300 arm movement repetitions in a 1-2 hour therapy session. 42 The therapist overseeing DDP 
will be permitted to reduce the dose if a subject reports substantial fatigue or pain. 
Participant remuneration: Study subjects will be paid $25 per study visit.  Subjects may attend 
up to a total of 23 study visits thus may receive up to $575 of total compensation for participating 
in the study.  Payments to subjects will be made via ClinCard.  Subject will have $25 added to 
their ClinCard for each study visit attended. 
10.0 Specimen Collection and Banking  
Blood specimens will be collected as part of the study procedures.  The specimens collected will 
be used to assess serum and plasma BDNF.  Blood samples will be processed and stored by The 
South Carolina Clinical and Translational Research (SCTR) Institute’s Laboratory and Bio-
repository at MUSC.  The specimens will be transported to the SCTR Research Laboratory in a 
clearly marked biohazard container by study staff or a SCTR nurse.  The PI and SCTR Research 
Laboratory staff will have access to the specimens and associated data.  Specimens will not be 
banked for future use after processing and analysis is completed.                  
11.0 Data Management  

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Power Analysis:  Although the primary goal of this proposal is to demonstrate feasibility and 
tolerability of AEx+DDP, the sample size is based on change in FMA-UE scores from recent work 
from Linder and colleauges. 6 These data, for individuals with moderate UE impairment (the target 
sample of this study) yielded a FMA-UE mean change score of 12.3 for AEx + UE task practice 
and a FMA-UE mean change score of 4.4 for UE task practice only.  Assuming the difference in 
mean FMA-UE change scores of 7.9 (pooled SD of 4.25), a sample size of n=5 for each group 
(AEx+DDP and DDP only) achieves 80% power with alpha = 0.05.  Although we will not enroll 
a DDP-only group, we will be able to compare AEx+DDP to historical controls from the Co-I’s 
lab. Two trials involving DDP have data from large samples (n=66 and n=103) providing ample 
data for comparison of AEx+DDP to DDP.  Considering recruitment rates from the Co-I’s previous 
trials (2-5 subjects/month) and anticipating a 20% dropout rate will inflate the sample size to n=10.  
Given recruitment rates and the timeline of this proposal (1 year) achieving this sample size 
appears feasible.  This sample size is comparable to published literature  6,8 and is sufficient to 
detect a large effect of AEx+DDP on FMA-UE compared to historical controls receiving DDP 
only. Additionally, this sample will provide a robust pilot data set for calculating effect sizes to 
power future trials examining AEx as primer for UE motor rehabilitation. 
 
Statistical Analysis Plan:  Feasibility and tolerability metrics of adherence, retention, and 
acceptability will be assessed (Aim 1). FMA-UE, WMFT, and SIS data will be compared to 
historical control data from previous DDP trials from Dr. Woodbury’s lab (Aim 2).  We will utilize 
ANOVAs to test the effect of adding AEx to DDP on the mean FMA-UE, WMFT, and SIS-hand 
item rating and the average SIS-recovery scores (PROC GLM, SAS v9.4).  Additionally, data 
describing the effect of AEx+DDP on UE impairment and function will be used to generate effect 
sizes for future research proposals.  Pre- and post intervention PAS assessment will be tested with 
a student’s T-test or Wilcoxon rank-sum test based on distributional assessment.  The acute (within 
session) and training (over the course of intervention) effect of AEx on BDNF and DDP on CME 
will be assessed with a generalized mixed model analysis (PROC MIXED).  Relationships of 
biomarkers of plasticity (PAS, BDNF, CME) and response to AEx+DDP (change in FMA-UE or 
WMFT) will be explored with Pearson or Spearman-rank order correlational analysis, depending 
on distributional assessment (Aim 3).     
Confidentiality: All records regarding participation in this study will be kept in locked file 
cabinets in the appropriate laboratories and/or offices, and stored on MUSC network storage. 
Access to linked identifiers is limited to research personnel intimately involved with the human 
subjects. All data and records acquired from subjects is for research purposes only and will be kept 
confidential and maintained in a secure database identifiable only by subject code. The results of 
the study may be published for scientific purposes; however, subjects’ identities will not be 
revealed and data will not be traceable to any individuals in any resultant publications. The 
information gathered during this study will be kept confidential to the extent permitted by law. 
 
12.0 Provisions to Monitor the Data to Ensure the Safety of Subjects (if applicable) 
An exercise physiologist or occupational therapist will be present during all treatment sessions.  In 
addition, the research staff will closely monitor the subject to ensure their comfort. Any adverse 
events will be recorded and monitored as required by our Institutional Review Board. In the event 
of an adverse medical event, standard facility emergency procedures will be followed and proper 
personnel notified. The PI on this proposal is trained in exercise physiology and the PI’s mentors 
on this project include a physical therapist and an occupational therapist.  
 

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Blood Specimen Collection Data Safety and Monitoring Plan: A registered nurse will conduct 
all blood specimen collections and be present during each testing session.  All specimens will be 
given unique identifiers and will be stored in the SCTR Research Nexus Biorepository.   
 
Brain Stimulation Data Safety and Monitoring Plan:  We will implement a screening tool for 
all participants undergoing TMS that is currently used in the FNL at MUSC.  In addition, the PI’s 
mentor will personally supervise the first several participants.  Stimulation sessions will be stopped 
immediately with any complaints of pain or burning at the stimulation sites or for any complaints 
of dizziness or light-headedness.  All brain stimulation techniques utilized in this project have been 
demonstrated to have minimal risk to participants and all parameters will be within the published 
guidelines.  All participants will be receiving TMS while in a recumbent position.  In the event of 
a seizure the participant will remain in the TMS chair and all study procedures will cease.  The 
immediate surrounding area will be cleared of all potential hazardous materials or objects. If the 
seizure persists for 5 minutes or longer, emergency personnel will be called.  Participants 
experiencing seizures that last for shorter periods of time will be observed for 20 minutes after the 
seizure has ended.  If a participant experiences a second seizure or remains confused or disoriented 
during this time frame then emergency personnel will be called.  Under no circumstances will 
study procedures continue after a participant has experienced a seizure.  
 
13.0 Risks to Subjects 
Screening:  This activity will involve answering a few questions that could cause the participant 
to become upset, emotionally distressed, or embarrassed.  To reduce this risk, screening will occur 
in a private office with only study personnel present.    
 
NeuroCom Balance Master Test:  The participant will wear a safety harness attached to the 
top of the machine so that a fall cannot occur (weight limit 500 lbs), and a research assistant will 
be in close proximity to provide assistance if a loss of balance does occur.  If a participant is unable 
to complete conditions due to loss of balance or dizziness, the assessment will be stopped. 
 
Aerobic Exercise:  The risks of exercising at submaximal intensities on a cycle ergometer (as 
proposed in this study) are minimal but could include fainting, abnormal blood pressure response, 
irregular heartbeat, dizziness, and muscle soreness.  However to ensure safety, all participants will 
complete an exercise tolerance test evaluated by a physician. The risk of serious adverse response 
to exercise testing, which is a greater intensity than will be prescribed in this study, has been 
reported to be less than 1 in 2500 cases.  Study personnel will monitor participants’ vital signs 
(heart rate and blood pressure) before, during, and after exercise. Given the low likelihood of an 
adverse response to submaximal exercise and screening prior to participation we believe the risk 
of exercise to be low.  In addition, professional staff (exercise physiologist, physical therapist) will 
be present and available throughout each session.  
 
 
Duck Duck Punch:  The treatment session duration and number of movement repetitions 
(200/session) may induce fatigue or pain, primarily in the paretic arm.  Subjects in Dr. Woodbury’s 
DDP studies have averaged ~200 repetitions per session and empirical evidence suggests that 
chronic stroke survivors can safely achieve 200-300 arm movement repetitions per in a 1-2 hour 
therapy session. 42 To assess and monitor pain and fatigue, subjects will be instructed in how to 
use the Borg Rating of Perceived Exertion 40 scale and a 10-point Pain Rating Scale. 43  
 

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Transcranial Magnetic Stimulation (TMS): There is a very low risk of a seizure during or after 
TMS. The risk of seizure induction by this protocol has been thoroughly assessed and the TMS 
parameters have been chosen to be well within published safety guidelines for the conduct of TMS 
studies in human subjects.  The risks of non-invasive brain stimulation via TMS are minimal when 
proper screening is conducted prior to participation.  Those with absolute contraindications (eg. 
history of seizures, metal implants) to TMS will be excluded from participating in the study. 
Headaches and complaints of short-term hearing difficulties have also been reported following 
TMS.  Headaches are temporary and manageable with common over-the-counter pain remedies 
and all subjects will wear foam earplugs for protection during TMS sessions.  To reduce the risk 
of an adverse event, all participants will be required to pass a TMS screen, wear foam ear plugs 
and will be continuously monitored for any abnormal responses to TMS.  Additionally, the TMS 
device is equipped with an automatic shut-off switch in case the coil delivering the stimulation 
begins to overheat.  
 
Muscle Activity Testing:  There is a slight risk of skin irritation with the use of surface EMG 
electrodes and tape.  To reduce this risk, study personnel will perform visual inspection of the 
participant’s skin before and after testing to ensure that the participant did not have an adverse 
reaction to the electrode.  
 
Paired Associative Stimulation (PAS):  The risks associated with PAS are the same as the risks 
for TMS, however some irritation of the skin at the site the peripheral nerve stimulation may occur.   
 
Blood Sample collection:  A nurse will perform all blood sample collections.  The risks of taking 
blood include pain, a bruise at the point where the blood is taken, redness and swelling of the vein 
and infection, and a rare risk of fainting.  To reduce this risk, only a nurse will be permitted to take 
blood sample collections.  Proper anti-septic procedures will be followed in order to minimize the 
risk of infection at the site of the puncture of the vein.   
 
Unforeseen risks:  The study may also have risks that are unforeseeable at this time. 
 
Protection against risks 
An exercise physiologist, occupational therapist, or physical therapist will be present during all 
testing and intervention sessions and a nurse will perform all blood draws.  All participants will be 
screened prior to participating in exercise or brain stimulation procedures to ensure safety. Any 
adverse events will be recorded and monitored as required by our Institutional Review Board. The 
PI on this proposal is an exercise physiologist, a certified strength and conditioning specialist and 
has approximately 10 years experience in the development and implementation of exercise 
interventions and three years experience delivering TMS. In the event of an adverse medical event, 
standard facility emergency procedures will be followed and proper personnel notified. Any 
adverse events will be recorded and monitored as required by the IRB. Subjects will be able to 
terminate the training or testing sessions at their request at any time without prejudice.  
 
Aerobic exercise:  During all exercise sessions the research staff will closely monitor the subject 
to ensure their comfort. Minimization of risk will be accomplished by monitoring vital signs within 
prescribed criteria for termination of aerobic exercise. We will follow the American College of 
Sports Medicine criteria for terminating an exercise session, which includes: subject complaints 
of light-headedness, confusion, or dyspnea; onset of angina; excessive blood pressure changes 
(systolic BP greater than 220 mmHg, diastolic BP greater than 110 mmHg); and inappropriate 
bradycardia (drop in heart rate >10 beats per minute). 
 

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Duck Duck Punch:  We will document subjects’ perceived exertion and pain before, during and 
after each therapy session in a written log. Ratings of 12-14 on the Borg scale (6-20) suggest that 
the activity is being performed at a moderate intensity level.  If a Borg rating ≥14, or if a pain 
rating ≥5 (moderate; 0-10 scale), then subjects will rest and we will reduce DDP game difficulty. 
Subjects’ ratings will be reviewed by study personnel and adjustments to the individual subject’s 
program will be made as needed. 
 
TMS testing: The primary safety concern with TMS is the induction of seizures; however, the 
incidence of seizures is very low and mostly associated with high frequency repetitive TMS 
(rTMS). We will use single-pulse TMS, which is safer yet, and we will follow published safety 
guidelines for diagnostic TMS to minimize the risk of inducing a seizure.  Hearing protection for 
all subjects during TMS will be provided. Stimulation sessions will be stopped immediately with 
any complaints of discomfort or for any complaints of dizziness or light-headedness. There are no 
lower-risk methods available to gain the same scientific information.  In addition the PI has also 
been trained in TMS through a training course provided by the Brain Stimulation Laboratory 
(BSL) at MUSC.  The PI, or study personnel that has been appropriately trained, will perform all 
TMS procedures.   
 
Confidentiality:  All records regarding participation in this study will be kept in locked file 
cabinets in the appropriate laboratories and/or offices, and stored on password-protected 
computers/servers in the offices and laboratories of the PI’s research team. There will be no direct 
link to participant identifying information (other than subject code) without access to a password-
protected computer containing the identifying information linking information to a given subject. 
Access to linked identifiers is limited to research personnel intimately involved with the human 
subjects. All data, video and records acquired from subjects is for research purposes only and will 
be kept confidential and maintained in a secure database identifiable only by subject code. The 
results of the study may be published for scientific purposes; however, subjects’ identities will not 
be revealed and data will not be traceable to any individuals in any resultant publications. The 
information gathered during this study will be kept confidential to the extent permitted by law. 
 
14.0 Potential Benefits to Subjects or Others 
 
Subjects who participate in this study may see improvements in UE function, but any benefit 
cannot be guaranteed.  Others may benefit from advancement of scientific knowledge.  Given the 
minimal risks involved and the potential for short-term benefits and advancement of scientific 
knowledge, the potential benefits of participation make the potential risks reasonable. 
While AEx has established functional and health benefits for stroke survivors, its ability to enhance 
concurrent UE motor rehabilitation programs, such as DDP, has largely been theorized.  
Combining AEx with UE motor rehabilitation has the potential to foster a perpetual cycle of 
improved health and physical function which stimulate improvements in other aspects of stroke 
recovery (eg. activity limitations, participation restrictions, recurrence of subsequent stroke).  
Given the minimal risks involved and the potential to add to the limited base of scientific 
knowledge describing this problem, the potential risks are reasonable.   
15.0 Drugs or Devices  
 
 
Transcranial Magnetic stimulation, specifically repetitive TMS (rTMS), is an FDA approved 
device to be used for the treatment of depression.  Although, in this project only single pulse TMS 
will be employed.  The TMS device will be stored and dispensed in the Functional 

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Page 17 of 23 
 
Neurostimulation Laboratory in the College of Health Professions Research Building at MUSC.  
The PI will be designated to store the device and the PI, Co-I’s, or appropriately trained study staff 
will be permitted to dispense the device.  TMS will only be dispensed according to the published 
guidelines and safety measures. 32 
 
Duck Duck Punch (DDP) has FDA clearance for use as a rehabilitation device for post-stroke 
upper extremity rehabilitation. DDP will be stored in the Upper Extremity Motor Function 
Laboratory in the College of Health Professions Research Building at MUSC.  The PI will be 
designated to store the device and the PI, Co-I’s, or appropriately trained study staff will be 
permitted to dispense the device. 
 
 
 
 
 
 
 
 
 
 
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