Forced Aerobic Exercise for Stroke Rehabilitation
Phase: NA
Conditions: Stroke
Sponsor: The Cleveland Clinic

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Submission Protocol for: Heart-Brain Retraining: Forced Aerobic Exercise for Stroke 
Rehabilitation 
 
Principal Investigator: Jay L. Alberts, PhD 
Co-Principal Investigator: Susan M. Linder, PT, DPT, NCS 
Date: 4/25/2012 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Specific Aims  
Stroke is the leading cause of disability in the United States with approximately 795,000 new or 
recurrent strokes per year1.  An estimated 25-50% of patients post-stroke remain disabled after 
rehabilitation2.  Repetitive task practice (RTP) and constraint-induced movement therapy 
(CIMT)3, 4, which focus on retraining motor function, have been shown to be effective in stroke 
recovery.  However, these promising approaches are time-intensive and have not been fully 
embraced clinically.  The development of an adjunctive intervention capable of facilitating 
neuromotor recovery, while simultaneously decreasing cardiovascular risk factors, would be 
valuable to current stroke rehabilitation approaches.  Forced aerobic exercise (FE) may be this 
promising intervention.  Animal studies using a FE paradigm, in which the rodent is exercised on 
a motorized treadmill at a rate greater than its voluntary rate, indicate an endogenous increase 
in neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and glial-derived 
neurotrophic factor (GDNF)5.  These neurotrophic factors are thought to underlie neuroplasticity 
and motor (re)learning6-8.  Previous studies have shown aerobic exercise can improve 
cardiovascular fitness post-stroke; however, these studies have not systematically examined the 
impact of exercise on motor recovery9-12.  It is hypothesized that patients with stroke, due to 
decreased motor cortical output13, cannot sustain high rates of voluntary exercise14 
necessary to trigger the endogenous release of neurotrophic factors which underlie 
neuroplasticity and recovery; therefore, forced-exercise is necessary to augment their 
voluntary efforts and will be superior to voluntary exercise in facilitating motor recovery. 
We have developed a safe and effective method of delivering forced-exercise to Parkinson’s 
disease (PD) patients (NIH R21HD056316). Clinical and imaging data with PD patients indicate 
forced-exercise, but not voluntary exercise, triggers a neurophysiologic response in the CNS 
resulting in global improvements in motor and non-motor functioning and increased cortical and 
subcortical activation15, 16. The aim of this project is to conduct a preliminary trial to 
compare the effects of forced to voluntary exercise in promoting the recovery of motor 
function in patients with stroke.   
A preliminary single-center, parallel-group, rater-blind study is proposed. A total of 30 
chronic (6-12 mos. post) stroke patients with residual hemiparesis will be randomized to one of 
three groups: combined forced-exercise and repetitive task practice (FE+RTP), combined 
voluntary exercise and RTP (VE+RTP) or a dose-matched RTP only (RTP only) group. All three 
groups will receive an identical dose of rehabilitation time over a course of 8 weeks (3X per 
week); however, the combination groups will perform forced or voluntary exercise for 50% of the 
session and RTP for the remaining 50% of the session.  The RTP only group will engage in RTP 
exclusively. Outcomes will be gathered at baseline, mid-treatment and end of treatment (EOT).   
Aim 1: To compare the effects of FE+RTP, VE+RTP, and RTP only on the recovery of 
upper extremity motor function.  The primary outcome is the change in the Wolf Motor 
Function Test (WMFT) from baseline to EOT. Secondary outcomes include changes in the Fugl-
Meyer Assessment and biomechanical variables quantifying bimanual dexterity16, 17.   
Hypothesis 1: The FE+RTP group will demonstrate greater improvements in upper extremity 
motor function compared to VE+RTP and dose-matched RTP.  
Aim 2: To compare the effects of FE+RTP, VE+RTP, and RTP only on non-motor function.  
The primary outcome is the change in the Beck Depression Inventory while secondary 
outcomes include the Stroke Impact Scale and the Trail Making Test A and B.   
Hypothesis 2: The FE+RTP group will demonstrate greater improvements in non-motor function 
compared to VE+RTP and dose-matched RTP. 
Aim 3: To compare the effects of FE+RTP, VE+RTP, and RTP only on aerobic capacity. 
The primary outcome is the change in VO2 max from baseline to EOT. The 6-minute walk test will 
serve as the clinical outcome.  
Hypothesis 3: Both exercise groups (FE+RTP and VE+RTP) will demonstrate significant 
improvements in aerobic capacity compared to dose-matched RTP. 

BACKGROUND AND SIGNIFICANCE  
Stroke, one of the endpoints of cardiovascular disease, is the leading cause of severe, long-
term disability among older adults in the United States.  The prevalence of stroke survivors with 
residual neurological deficits is approximately 5.8 million18.  Despite advances in rehabilitation, 
six months after stroke, nearly two thirds of patients cannot incorporate the more affected hand 
into daily activities19. Rehabilitation therapies that incorporate principles of motor learning, such 
as constraint-induced movement therapy (CIMT) and repetitive task practice (RTP) have been 
found to be effective in facilitating cortical reorganization20.  The translation of these 
interventions into clinical practice has been limited by required minimal movement criteria and 
reliance on intensive therapist-directed treatment21.  The latter makes these approaches 
unrealistic in a managed care environment.   
In addition to compromised motor function, patients post-stroke experience significant 
cardiovascular deconditioning, which limits their participation in activities of daily living (ADL’s)9.  
For these patients, the performance of simple ADL’s result in a significant increase, into the 
anaerobic heart rate range, in cardiovascular output9.  Despite the potential value of aerobic 
exercise in rehabilitation9-12, 22, typical stroke interventions are of relatively low aerobic intensity 
as patients’ heart rates are in the aerobic zone for less than three minutes10. Furthermore, 
studies investigating the value of aerobic exercise post-stroke have focused on cardiovascular 
endpoints, neglecting to systematically identify the potential neurophysiologic benefits evident in 
animal studies23. The identification of a safe, cost-effective approach, such as forced aerobic 
exercise, may have the potential to prime the CNS to augment the recovery of function while 
simultaneously improving cardiovascular health and fitness.  This preliminary project will assess 
the potential for two approaches of exercise training and task practice to improve motor and 
non-motor functioning in patients with stroke.    
Aerobic exercise and brain function:  Although the cardiovascular benefits of aerobic 
exercise have been well documented, only recently have investigations been conducted to 
determine the global effects of aerobic exercise, particularly as they relate to improving brain 
function24-27.   A recent systematic review found that acute aerobic exercise transiently 
increased basal peripheral concentrations of brain-derived neurotrophic factor (BDNF) in 
healthy young adults6. This increase in BDNF was only evident with acute aerobic exercise, not 
strength training, suggesting a relationship between cardiovascular exertion during exercise and 
BDNF response.  The release of BDNF into the bloodstream and subsequently into tissues is 
thought to be responsible for a cascade of neuroprotective and neuroplastic mechanisms, 
possibly facilitating neuromotor recovery6. Increased concentrations of endogenous 
neurotrophins have also been implicated as the mechanism for improved cognition, learning, 
and memory in healthy older adults28-30.  Animal data have shown enhanced motor training and 
behavioral recovery with high-intensity aerobic exercise, resulting in lasting neuronal changes 
within the brain6, 30, 31. To date, the role of aerobic exercise, forced or voluntary, in stroke 
recovery has not been systematically examined7, 22.  This project will, for the first time, examine 
the relationship between aerobic exercise and neuromotor recovery following stroke. 
Innovation 
Applying the forced aerobic exercise model to patients with stroke 
Significant pathophysiologic and logistical barriers prevent patients with stroke from obtaining 
the potential global neurologic and cardiovascular benefits of aerobic exercise training. Cellular 
changes in skeletal muscle post-stroke include alterations in fiber-type proportions, fiber 
atrophy, and reduced oxidative capacity9, 11, 12. These changes, combined with profound 
cardiovascular deconditioning, result in diminished motor output, preventing stroke patients from 
achieving the intensity of exercise necessary to reach the aerobic threshold. In addition to the 
physiological barriers, endurance training has not been a standard component of stroke 
rehabilitation as rehabilitation clinicians traditionally focus on motor learning or compensatory 
strategies to improve basic mobility and ADL skills12, 32.  When aerobic exercise is included as a 

part of stroke rehabilitation, the most common method currently being used is treadmill training.  
Due to safety concerns and diminished motor function, however, patients are either harnessed 
using a partial body-weight support system or require the direct assistance of the therapist to 
complete the training intervention.  The personnel and equipment requirements associated with 
treadmill training limit its scalability, especially in those patients with chronic stroke as they are 
unable to continue this exercise protocol long-term, leading to greater declines in cardiovascular 
fitness due to physical inactivity11.  As stated by Macko and colleagues, “Novel exercise 
interventions are needed to realize the potential for long-term functional recovery and 
cardiovascular health in the chronic hemiparetic condition”9. The forced aerobic exercise 
intervention developed in our lab, initially for PD patients, is a novel exercise intervention that 
augments the voluntary efforts of patients15, 16.  This intervention facilitates neurologic changes 
and produces cardiovascular benefits of aerobic exercise in a safe and cost-effective manner.  
The promising results from our PD studies, briefly outlined below, provide rationale for 
extending this intervention to patients with stroke as a means to prime the CNS for recovery.  
Forced-exercise improves global motor function in Parkinson’s disease:  Fifty-four 
patients with idiopathic Parkinson’s disease have completed a preliminary randomized clinical 
trial comparing the effects of forced (FE) versus voluntary aerobic exercise (VE) on motor and 
non-motor function. As part of this project, we developed a motor-driven cycle to safely deliver a 
forced exercise intervention by mechanically augmenting pedaling rate beyond the voluntary 
efforts of the patient.  This cycle will be used in our upcoming NIH R01 project (NIH 
R01NS073717; Alberts, PI).  It is important to note that the participants are actively contributing 
to the exercise; they are not being moved passively through the pedaling action.  Thus, exercise 
intensity, from an aerobic perspective, is identical across groups.  However, the FE group’s 
pedaling rate is significantly (35%) faster than the VE group.    
The Unified Parkinson’s disease Rating Scale-III (UPDRS-III) Motor assessment was the 
primary clinical outcome.  Rater-blinded UPDRS-III scores improved more than a 25% for those 
in the FE group while improving 11% in the VE group at end of treatment (EOT). Clinical ratings 
for the FE group were still improved by 14% at EOT + 8 weeks compared to baseline. Despite 
the comparable gains in aerobic fitness between the two groups, only the FE group 
demonstrated these relatively long-term gains in motor function, suggesting that exercise rate 
may be critical in altering 
brain function.  
 
 
 
 
 
 
 
 
In addition to 
improvements in motor 
function, gains in non-motor 
function were also present, 
primarily in the FE group, 
suggesting a global CNS 
response to high-rate 
exercise.  Anosmia has been 
identified as an early 
indicator of PD and there are 
no data suggesting 
medication or surgical 
interventions can improve or 
alter anosmia levels33.  The 
University of Pennsylvania 
Smell Identification Test (UPSIT) was used to assess level of  
Figure 1: Improvements in olfaction are present relative 
to increased pedaling rate.  

anosmia34.  Patients completed the UPSIT on three occasions: Baseline, end of treatment 
(EOT) and four weeks after EOT (EOT+4). Patients did not exercise during this four-week follow 
up period.  Figure 1 illustrates the change in UPSIT score from Baseline to EOT+4 for PD 
patients in our current trial as a function of pedaling rate (RPMs) over the course of the trial.   
These initial data suggest that anosmia levels can be maintained or improved (higher scores are 
better) in individuals who are typically pedaling at relatively high rates, between 80-90 RPMs.  It 
is important to note that two of the PD patients in the voluntary group that pedaled within this 
range did exhibit improvements in anosmia.  Overall, these data suggest that improvements in 
anosmia or CNS functioning may be rate-dependent, implying that rate may be an important 
variable to control or monitor in the prescription of effective exercise.  From a stroke 
perspective, these data provide further evidence that high rate aerobic exercise can alter brain 
function and could be a reasonable adjunct to traditional rehabilitation approaches.  The effects 
of acute FE on brain activation patterns were studied in 10 mild to moderate PD patients using 
an MRI protocol including whole brain T1-weighted anatomic images and a set of fMRI scans. 
Subjects were scanned under three conditions:  1) off meds, 2) on meds and 3) following 
forced-exercise while off meds.  Figure 2 shows 
activation maps averaged across subjects for 
two axial slices (showing sub-cortical regions) in 
Talairach space, displayed on averaged T1 
anatomic image. In all regions of interest, 
significant correlations were observed, 
indicating a similar change in BOLD MRI 
response for FE and medication.  These results 
indicate forced-exercise and medication utilize 
similar pathways to produce symptomatic relief.  
We are unaware of any other data that demonstrates exercise in PD leads to an increase in 
cortical and subcortical activation. 
Rationale to translate the Forced-Aerobic Exercise Paradigm to Patients Post-Stroke 
Our FE and PD studies indicate that FE enhances brain function and possibly plasticity.  Based 
on animal studies, the mechanism underlying global changes in motor function is likely 
increased neurotrophic factors as a result of FE.  Models of stroke provide a theoretical 
framework for using FE in stroke rehabilitation, as stroke patients, similar to PD patients have 
decreased cortical output13, 35.  This impairs patients with stroke from sustaining high rates of 
voluntary exercise14 which appear necessary to trigger the endogenous release of neurotrophic 
factors.  Collectively, the promising results from both animal and human data, in addition to our 
preliminary results in patients with PD, suggest that high-rate (forced) aerobic exercise has the 
potential to alter brain function and may promote neuroplasticity. Incorporating forced aerobic 
exercise into rehabilitation practice to prime the CNS and improve cardiovascular health would 
be a clinically-relevant, cost-effective adjunct to current models of neurorehabilitation.  It is 
important to note that our approach is different from animal models testing the efficacy of FE 
and stroke recovery.  Recent evidence from animal literature has suggested that FE results in 
lower BDNF, higher serum corticosterone levels, and decreased behavioral learning than VE36. 
However, the FE intervention in these models was introduced 24-hours after lesioning, a critical 
time during which the metabolic demands and diminished homeostasis in the brain are too 
significant to foster an environment conducive to recovery36, 37. A similar negative behavioral 
effect, presumably due to excitotoxicity,38-40 has been reported in animal and human models in 
which intensive CIMT was introduced in the acute phase of stroke recovery.  However, the 
same intensive intervention, when applied to individuals ≥ three months post-stroke, resulted in 
significant motor recovery and fMRI evidence of neural reorganization.  We propose to enroll 
patients 6-12 months post-infarct, well after neurophysiologic homeostasis has been restored, 
and an optimal environment for neuroplastic recovery is present. With appropriate 
Figure 2:  Forced-exercise produces a similar 
subcortical response as medication in PD. 

cardiopulmonary screening, testing and monitoring, patients post-stroke have been shown to 
safely tolerate aerobic exercise and improve cardiovascular fitness9, 11, 12, 32, 41-43.The goal of this 
project is to compare the effectiveness of two modes of aerobic exercise, forced and voluntary, 
in augmenting recovery of function in patients with stroke.  
Research Design and Methods 
Experimental Overview:   A preliminary 
single-center, parallel-group, rater-blind 
study will be completed over two years. A 
total of 30 chronic (6-12 mos. post) stroke 
patients with residual hemiparesis will be 
randomized to one of three groups: 1) 
forced-exercise and RTP (FE+RTP), 2) 
voluntary exercise and RTP (VE+RTP) or 3) 
dose-matched RTP only. All groups will 
receive an identical dose of rehabilitation 
time (36 hours) over a course of 8 weeks 
(3X per week).  The combination groups will 
perform FE on a motor-driven cycle or VE 
on a recumbent cycle for 50% of the time, 
followed by RTP for the remaining 50% of 
the session, while the RTP only group will 
engage in RTP only. Outcomes will be 
gathered at baseline, mid-treatment and 
EOT. A schematic of the study flow is 
provided in Figure 3.  
Recruitment and Sample: In collaboration 
with Dr. Fred Frost, Department Chair, 
Physical Medicine and Rehabilitation, 30 
patients from the Cleveland Clinic Health System 
(CCHS) with chronic stroke will be recruited to 
participate in this study.  An initial chart review indicates that over the past year approximately 
600 patients CCHS would meet study criteria.  The targeted population represents a collective 
cohort in whom spontaneous recovery is typically no longer occurring and substantial potential 
exists to optimally engage neuronal structures promoting plasticity toward functional 
improvement. Primary inclusion criteria include: 1) 6-12 months post single ischemic or 
hemorrhagic stroke confirmed by neuroimaging; 2) Approval from patient’s primary care 
physician; 3) Upper extremity Fugl-Meyer Motor Score 19-55.  Primary exclusion criteria 
include: 1) Hospitalization for myocardial infarction, congestive heart failure, or heart surgery 
(CABG or valve replacement) during the past 3 months; 2) Serious cardiac arrhythmias; 3) 
Hypertrophic cardiomyopathy; 4) Severe aortic stenosis; 5) Pulmonary embolus32, 43. Prior to 
randomization, all subjects satisfying initial screening criteria for participation will undergo 
complete cardiopulmonary exercise (CPX) testing. A 12 lead electrocardiogram will be 
assessed prior to exercise and monitored continuously throughout exercise and recovery.  A 
continuous incremental protocol starting at 25 Watts (W) and increasing in 10W stages every 
two minutes will be employed.  Peak VO2 will be determined for each subject as the highest 30 
sec average of VO2 during the test.  If the test is terminated due to electrocardiographic findings, 
the subject will be managed medically, referred for further care, and will be excluded from 
participation in the trial. Dr. Blackburn, Director of Cardiac Rehab, will conduct and interpret the 
results of the CPX testing to ensure the participant safety.  
Experimental Groups 
Figure 3: Study flow diagram 

Forced Aerobic Exercise and Repetitive Task Practice (FE+RTP): Subjects in the FE+RTP 
group (N=10) will use the motor-driven cycle to augment their pedaling rate 35% greater than 
their voluntary rate, determined from the baseline CPX.  The rationale for a 35% rate increase is 
based on the positive preliminary studies with PD patients15, 16.  Target heart rate zone will be 
calculated using the Karvonen formula and will be set to 60-80%.  Each training session will last 
approximately 1.5-2 hours; 45 minute exercise session followed by 45 minutes of RTP.  The 
exercise session will consist of a 5 minute warm-up, 35 minute main exercise set, and 5 minute 
cool down. For those patients who may be deconditioned upon study enrollment, the 35 minute 
main exercise set will include ‘on the cycle’ rest breaks of 2 minutes, every 10 minutes if 
necessary. If any patient exhibits signs of cardiac distress or hemodynamic compromise as 
determined by therapist or patient, the session will be stopped immediately and the on-call 
physician will be paged to the laboratory.  Hemodynamic response to exercise will be monitored 
via blood pressure measurements prior to initiating the exercise protocol, every 10 minutes 
during exercise, and immediately following exercise cessation, in addition to continuous heart 
rate monitoring. All exercise training will be supervised by an exercise physiologist or physical 
therapist certified in Basic Cardiac Life Support.  
A 45-minute session of upper extremity RTP will occur within ~15 minutes of exercise 
session completion.  RTP is the considered the current standard of care for upper extremity 
stroke rehabilitation44, 45. Tasks performed with the more impaired upper extremity will be 
selected from a battery of over 60 activities developed for the EXCITE trial35 and currently being 
used as part of our ongoing stroke study. All RTP will be completed with the guidance of a 
neurologic PT or OT experienced in stroke rehabilitation.  
Voluntary Aerobic Exercise and Repetitive Task Practice (VE+RTP): Subjects in the VE+RTP 
group (N=10) will complete a 45-minute exercise session consisting of a 5 minute warm-up, 35 
minute main exercise set, and 5 minute cool down using a recumbent stationary bike, exercising 
at their self-selected rate.  All exercise training will occur under the supervision of an exercise 
physiologist or PT who will adjust resistance on the cycle to ensure that the subject is exercising 
within his/her target heart rate zone during the main exercise set (60-80% range using the 
Karvonen formula, based on ACSM recommendations for older adults). Rest breaks and 
hemodynamic response monitoring will be conducted in an identical manner by the same 
personnel as described above with forced-exercise. A 45-minute session of upper extremity 
RTP will occur within ~15 minutes of exercise session completion in an identical manner as 
described above with the forced-exercise group.  
Repetitive Task Practice only (RTP): Subjects in the RTP only group (N=10) will complete 2 45-
minute sessions of RTP as described above separated by a 15-minute rest break, under the 
guidance of the same neurologic physical or occupational therapist overseeing RTP for the 
combination groups. This dosage of RTP is feasible, common in current clinical practice, and 
has been found to be efficacious46  
Aim 1: To compare the effects of FE+RTP, VE+RTP, and RTP only on the recovery of 
upper extremity motor function.  The primary outcome is the change in the Wolf Motor 
Function Test47 (WMFT) from baseline to EOT. Secondary outcomes include change in the 
Fugl-Meyer Assessment and biomechanical variables quantifying bimanual dexterity used in our 
previous work17. 
Expected results and interpretation: It is hypothesized that the FE+RTP group will demonstrate 
greater improvements in upper extremity motor function compared to VE+RTP or dose-matched 
RTP only. Animal and human studies suggest that high-rate aerobic exercise facilitates the 
release of neurotrophins in the brain which may serve to prime the CNS in promoting 
neuroplasticity6, 8. Our initial studies in PD patients demonstrated increased cortical and 
subcortical activation on fMRI following FE15. The FE paradigm will allow stroke patients to 
attain and sustain the high rate of exercise necessary to trigger this neuroplastic response, 
creating an environment in which motor learning is optimized.  

Aim 2: To compare the effects of FE+RTP, VE+RTP, and RTP only on non-motor function.  
The primary outcome is the change in the Beck Depression Inventory (BDI), Stroke Impact 
Scale (SIS), and the Trail Making Test A and B (TMT).   
Expected results and interpretation: It is hypothesized that the FE+RTP group will demonstrate 
greater improvements on the BDI, SIS and TMT compared to VE+RTP or dose-matched RTP. 
Human studies on healthy older adults, adults with dementia, and individuals with PD have all 
demonstrated improvements in mood, cognition, and quality of life following high-rate aerobic 
exercise24-27. Forced aerobic exercise will facilitate this same response in stroke patients 
previously not seen with voluntary rate exercise, possibly through increased concentrations of 
neurotrophic factors.  
Aim 3: To compare the effects of FE+RTP, VE+RTP, and RTP only on aerobic capacity. 
The primary outcome is the change in VO2 max from baseline to EOT. The 6-minute walk test will 
serve as the secondary outcome.  
Expected results and interpretation: It is hypothesized that both the FE+RTP and VE+RTP 
groups will demonstrate comparable improvements in aerobic capacity and ambulatory 
efficiency compared to dose-matched RTP. Numerous studies have demonstrated the positive 
effects of aerobic exercise training in patients post-stroke on cardiovascular fitness9, 11, 12, 41-43.  
Because patients in both combination groups will be exercising at comparable target heart 
rates, improvements in cardiovascular fitness are expected to be similar.  The RTP only group is 
not expected to show significant gains in cardiovascular fitness.  Improved cardiovascular 
fitness in both exercise groups, but greater improvements in motor functioning in the FE group 
will provide evidence for the concept that aerobic exercise alone is not sufficient, in this 
neurological population, to impact brain function in a manner that leads to improved motor 
recovery, but that FE is necessary to prime the CNS for remodeling after stroke.  
Statistical Analysis and Design:  Subjects in all three groups will be compared descriptively 
on potentially confounding baseline variables (i.e., age, fitness, co-morbidities, degree of 
hemiplegia, location/type of stroke, side of lesion) to assess the extent of any imbalance across 
groups.  The FE+RTP, VE+RTP, and RTP only groups will be compared on each primary 
outcome using repeated measures analysis of covariance.  The effects of group, time, and the 
group-by-time interaction will be assessed.  In the case of a significant interaction, the groups 
will be compared at each time point. In addition to p-values, the estimated treatment effect and 
its 95% confidence interval will be of interest as these data will be used for sample size 
calculation for a subsequent clinical trial.  
Implications:  An unmet clinical need remains in identifying effective and efficient rehabilitation 
approaches that drive neuroplasticity and optimize recovery post-stroke. Determining the 
interactions between aerobic exercise and motor recovery following stroke can address this 
unmet need.  The promising results from both animal and human studies, in addition to our 
preliminary results in PD patients, suggest that high-rate (forced) aerobic exercise has the 
potential to alter physiology in the CNS leading to improvements in function. This approach 
merits testing in patients with stroke.   
Limitations:  Previous animal data suggest that the effectiveness of FE is due to an increase in 
the release of neurotrophic factors23.  Based on these data, we hypothesize that the same 
mechanism may be operating in humans.  It is fully acknowledged, however, that the accurate 
measurement of neurotrophic factors is not feasible in this population.  The most reliable 
method of measuring neurotrophic factors within the brain is through tissue sampling, which is 
obviously not feasible in human studies.  An alternative method is via jugular blood draws8; for a 
preliminary study this very invasive procedure is not practical.  To address this limitation, 
objective measures of upper extremity and non-motor performance will serve as proxy for CNS 
function.   
Future Directions: The preliminary data gathered from this project will be used for the 
submission of a larger NIH R01 randomized clinical trial to determine the precise role of 

exercise in stroke rehabilitation and whether improved cardiovascular fitness can decrease the 
risk for recurrent stroke.  Furthermore, fMRI will be used to provide insight into the potential 
mechanism(s) that may underlie greater recovery of function associated with FE. 

Protection of Human Subjects 
Risks to the Subject: 
Human Subjects Involvement and Characteristics 
A total of 30 subjects who meet inclusion criteria outlined in this section will be selected 
for study participation. Males and females from any racial or ethnic background will be 
eligible. Individuals will be recruited from the Rehabilitation Institute at the Cleveland 
Clinic, in collaboration with Dr. Fred Frost, department chair.  Patients will be screened 
by a neurologic physical therapist to ensure eligibility.  Patients selected for the study 
protocol will meet the following inclusion and exclusion criteria: 
Inclusion Criteria: 
a. Able to provide informed consent 
b. Within 6-12 months of diagnosis of single ischemic or hemorrhagic stroke, confirmed 
with neuroimaging 
c. Fugl-Meyer Motor Score 19-55 in involved upper extremity 
d. Approval from patient’s primary care physician 
e. Age between 18 and 80 years 
Exclusion Criteria: 
a. Hospitalization for myocardial infarction, congestive heart failure, or heart surgery 
(CABG or valve replacement) within 3 months of study enrollment 
b. Serious cardiac arrhythmia 
c. Hypertrophic cardiomyopathy 
d. Severe aortic stenosis 
e. Cardiac pacemaker 
f. Pulmonary embolus 
g. Other medical or musculoskeletal contraindication to exercise 
h. Significant cognitive impairment (MMSE <24) or major psychiatric disorder (major 
depression, generalized anxiety) that will cause difficulty in study participation 
i. 
Anti-spasticity injection (botox) in upper extremity within 3 months of study enrollment 
j. 
Pregnancy 
Sources of Material: 
Clinical assessment will serve as a measure of degree of impairment and therapeutic 
efficacy. Patients will receive three clinical and motor assessments over the course of 
the study. Data will be obtained from subjects specifically for research purposes. 
Existing records or data will not be used. The identity of individual subjects will not be 
disclosed in any report of the results of this study. The data collected during this study 
will remain under the control of the investigators. Confidentiality of medical records and 
other forms of data will be maintained, with the exception that all such information will 
be subject to review by representatives of CCF.  
Potential Risks: 
There are potential risks and discomforts associated with any exercise intervention 
study. Every effort will be made to minimize these risks using information from the pre-
exercise medical evaluation and cardiopulmonary stress test.  A defibrillator is located 
within the exercise area, and a full crash cart readily available within an adjacent clinical 
area.  All research staff that will be supervising exercise sessions is trained in BCLS 
including emergency resuscitation and life-sustaining measures. A cardiac arrest and 
resuscitation team is available 24 hours a day within the hospital and can respond 
immediately to any medical emergency. The intensity of the exercise and exertion it 

requires may be physically taxing, however, patients will be permitted to rest at any time 
during the 45-minute exercise session. The appropriate exercise intensity will be 
personalized to the age, general activity, and medical condition of each individual. 
Although the exercise bicycle is stationary and sturdy, there is a risk of injury while 
mounting and dismounting the cycle.  The exercise trainer will assist the patient when 
mounting or dismounting the cycle. If patients experience any sensation that appears to 
be unusual or uncomfortable, they will be advised to stop the exercise and inform the 
research staff immediately. Generalized fatigue or muscle soreness may occur as a 
result of the exercise or repetitive task practice intervention, comparable to what is 
anticipated during traditionally rehabilitation post-stroke. There may be other risks as of 
yet unknown. No adverse events or effects occurred using this exercise intervention 
with Parkinson’s disease patients.  
Adequacy of Protection Against Risks: 
Recruitment and Informed Consent: Patients will be asked to read and sign a consent 
form that describes the nature and goals of the study, methods to be used, and potential 
risks and benefits of procedures. CCF IRB will have approved the consent form and 
experimental protocol. Originals will be retained in a secure location and photocopies 
will be given to the subject.  
Protection Against Risk:  Strict adherence to the outlined inclusion and exclusion 
criteria, in addition to thorough interpretation of the pre-intervention cardiopulmonary 
stress test will serve to rule out candidates unsafe for the study protocol.  Hemodynamic 
response to exercise will be monitored via blood pressure measurements prior to 
initiating the exercise protocol, every 10 minutes during exercise, and immediately 
following exercise cessation, in addition to continuous heart rate monitoring. Previous 
studies have found that patients post-stroke can safely participate in an intensive 
aerobic exercise intervention with similar screening and monitoring procedures in place. 
If a subject experiences any of the risks previously described, they will be asked to 
report it immediately to the research team. Injuries will be assessed, and if necessary, 
will be either treated by the medical staff or another referring physician. Any events will 
be reported to the IRB by the PI’s.  Dr. Linder will assume the responsibility of 
monitoring, ensuring the safety and confidentiality of the data. The research team will 
meet regularly to discuss issues related to this project; especially issues regarding 
safety and data security.  
Potential Benefits of the Proposed Research to Subjects and Others: 
Cardiovascular fitness is likely to improve over the course of the study for those 
randomized to either of the two exercise groups and upper extremity function is likely to 
improve for all three groups. Improvements in cardiovascular fitness post-stroke often 
lead to increases in ambulatory efficiency and decreased risk for future cardiovascular 
events or recurrent stroke. In general, society may benefit from a clearer understanding 
of the role of aerobic exercise, and particularly, forced aerobic exercise in the recovery 
of function post-stroke.  This could lead to improved rehabilitation outcomes for patients 
after stroke. Given the low risks involved and potential substantial benefits, we feel that 
the risk/benefit ratio is strongly in favor of proceeding with the study proposed in the 
present application. 
Importance of the Knowledge to be Gained: The proposed research is intended to 
provide information about the effects of forced versus voluntary-rate aerobic exercise on 

the recovery of upper extremity function and cardiovascular fitness post-stroke.  
Furthermore, identifying an aerobic exercise intervention that patients with stroke can 
safely participate in, would serve to fulfill an unmet need in this chronically disabled 
population.  This information will help guide the direction of stroke rehabilitation in 
optimizing neurorecovery, while simultaneously addressing the cardiovascular co-
morbidities frequently seen post-stroke.  
Data and Safety Monitoring Plan: A five-member panel will be assembled to protect 
the safety of the participants and ensure the integrity of this study.  This committee will 
consist of Staff within the Cleveland Clinic or outside institutions from the departments 
of cardiovascular medicine, neurology, rehabilitation medicine, biomedical engineering 
and bio-statistics. The primary role of this committee will be to: advise the investigators 
on matters related to safety, project execution, project cessation, adverse events or 
other activities deemed appropriate by the investigators or NIH. These members will 
have no direct involvement in the study and will serve as independent monitors. 
Inclusion of Women and Minorities: 
Women grater than or equal to 18 years of age will be included in this trial. We are 
targeting a 50% female enrollment in the trial.  Based on the 2000 census figures, the 
racial distribution of the Cleveland metro area is 67.4% White, 27.4% African American, 
1.8% Asian, 0.2% American Indian/Alaskan Native, 0.0% Native Hawaiian /Other Pacific 
Islander, and 3.2% multiracial. The ethnic distribution is 3.4% Hispanic or Latino. 
Therefore, members of minority groups and their subpopulations will be included in this 
trial. In our current stroke clinical trial, women comprise 33.3% of our enrollment; 
African-Americans 50%; Asians 16.7%; and of Hispanic ethnicity, 16.7%. Drs. Alberts 
and Linder frequently participate in patient education meetings and support groups 
throughout the Cleveland metropolitan region. As these groups are representative of the 
population of the Cleveland area, we anticipate recruitment distribution of women and 
minorities to reflect the Cleveland metropolitan population. All persons meeting eligibility 
criteria will be afforded the opportunity to participate in the trial. Plans to conduct valid 
analyses of the intervention effect in sex/gender and/or racial/ethnic groups (without 
requiring high statistical power for each subgroup) will occur following completion of the 
study.  
Targeted/Planned Enrollment Table 
TARGETED/PLANNED ENROLLMENT: Number of Subjects 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
1 
1 
2 
Not Hispanic or Latino 
14 
14 
28 
Ethnic Category: Total of All 
Subjects 
15 
15 
30 
Racial Categories 
 
American Indian/Alaskan Native 
0 
0 
0 
Asian 
1 
1 
2 
Native Hawaiian or Other Pacific 
Islander 
0 
0 
0 
Black or African-American 
4 
4 
8 
White 
10 
10 
20 

Racial Categories: Total of All 
Subjects 
15 
15 
30 
  
Inclusion of Children 
The proposed research will not utilize children as stroke does not typically occur in 
children and those under the age of 18. 
 
REFERENCES 
1. 
Roger VL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD, Brown TM, Carnethon MR, 
Dai S, de Simone G, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Greenlund KJ, Hailpern 
SM, Heit JA, Ho PM, Howard VJ, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, 
Lisabeth LD, Makuc DM, Marcus GM, Marelli A, Matchar DB, McDermott MM, Meigs JB, 
Moy CS, Mozaffarian D, Mussolino ME, Nichol G, Paynter NP, Rosamond WD, Sorlie 
PD, Stafford RS, Turan TN, Turner MB, Wong ND, Wylie-Rosett J. Heart disease and 
stroke statistics--2011 update: A report from the american heart association. Circulation. 
2011;123:e18-e209 
2. 
Dobkin B. Clinical practice: Rehabilitation after stroke. New England Journal of Medicine. 
2005;352:1677=1684. 
3. 
Langhorne P, Bernhardt J, Kwakkel G. Stroke rehabilitation. The Lancet. 
2011;377:1693-1702 
4. 
Kaplon RT PM, Kushi CL, Winstein CJ. Six hours in the laboratory: A quantification of 
practice time during constraint-induced therapy (cit). Clinical Rehabilitation. 
2007;21:950-958 
5. 
Tillerson J. Exercise induces behavioral recovery and attenuates neurochemical deficits 
in rodent models of parkinson's disease. Neuroscience. 2003;119:899-911 
6. 
Knaepen K GM, Heyman EM, Meeusen R. Neuroplasticity - exercise-induced response 
of peripheral brain-derived neurotrophic factor. Sports Med. 2010;40:765-801 
7. 
Ploughman M, McCarthy J, Bosse M, Sullivan HJ, Corbett D. Does treadmill exercise 
improve performance of cognitive or upper-extremity tasks in people with chronic stroke? 
A randomized cross-over trial. Arch Phys Med Rehabil. 2008;89:2041-2047 
8. 
Seifert T, Brassard P, Wissenberg M, Rasmussen P, Nordby P, Stallknecht B, Adser H, 
Jakobsen AH, Pilegaard H, Nielsen HB, Secher NH. Endurance training enhances bdnf 
release from the human brain. Am J Physiol Regul Integr Comp Physiol. 
2010;298:R372-377 
9. 
Ivey FM, Hafer-Macko CE, Macko RF. Exercise rehabilitation after stroke. NeuroRx. 
2006;3:439-450 
10. 
MacKay-Lyons M. Cardiovascular stress during a contemporary stroke rehabilitation 
program: Is the intensity adequate to induce a training effect? Arch Phys Med Rehabil. 
2002;83:1378-1383 
11. 
Pang MYC EJ, Dawson AS, Gylfadottir S. The use of aerobic exercise training in 
improving aerobic capacity in individuals with stroke: A meta-analysis. Clinical 
Rehabilitation. 2006;20:97-111 
12. 
Ivey FM H-MC, Macko RF. Exercise training for cardiometabolic adaptation after stroke. 
J Cardiopulm Rehab and Prevention. 2008;28:2-11 
13. 
Stinear CM, Barber PA, Coxon JP, Fleming MK, Byblow WD. Priming the motor system 
enhances the effects of upper limb therapy in chronic stroke. Brain. 2008;131:1381-1390 
14. 
Chen H, chen SH, Jason Chen JJ, Fu, LL, Wnag, YL. Kinesiologial and kinematical 
analysis for stroke for stroke subjects with asymmetrical cycling movement patterns. J 
Electromyography Kinesiology. 2005;15:587-595 

15. 
Alberts JL,  Linder SM, Penko AL, Lowe MJ, Phillips M. It is not about the bike, it is 
about the pedaling: Forced exercise and parkinon's disease. Exercise Sports Science 
Reviews. 2011;37:177-186 
16. 
Ridgel AL, Vitek JL, Alberts JL. Forced, not voluntary, exercise improves motor function 
in parkinson's disease patients. Neurorehabil and neural rep. 2009;23:600-608 
17. 
Alberts JL EC, Okun MS, Vitek JL. . Comparison of pallidal and subthalamic stimulation 
on force control in patient's with parkinson's disease. Motor control. 2004;8:484-499 
18. 
Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N, Hailpern SM, Ho M, 
Howard V, Kissela B, Kittner S, Lloyd-Jones D, McDermott M, Meigs J, Moy C, Nichol G, 
O'Donnell C, Roger V, Sorlie P, Steinberger J, Thom T, Wilson M, Hong Y. Heart 
disease and stroke statistics--2008 update: A report from the american heart association 
statistics committee and stroke statistics subcommittee. Circulation. 2008;117:e25-146 
19. 
Dobkin BH. Clinical practice. Rehabilitation after stroke. N Engl J Med. 2005;352:1677-
1684 
20. 
Kaplon RT, Prettyman MG, Kushi CL, Winstein CJ. Six hours in the laboratory: A 
quantification of practice time during constraint-induced therapy (cit). Clin Rehabil. 
2007;21:950-958 
21. 
Blanton S WH, Wolf SL. Constraint-induced movement therapy in stroke rehabilitation: 
Perspectives on future clinical applications. NeuroRehabil. 2008;23 
22. 
Smith PS TM. Treadmill training post-stroke: Are there any secondary benefits? A pilot 
study. Clinical Rehabilitation. 2008;22:997-1002 
23. 
Hayes K, Sprague S, Guo M, Davis W, Friedman A, Kumar A, Jimenez DF, Ding Y. 
Forced, not voluntary, exercise effectively induces neuroprotection in stroke. Acta 
Neuropathol. 2008;115:289-296 
24. 
Colcombe SJ KA. Fitness effects on the cognitive function of older adults: A meta-
analytic study. Psychol Sci. 2003;14:125-130 
25. 
Colcombe SJ EK, Scalf PE, Kim JS, Prakash R, McAuley E, Elavsky S, Marquez DX, Hu 
L, Kramer AF Aerobic exercise training increases brain volume in aging humans. J 
Gerontology. 2006;61:1166-1170 
26. 
Burdette JH, Laurienti PJ, Espeland MA, Morgan A, Telesford Q, Vechlekar CD, 
Hayasaka S, Jennings JM, Katula JA, Kraft RA, Rejeski WJ. Using network science to 
evaluate exercise-associated brain changes in older adults. Front Aging Neurosci. 
2010;2:23 
27. 
Voss MW, Prakash RS, Erickson KI, Basak C, Chaddock L, Kim JS, Alves H, Heo S, 
Szabo AN, White SM, Wojcicki TR, Mailey EL, Gothe N, Olson EA, McAuley E, Kramer 
AF. Plasticity of brain networks in a randomized intervention trial of exercise training in 
older adults. Front Aging Neurosci. 2010;2 
28. 
Tanaka K, Quadros AC, Jr., Santos RF, Stella F, Gobbi LT, Gobbi S. Benefits of physical 
exercise on executive functions in older people with parkinson's disease. Brain Cogn. 
2009;69:435-441 
29. 
Baker L FL, Foster-Schubert K, Green PS, Wilkinson CW, McTiernan A, Plymate SR, 
Fishel MA, Watson GS, Cholerton BA, Duncan GE, Mehta PD, Craft S. Effects of 
aerobic exercise on mild cognitive impairment. Arch Neurol. 2010;67:71-79 
30. 
Hirsch MA FB. Exercise and neuroplasticity in persons living with parkinson's disease. 
European Journal of Physical and Rehabilitation Medicine. 2009;45:215-229 
31. 
Zigmond MJ CJ, Leak RK, Mirnics K, Russell VA, Smeyne RJ, Smith AD. Triggering 
endogenous neuroprotective processes through exercise in models of dopamine 
deficiency. . Parkinsonism and Related Disorders. 2009;15 Suppl:S42-45 
32. 
Yates JS SS, Gollub S, Whitman R, Perera S, Lai SM, Duncan PW. Bicycle ergometry in 
subacute stroke survivors: Feasibility, safety and exercise performance. J Aging and 
Physical Activity. 2004;11:64-74 

33. 
Mesholam RI MP, Mahr RN, Doty RL. Olfaction in neurodegenerative disease. Arch 
Neurol. 1998;55:84-90 
34. 
Doty RL SP, Kimmelman CP, Dann MS. University of pennsylvania smell identification 
test: A rapid quantitative olfactory test for the clinic. Laryngoscope. 1984;94:176-178 
35. 
Wolf SL WC, Miller JP, Taub E, Uswatte G, Morris D, Giuliani C, Light KE, Nichols-
Larsen D. Effect of constraint-induced movement therapy on upper extremity function 3 
to 9 months after stroke: The excite randomized clinical trial. JAMA. 2006;296:2095-
2104 
36. 
Ke Z, Yip SP, Li L, Zheng XX, Tong KY. The effects of voluntary, involuntary, and forced 
exercises on brain-derived neurotrophic factor and motor function recovery: A rat brain 
ischemia model. PLoS One. 2011;6:e16643 
37. 
Kinni H, Guo M, Ding JY, Konakondla S, Dornbos D, 3rd, Tran R, Guthikonda M, Ding Y. 
Cerebral metabolism after forced or voluntary physical exercise. Brain Res. 
2011;1388:48-55 
38. 
Dromerick AW LC, Birkenmeier RL, Wagner JM, Miller JP, Videen TO, Powers WJ, Wolf 
SL, Edwards DF. Very early constraint-induced movement during stroke rehabilitation 
(vectors). Neurology. 2009;73:195-201 
39. 
Humm JL KD, Bland ST, James DC, Schallert T. Use-dependent exaggeration of brin 
injury: Is glutamate involved? Experimental Neurology. 1999;157:349-358 
40. 
Bland ST, Schallert T, Strong R, Aronowski J, Grotta JC, Feeney DM. Early exclusive 
use of the affected forelimb after moderate transient focal ischemia in rats : Functional 
and anatomic outcome editorial comment: Functional and anatomic outcome. Stroke. 
2000;31:1144-1152 
41. 
Luft A M, R, Forrester L, Goldberg A, Hanley DF. Post-stroke exercise rehabilitation: 
What we know about retraining the motor system and how it may apply to retraining the 
heart. Cleveland Clinic Journal of Medicine. 2008;75:S83-S86 
42. 
Tang A, Marzolini S, Oh P, McIlroy WE, Brooks D. Feasibility and effects of adapted 
cardiac rehabilitation after stroke: A prospective trial. BMC Neurol. 2010;10:40 
43. 
Potempa K BL, Tinknell T, Popovich J. Benefits of aerobic exercise after stroke. Sports 
Med. 1996;21:337-346 
44. 
Kleim JA JT. Principles of experience-dependent neural plasticity: Implications for 
rehabilitation after brain damage. J of Speech, Lang, Hearing Res. 2008;51:S225-239 
45. 
Miller EL, Murray L, Richards L, Zorowitz RD, Bakas T, Clark P, Billinger SA. 
Comprehensive overview of nursing and interdisciplinary rehabilitation care of the stroke 
patient: A scientific statement from the american heart association. Stroke. 
2010;41:2402-2448 
46. 
Birkenmeier RL, Prager EM, Lang CE. Translating animal doses of task-specific training 
to people with chronic stroke in 1-hour therapy sessions: A proof-of-concept study. 
Neurorehabil Neural Repair. 2010;24:620-635 
47. 
Wolf SL, Thompson PA, Morris DM, Rose DK, Winstein CJ, Taub E, Giuliani C, Pearson 
SL. The excite trial: Attributes of the wolf motor function test in patients with subacute 
stroke. Neurorehabil Neural Repair. 2005;19:194-205