Incline Training to Personalize Motor Control Interventions After Stroke
Phase: NA
Conditions: CVA (Cerebrovascular Accident)
Sponsor: VA Office of Research and Development

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PROTOCOL TITLE: 
Incline Training to Personalize Motor Control Interventions after Stroke 
 
PRINCIPAL INVESTIGATOR: 
Brian Cence  
1.0 
Objectives / Specific Aims 
Specific Aim 1: Determine the efficacy of motor control deficit guided personalized training on SSWS 
compared to non-personalized and control interventions. Hypothesis: Individuals receiving walking 
rehabilitation personalized to their baseline motor control deficit (INCLINE for low Pp and DECLINE for 
high Pp) will exhibit significantly improved SSWS compared to those receiving non-personalized and 
control interventions. 
 
Specific Aim 2: Determine the efficacy of motor control deficit guided personalized training on increasing 
symmetry of Pp compared to non-personalized and control interventions. Hypothesis: Individuals receiving 
walking rehabilitation personalized to their baseline motor control deficit will exhibit significantly 
improved symmetry of Pp compared to those receiving non-personalized and control interventions. 
 
Specific Aim 3: Determine if the personalized intervention increase the positive response rate compared to 
non-personalized and control interventions, and to further advance personalize interventions by identifying 
factors that predict response. Hypothesis 3.1: A higher percentage of individuals receiving personalized 
interventions will “respond” than those receiving non-personalized and control interventions. Hypothesis 
3.2: Discreet sets of clinical and biomechanical variables will predict responses in those with differing 
baseline motor control deficits. 
 
2.0 
Background 
BACKGROUND AND SIGNIFICANCE 
Deficits Associated with stroke:  Stroke is the leading cause of long-term disability in the United States, 
affecting approximately 795,000 people each year, with a surviving cohort of nearly 6.5 million.1 Seventy-
three percent of those surviving stroke will have some degree of long mobility deficits,2 and less than 50% 
of survivors progress to independent community ambulation.3 Even among those who achieve independent 
ambulation, significant residual deficits persist in balance and gait speed, with 60% of persons post-stroke 
reporting limitations in mobility related to walking.4,5 Improving walking is the most often stated goal of 
patients immediately following a stroke6 and after discharge to the community,7 and interventions designed 
to maximize functional ambulation skills are critical to promote activity and  social reintegration.8 The 
ability to walk an adequate distance at sufficient speed is a critical predictor of mortality, cardiovascular 
disease, and mobility disability9 and improving gait function has the potential to improve the quality of life 
of the 15,000 Veterans who survive stroke annually.10 
Anterior propulsion is critical for retraining walking:  Generation of forces required to propel the body 
forward during walking is an essential requirement of locomotion.11 We developed the measure, paretic 
propulsion (Pp) to quantify this crucial force generation in those with post-stroke hemiparesis and it has 
emerged as perhaps the most used mechanistic measure of walking performance. Pp describes the 
contribution of the paretic leg in propelling the center of mass (COM) forward during walking and is defined 
as the percentage of propulsion performed by the paretic leg.12 The percentage of propulsion generated by 
the paretic leg is calculated by dividing the total propulsive impulse (the positive time integral of the 
anterior/posterior force curve) performed by the paretic leg by the sum of the propulsive impulse performed 

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by both legs (see Preliminary Studies). Importantly, Pp has relatively little dependence, if any, on walking 
speed. Propulsion is associated with the muscle activity in the plantarflexors, with increased gastrocnemius 
and soleus electromyographic activity relating to increased propulsion of the paretic limb.13 This increased 
activity in the muscles that contribute to propulsion is also associated with improvements in functional 
walking tasks, while increased activation in the non-paretic muscles is associated with increased 
compensatory behavior.14 In addition, propulsion is improved by increasing the posterior position of the 
trailing leg relative to the full body center of mass.15 However, early activation of flexor muscles such as 
the tibialis anterior and the rectus femoris are inversely related to propulsion, implying that coordination 
between flexors and extensors is required to optimize the mechanics of propulsion.  Kinematically, hip 
extension increases the anteriorly directed force and is a significant positive predictor of Pp.16 Since Pp is 
influenced by many different biomechanical measures, we believe that it represents the coordinated output 
of the paretic leg. The measure has been used in over 40 examinations of hemiparetic walking and recently 
therapies have targeted propulsion as a primary outcome17 and predictor of gait outcomes.18 This proposal 
aims to not only expand the use of propulsion to define the motor control deficit but also to indicate an 
intervention tailored to specifically to that pattern of deficit in order to improve the overall effects of the 
intervention. 
Relevance to the VA: According to the 2014 VA Stroke Quality Enhancement Research Initiative 
(QUERI), approximately 15,000 VA admissions occur each year for acute ischemic stroke, with a cost 
approaching $275 million in the first 6 months.10,19 As the stated mission of the Stroke-QUERI is to 
“improve care and outcomes for Veterans at risk of ischemic stroke and those who have sustained an 
ischemic stroke,” it is imperative to develop interventions and frameworks to manage care efficiently and 
optimize outcomes. The VA stroke clinical practice guideline strongly recommends a comprehensive motor 
recovery program early in stroke rehabilitation “emphasizing progressive difficulties, repetition, and 
functional task practice.”20 This guideline further suggest that motor recovery interventions, including 
ambulation interventions, should include cardiovascular fitness and strengthening.20 In addition, the VA 
Blueprint for Excellence lists as one of its primary strategies to “advance health care that is personalized, 
proactive, and patient-driven, and engages and inspires Veterans to their highest possible level of health 
and well-being.”21 Interventions that are specifically tailored to baseline biomechanical assessments, that 
are designed to improve force production and cardiovascular status via task-specific training, and are 
translatable to VA clinics and beyond meet the critical needs of the VA in support of its Veterans with 
stroke. 
 
INNOVATION 
Biomechanical Definition of Motor Control Deficits:  We have biomechanically defined post-stroke 
walking patterns based on Pp:  1) low Pp is the predominant pattern and is associated with increased and 
early paretic flexor EMG activity, lengthened paretic step length, and decreased paretic hip extension13,22; 
and 2) high Pp pattern is characterized by increased paretic extensor EMG during terminal stance, shortened 
paretic step length, and prolonged paretic hip extension13,22 (see Preliminary Studies for how these are 
defined).23 This project will focus on the comparison between high and low Pp, as those with symmetric 
propulsion represents a small portion of the population with post-stroke deficits. 
 
Treatment Determined by Baseline Motor Control Deficit:  Our pilot data reveal that the two patterns 
are most effectively rehabilitated by different treatment strategies: 1) low Pp by walking on an inclined 
treadmill requiring increased force production and promoting increased and symmetrical hip extension24,25; 
and 2) high Pp by walking on a declined treadmill, limiting hip extension and promoting effective stance to 
swing transitions, increasing knee flexion, and encouraging improved knee extensor eccentric control.24,25 
 
Manipulation of Task Mechanics to Meet Specific Training Goals: Successful uphill walking requires 
increased force production bilaterally in order to maintain forward progression.  Specifically, 

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spatiotemporal symmetry and paretic hip extension are increased following incline walking post-stroke 
when the incline is at least eight degrees.26  Ground reaction forces and joint moments increase with 
concomitant increases in slope, particularly in the anterior-posterior direction representative of 
propulsion,27  and incline walking is associated with increased knee extensor and ankle plantarflexion 
activity producing the additional propulsion required to step uphill.28 Gama et al. recently trained 
individuals post-stroke with body-weight support (BWS) and a 10% incline and compared to a group 
undergoing level treadmill training with BWS.29 Incline-trained individuals demonstrated significant 
improvements over the control group in walking speed (p=0.002) and paretic step length (p=0.02). 
However, all individuals trained at the same direction of treadmill inclination.29 
Although less studied, downslope walking has also been utilized in the training of individuals after 
neurologic injury. Incline and decline training are both associated with improved endurance, overground 
walking speed, and dynamic balance control.30 Randomized controlled trials in individuals with Parkinson’s 
Disease31 and Multiple Sclerosis32 demonstrate significant improvements associated with downhill walking 
in mobility, functional activities, balance, and strength of the knee extensors. This knee extensor strength 
improvement primarily is associated with improved eccentric control of the knee extensors, and the trailing 
limb increases negative (eccentric) work production with increased slope of the treadmill.33 The increased 
negative work production at the knee is likely associated with the decline training effects of increased knee 
flexion and improved stance to swing transitions. Electromyographic and kinetic analyses demonstrate an 
increase in power absorption during downslope walking and increases in extensor activity, representative 
of increased eccentric control of the knee extensors.27,34 Downslope walking is also effective in the 
examination of spinal neurophysiology, demonstrating decreases in spinal level excitability in 
neurologically healthy adults.35 In addition, acceleration of the center of mass (see Preliminary Studies) is 
significantly increased in the transition from stance to swing,24,25 further indicating the viability of this 
treatment for individuals with deficits related to decreased knee flexion, poor power absorption, and 
difficulty transitioning from stance to swing.  
 
Predicting Responders to a Novel Locomotor Rehabilitation Intervention:  Many types of locomotor 
rehabilitation techniques (activity-based therapies,36 lower extremity strengthening,37 aerobic 
conditioning,38 functional electrical stimulation39) produce robust changes in functional outcomes such as 
increased self-selected walking speed (SSWS). However, no single intervention is shown to be superior in 
producing these functional changes.40 In addition, a critical need exists to be able to understand mechanisms 
associated with recovered function in order to predict responders from non-responders prior to a therapeutic 
intervention. Currently, mechanistic outcomes are too inconsistently applied to locomotor rehabilitation 
interventions to draw clear conclusions as to how recovery is generated.41,42 Recent analyses have begun to 
examine the patterns of response in rehabilitation participants in an effort to delineate which participants 
respond to an intervention and how they improve.43-45 These analyses, however, typically lack a thorough 
outcome battery that includes broad-based biomechanical and clinical outcome measures. We believe that 
a full battery of biomechanical and clinical variables will prove crucial for determining a broader set of 
factors contributing to response to rehabilitation interventions that clinicians can apply to improve decision 
making regarding intervention selection. This proposal is guided by the overall hypothesis that when 
provided an intervention tailored to the baseline motor control deficit, there will be fewer non-responders 
leading to more robust functional effects. 
 
 
 
 
3.0 
Intervention to be studied 
Intervention 

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Personalized Intervention:  Each participant will be randomized to receive either INCLINE, DECLINE, or 
CONTROL training. During training, each participant will be asked to walk without an assistive device or 
ankle-foot orthosis (although an AirCast will be allowed for medial-lateral stability if necessary). For all 
INCLINE and DECLINE training, individuals will walk for 20 minutes at a 10-degree treadmill tilt, 
stopping each five minutes for monitoring of vital signs (see “Vital Sign Monitoring” below). As many 
subjects post-stroke take a beta blocker or other medications that prevent heart rate and blood pressure 
increases during exertion, a rating of perceived exertion (RPE, must be below “very hard”) will also be 
collected and adverse events will be strictly monitored. For DECLINE training, the treadmill will be tilted 
to 10 degrees with the belt reversed and the participant facing in the opposite direction.  While participants 
will be allowed to support themselves with the use of handrails for balance as required, they will wear a 
climbing harness attached to an overhead support system to prevent falls and thus minimize handrail use. 
Our previous work was completed at 8 degrees of tilt (see Preliminary Studies), based on work by Werner 
et al. demonstrating that 8 degrees was required to improve gait symmetry and hip extension in patients 
with stroke.46 Subsequent reports29,47 demonstrate that 10 degrees is equally feasible and offers a more 
intense training opportunity. Individuals will walk at a speed at least 50% of their current overground 
SSWS, determined at the beginning of each training week, but training as fast as they feel comfortable up 
to the overground SSWS. Pilot work demonstrated that individuals are not capable of walking on the 
INCLINE or DECLINE at the overground SSWS secondary to the increased workload associated with the 
treadmill tilt. Each INCLINE and DECLINE session will be followed by one 6-minute bout of overground 
walking training as fast as comfortable for each participant focusing on specific gait details targeted in the 
INCLINE/DECLINE trials (e.g. increased hip extension, increase paretic leg loading, or improved stance 
to swing transition).  
Vital Sign Monitoring: For all training groups, criteria for termination of training include subject complaints 
of shortness of breath, light-headedness, confusion, severe headache, or dyspnea; onset of angina; excessive 
blood pressure (systolic BP > 200mm Hg, diastolic BP >110 mm Hg), or drop in systolic BP >10 mm Hg 
and inappropriate bradycardia (drop in heart rate >15 bpm).48,49 In addition, we will stop training for a rest 
break if the RPE exceeds “very hard” (17 on a 6-20 scale). 
 
4.0 
Study Endpoints 
Outcome Measurement 
Paretic Propulsion (Pp):  Pp is a quantitative measure of the coordinated output of the paretic leg and is 
defined as the percentage of propulsion performed by the paretic leg.12 The percentage of propulsive forces 
generated by the paretic leg will be calculated by dividing the total propulsive impulse (the time integral of 
the anterior/posterior force curve) performed by the paretic leg by the sum of the propulsive impulse done 
by both legs. Importantly, Pp has relatively little dependence, if any, on walking speed. Our instrumented 
treadmill gives us the ability to measure this quantity in much more detail than would be possible in a 
conventional gait laboratory because we can easily record a large number of step cycles in a single 30-
second trial. Statistics will be run on the absolute deviation from normal (Deviation = |0.5 - Pp|). 
Biomechanical Walking Testing: For instrumented treadmill assessments, participants will wear their own 
low-heeled shoes. A safety harness (Robertson Mountaineering) mounted to the laboratory ceiling will be 
worn by the participant for protection in the event of loss of balance. Each participant will be asked to walk 
without an assistive device or ankle-foot orthosis (although an AirCast will be allowed for medial-lateral 
stability if necessary). Participants will be permitted to practice treadmill walking until they feel 
comfortable walking without assistive devices, orthotic devices or support from the handrails. During the 
acclimation period, a trained staff member will offer any support the subject may require. This will continue 
until the participant feels comfortable enough to begin data collections. Ground reaction force data will be 

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low-pass filtered with a fourth-order, zero-lag digital Butterworth filter. To optimize capture of steady state 
data on the treadmill, subjects will walk for approximately 10 seconds to achieve steady state prior to the 
30 seconds of data collection (40 seconds per trial). Two trials will be collected at the treadmill self-selected 
speed and two trials at the fastest comfortable speed. Biomechanical data collections will allow for 
secondary analyses of associated kinematic and kinetic variables (e.g. force impulse, COMa by gait cycle 
phase, joint moments/power/work, and joint angles). At baseline testing, post-testing, and at the beginning 
of each session, participants will walk on a 16 ft. long gait mat (GAITRite) to measure SSWS and fastest 
comfortable walking speed (FCWS) and other spatiotemporal parameters. Subjects will be permitted a 
practice trial, and then be asked to complete two trials at each speed. A safety harness mounted to the ceiling 
will protect the subject but will only support their body weight in the case of a loss of balance.  
Trained study personnel will be present for all testing sessions as needed. 
 
Clinical Assessments: The proposed assessments are standard to most post-stroke intervention trials. As 
the primary aim of this proposal is to improve functional outcomes using an intervention that is clinically 
translatable, it is imperative to include assessments routine to clinical rehabilitation. The below measures 
reflect a battery of body structure and function, activity, and participation measurement to reflect a broad 
range of clinical assessment across the rehabilitation model (ICF) as has been previously advocated.50 All 
clinical assessments will be conducted by a physical therapist evaluator blinded to group allocation 
(different than the training physical therapist) within the Center for Rehabilitation Research in Neurological 
Conditions. 
• Walking Speed: We will assess SSWS and fastest comfortable walking speed in meters per second 
over a 16 foot GAITRite walkway. Mean SSWS for individuals post-stroke has been established at 
0.84m/s,51 with excellent test-retest reliability (ICC=0.95 to 0.99) and interrater/intrarater reliability 
(0.87 to 0.88).3,52 Minimally Clinically Important Difference (MCID) for SSWS for stroke survivors 
of 0.16 m/s53 allows for the clinician to set meaningful walking speed goals, while providing a 
classification for researchers via cut off scores:  <0.4 m/s representing likely limited household 
ambulators, 0.4-0.8 as limited community ambulatory profile, and >0.8 m/s as community ambulators.3  
• 6-Minute Walk Test (6MWT): Timed walking tests are primarily a measure of functional capacity.54 
The 6MWT tests populations who present with little functional walking capacity and is validated 
against the Rivermead Mobility Index (r=0.75) and 10-meter walk time (r=-0.61).55 The 6MWT has a 
high intra- and interrater reliability (ICCs = 0.82-0.95).56 The Minimal Detectable Change (MDC) for 
individuals with chronic stroke is 120 feet57 and the MCID is 113 feet.58  
• Functional Gait Assessment (FGA):  The FGA is modified from the Dynamic Gait Index and includes 
10 items to assess dynamic balance stability during gait.  Each item is scored on a 4-point scale from 
0 (poor) to 3 (excellent) with a maximum score of 30.  The MDC is 4.2 points,59 A score 22 or below 
out of 30 is predictive of falls in older adults (sensitivity and specificity each 85%).60   
• Fugl-Meyer Assessment of Motor Function:  We will utilize the lower extremity (LE FM Assessment) 
portion of the assessment to characterize our participant sample. The LE FM Assessment is a measure 
of motor recovery post-stroke and includes measures of reflex, motor control, and coordination with a 
total score of 34.  We will also evaluate separately the 22-point motor sub-score as well as the LE 
sensory portion.61  
• Stroke Impact Scale (SIS):  The SIS is a stroke-specific outcome measure that includes 59 items 
covering nine domains: Strength, Hand function, ADL/IADL, Mobility, Communication, Emotion, 
Memory and thinking, Participation/Role function, and Perceived recovery. Standard error of 
measurement, MDC, and MCID have been published providing clinicians key metrics to measure the 
clinical change and significance of the questionnaire.59  The SIS is responsive to change at 1-3 and 1-
6 months62 (with a greater total responsiveness than the Stroke Specific Quality of Life Scale (SRM 

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difference =0.36).59  Test-retest (ICC = 0.7 to 0.92)62 and interrater/intrarater reliability are all excellent 
(ICC = 0.82 and 0.80 respectively)63 with some deviations for specific domains.   
• Activities of Balance Confidence: The ABC is a commonly used 16 item subjective measure of 
confidence in performing various ambulatory activities without falling or experiencing a sense of 
unsteadiness (falls self-efficacy). Items are graded 0-100% with higher scores representing increasing 
confidence in functional activities.  Standard error of measurement has been published as 6.81 in 
chronic stroke,64  whereas the MDC and MCID have yet to be published.  A cut-off score of 81.1 can 
provide some evidence that the patient/subject doesn’t have a history of falls.65 Total score normative 
data reveals a mean (SD) of 86.3 ±17.364 indicating that the average stroke survivor likely has some 
reduced confidence in their ability to perform ADLs/iADLs without loss of balance.  The ABC is 
designed to be used multiple times on a single patient with excellent 4-week test-retest reliability (ICC 
= 0.85) including item level metrics (ICC = 0.53-0.93).64 
 
5.0 
Inclusion and Exclusion Criteria/ Study Population 
Subjects:  We will recruit 72 individuals post-stroke, specifically targeting Veterans, with persistent 
motoric disability following a clinical diagnosis of stroke, the most recent no less than six months prior to 
enrollment. Individuals must present with unresolved propulsion asymmetry (Pp ≤ 0.47 or ≥ 0.53). Subjects 
will be aged 25 to 75 years to control for the effects of advanced age on the ability to maintain the effects 
of motor adaptation training.66 Participants may be of either gender and will be of diverse ethnic background 
representing the community. We will also perform a battery of clinical assessments to evaluate degree of 
function and disability.  
 
Inclusion criteria: 1) 25-75 years of age, 2) stroke ≥ 6 months, 3) residual paresis in the lower extremity 
(Fugl-Meyer LE motor score <34), 4) ability to walk without assistance at speeds ranging from 0.2 – 1.0 
m/s (with a support harness for biomechanical testing); 5) Pp ≤ 0.47 or ≥ 0.53; 6) Ability to walk on a 
treadmill without orthotic or assistive device using overhead harness system; 7) provision of informed 
consent, and 8) written approval from the primary physician (see attached sample of Medical Approval 
Cover Letter).  
 
Exclusion criteria will be: 1) history of congestive heart failure, unstable cardiac arrhythmias, hypertrophic 
cardiomyopathy, severe aortic stenosis, angina or dyspnea at rest or during ADLs; 2) History of COPD or 
oxygen dependence; 3) Pre-existing neurological disorders or dementia; 3) History of major head trauma; 
5) Legal blindness or severe visual impairment; 6) Severe arthritis or other problems that limit passive 
ROM; 7) History of DVT or pulmonary embolism within 6 months; or 8) Severe hypertension with systolic 
>200 mmHg and diastolic >110 mmHg at rest. 
 
Statement of Inclusion of Women and Minorities in Research: This research will include women and 
minorities to the extent reflected by composition of the population in Charleston, SC and its surrounding 
areas. There are no exclusion or inclusion criteria which would exclude or preclude women or minorities 
from participating in this study. 
 
 
 

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Targeted/Planned Enrollment Table 
TARGETED/PLANNED ENROLLMENT: Number of Subjects 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
5 
5 
10 
Not Hispanic or Latino 
31 
31 
62 
Ethnic Category: Total of All Subjects * 
36 
36 
72 
Racial Categories 
 
American Indian/Alaska Native 
0 
0 
0 
Asian 
2 
2 
4 
Native Hawaiian or Other Pacific Islander  
0 
0 
0 
Black or African American  
16 
16 
32 
White 
18 
18 
36 
Racial Categories: Total of All Subjects * 
36 
36 
72 
 
6.0 
Number of Subjects 
Sample Size Determination and Statistical Approach:  A total of 72 individuals post-stroke will be 
recruited for this study. We are assuming an attrition rate of 20% resulting in a final sample size of 60 for 
statistical analyses, ideally 10 in each combination of baseline group (low and high Pp) and intervention 
(INCLINE, DECLINE, and CONTROL training). 10% is consistent with attrition rates from previous trials 
of locomotor rehabilitation conducted by our group,43 but we have chosen a more conservative rate of 20% 
based on the novelty and intensity of the intervention. There will be two strata of 30 individuals each with 
baseline low Pp and high Pp, respectively. From those strata, using block randomization, the subjects will 
be equally randomized into the INCLINE, DECLINE, and CONTROL training (10 in each training cell).  
 
7.0 
Setting 
The research will be done at the MUSC/VA Rehabilitation Research space located at 77 President St. 
Charleston, SC 29425.  The following labs will be utilized: 
Locomotor Energetics and Assessment Laboratory (LEA): The LEAis a 988 square foot laboratory 
located in the College of Health Professions Research Building on the campus of Medical University of 
South Carolina. The laboratory is a shared resource of the college and is supported in part by the 
Department of Health Sciences and Research. The laboratory is located in the same building as the offices 
of the PI, Co-I and staff. It features equipment capable of collecting kinematic, kinetic, 
electromyographic, strength, and metabolic data. A substantial investment in improving the capabilities of 
the laboratory will be funded by the startup funds of the PI. The motion analysis laboratory is adjacent to 
a small workshop available for the construction, repair, and alteration of simple mechanical devices. 

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The Locomotor Rehabilitation Laboratory (LRL): is a state-of-the-art treatment laboratory, designed to 
offer a full range of locomotor interventions for those with impaired walking secondary to neurologic 
injury. The LRL is an 808 square foot laboratory located on the second floor of the College of Health 
Professions Research Building, Room C-213. The laboratory houses a ZeroG mobile body weight support 
system (only the 6th one installed nationally) designed to create a permissive environment for retraining 
walking ability not only over a treadmill, but also over level ground and environmental obstacles. 
Research participants will have access to a Woodway split-belt treadmill, for training cardiovascular 
endurance as well as lower extremity strength and power. Additional assessment capabilities include: 8 
camera Phase Space Motion Capture system, Delsys Wireless EMG system, and Biodex Dynamometer. 
The research will focus on a multi-faceted approach to locomotor recovery after neurological injury, 
initially targeting stroke and spinal cord injury. The overall goal is to understand and improve clinical 
decision making relative to locomotor interventions. 
Motor Performance Laboratory (MPL): The MPL is an approximately 914 ft2 room located in the College 
of Health Professions Research Building, Room C102. The primary focus of the MPL is to investigate the 
neural and muscular mechanisms underlying muscle function in people with neurological conditions, such 
post-neurological injury i.e. stroke or spinal cord injury and/or healthy controls. An additional focus is the 
development of effective interventions to counteract these neuromuscular impairments and improve 
overall function, activity, and participation. Research participants will have access to a Woodway 
treadmill, a Precor elliptical trainer, Shuttle Systems jump trainers (MVP and 2000), recumbent and 
upright bikes, NUSTEP Recumbent Stepper, Full metabolic and EKG cart, and passive safety rail and 
harness system all aimed at improving and measuring lower extremity function and physical function.   
The Functional Neuro-Stimulation Laboratory (FNSL): The FNSL is located on the 2nd floor of the 
College of Health Professions Research Building on the campus of Medical University of South Carolina. 
FNSL studies use electromagnetic approaches as either research tools investigating neuroscience 
questions or as investigational or FDA approved treatments for brain diseases. Techniques actively being 
used by FNSL researchers and their collaborators include transcranial magnetic stimulation (TMS) and 
transcranial direct current stimulation (tDCS) 
 
8.0 
Recruitment Methods 
Subject Recruitment:  Participants for this program will be recruited from the Ralph H. Johnson VA 
Health Care Systemand the Medical University of South Carolina (MUSC). The Ralph H. Johnson 
VAHCSand MUSC share core facilities through a memorandum of understanding which provide a unique 
environment from which to recruit participants. The combination of the Ralph H. Johnson VAHCS and 
the MUSC Stroke Program sees over 60 new stroke patients per month and all patients are routinely 
screened for eligibility to our various research studies. Potential participants will be given information 
while inpatient and again when they are seen for follow up in the outpatient clinic. We currently have an 
IRB-approved existing recruitment database through the Ralph H. Johnson VAHCS (IRB# 43107 “VA 
Stroke Rehabilitation Research Database”, Cence, PI). This database is initially populated with an existing 
patient registry kept by Neurology Service which includes approximately 500 post-stroke patients seen at 
the Ralph H. Johnson VAHCS or one of the 5 affiliated community-based outpatient clinics (CBOC’s). 
Of these, approximately 350 meet the age criteria for enrollment in the proposed study (excluding 
duplicates from our MUSC registry, see below). Ongoing recruitment is expected to add 5-8 more 
subjects each month.  
The MUSC Stroke Program holds Joint Commission's Certificate of Distinction for Primary Stroke 
Centers which recognizing centers that make exceptional efforts to foster better outcomes for stroke care. 
The MUSC Stroke Program alone sees over 50 new stroke patients per month and routinely screens all 
patients for eligibility to our various research studies. In addition, since the proposed research investigates 

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stroke recovery, it will have access to resources at the NIH-funded Center of Biomedical Research 
Excellence (COBRE) in Stroke Recovery at MUSC. Dr. Bowden is a currently a junior investigator in this 
center and will be able to access the Clinical and Translation Tools and Resources (CTTR) Core for 
subject recruitment support. The CTTR Core provides recruitment resources through a bioinformatics-
enabled database registry via a separate IRB approved database (IRB# 37803 “RESTORE”). Currently, 
there are 682 post-stroke subjects (93 veterans), 560 of whom are ≤ 75 years old, in our database registry 
and recruitment is expected to add 3-5 more subjects each week. Thus, with such a large cohort of stroke 
patients, we should have no difficulty in recruiting the subjects required to address our aims. 
The study coordinator will obtain contact information from the recruitment database(s) and will make 
initial contact via the telephone. If they meet inclusion criteria as capable of being obtained over the 
phone, potential participants will be requested to come in person to the research laboratories where they 
will participate additional testing as allowed by the database IRB (Pro00037803 or Pro00043107). The 
participant will engage in the consent process in a privated area in the research space, and consent may be 
obtained by the PI, the study coordinator, or a member of the investigative team. 
 
9.0 
Consent Process 
The consent process will take place in the labs or private office of the study coordinator at the time of the 
subjects' visit. The PI, Co-PI's, investigators and study coordinator are experienced in consenting subjects. 
At least one of these study personnel will be onsite to review the consent document with the subject and 
answer any questions. The subject will be asked to document his or her consent in writing on the informed 
consent document. The process will occur in privacy in one of several labs listed in the protocol. 
The participant will be given the opportunity to discuss the protocol and ask any questions that they may 
have. After the conversation, the participant will be given the opportunity to consent or not. The PI, the 
study coordinator, or members of the research team may obtain consent. 
 
 
 
10.0 Study Design / Methods 

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This proposal seeks to develop a theory-based clinical decision-making framework for the training of 
walking recovery after stroke based on how different biomechanical patterns of walking illustrate distinct 
motor control deficits. 72 individuals with unresolved propulsion asymmetry after chronic stroke (greater 
than six months post-stroke, so 
additional natural recovery is 
not expected) will be evaluated 
to determine their baseline 
level of Pp:  low Pp (≤ 0.47) 
and high Pp (≥ 0.53) (0.47 to 
0.53, equal to 3 standard 
deviations around the mean for 
healthy controls). Individuals 
will be randomly assigned to 
one of three 
intervention 
groups (INCLINE, DECLINE, 
or CONTOL training), and we 
will recruit into each training 
group an equal number of 10 
individuals with low or high 
Pp (Figure 6). Each participant 
in INCLINE training will walk 
four 5-minute bouts at the at 
the highest speed they can 
tolerate for 5 minutes (up to 
SSWS and at least 50% of 
SSWS) on a 10% up-sloped 
treadmill followed by 6 minutes of level overground walking at the pace that they can maintain (breaks are 
allowed as necessary while the clock continues to run). INCLINE training will focus on increasing force 
production and promoting increased and symmetrical hip extension. Those in DECLINE training will also 
walk with the same number of bouts, intensity, and overground walking as INCLINE on a 10% down-
sloped treadmill, limiting hip extension, and promoting effective stance to swing transitions through 
increased knee flexion and eccentric control of the knee. During the 6-minute walk, each participant will 
focus on specific gait details targeted in the INCLINE/DECLINE trials (e.g. increased hip extension, 
increase paretic leg loading, or improved stance to swing transition. CONTROL participants will walk four 
5-minute bouts at their SSWS on a flat treadmill followed by 6 minutes of level overground walking at the 
SSWS, controlling for equal time of walking activity. Placement into the INCLINE, DECLINE, or 
CONTROL training groups will be randomized based on a computerized randomization by the study 
statistician. Each individual will complete 12 sessions (three times a week for four weeks). Clinical and 
biomechanical outcome measures will be collected pre- and post-training and after a one-month follow-up 
period. In addition, we will collect a battery of clinical outcome measures before and after training. 
Spatiotemporal variables (including SSWS) will be collected before and after each session. All clinical and 
biomechanical assessments will be conducted by an evaluator blinded to training group allocation.  
 
11.0 Data Management  
As a clinical trial, the details of this project will be entered into clintrials. Clinical data from assessment 
sessions will be recorded on hard copies (stored in a locked file cabinet in the Ralph H. Johnson VAHCS 
rehabilitation research space) and entered into a RedCAP electronic database by the project coordinator 
immediately after each session. These data will be de-identified for further analysis. Only the PI will have 
Figure 6. Study design and flow of assessments and training. 

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access to de-identified data. Gait data will be analyzed using a custom MATLAB program, automatically 
populating a LabView Data Viewer from which customized data may be retrieved. The research 
coordinator will check the data entry, and pool all data into a group-wide de-identified spreadsheet. All 
data from training sessions will also be analyzed and stored using an automated MATLAB program. All 
electronic data will be stored on a secure server that is backed-up nightly. Upon completion of all Aims, 
the de-identified spreadsheets and group assignment list will be shared with the statistician for analysis. 
The de-identified dataset will be available for sharing with other investigators, and this trial will be 
registered in the NIH-supported registry. 
 
Sample Size Determination and Statistical Approach:  A total of 72 individuals post-stroke will be 
recruited for this study. We are assuming an attrition rate of 20% resulting in a final sample size of 60 for 
statistical analyses, ideally 10 in each combination of baseline group (low and high Pp) and intervention 
(INCLINE, DECLINE, and CONTROL training). 10% is consistent with attrition rates from previous trials 
of locomotor rehabilitation conducted by our group,43 but we have chosen a more conservative rate of 20% 
based on the novelty and intensity of the intervention. There will be two strata of 30 individuals each with 
baseline low Pp and high Pp, respectively. From those strata, using block randomization, the subjects will 
be equally randomized into the INCLINE, DECLINE, and CONTROL training (10 in each training cell). 
The power analysis was based on our pilot training data for INCLINE and DECLINE combined compared 
to CONTROL. For the power analysis, we used a repeated measures model with an AR(1) correlation value 
of 0.45 which we obtained from the pilot data. With an average standard deviation of 0.35 (also obtained 
from the pilot data) and 80% power, with 10 subjects per group we will be able to detect a difference of at 
least 0.20 between the intervention groups and CONTROL group. A log transformation was applied to 
achieve normality. Also, we will longitudinally evaluate speed at each session. We will therefore conduct 
a repeated measures 2-way ANOVA and test the relevant hypotheses using contrasts in a Bonferroni post-
hoc analysis. We will include an adjustment for baseline Pp group, intervention group, time, and their 
interactions. Depending on the within subject correlation across time (which we anticipate to be high) this 
could also provide additional power. Therefore, in a secondary analysis we will be able to examine several 
covariates, including the sub-types mentioned above. For each Aim, each variable will be assessed utilizing 
a repeated measures analysis of variance (baseline Pp, group and time) to evaluate the interaction between 
baseline Pp, group and time as well as the main effects of treatment for each group and group assignment 
at each time point. Since pilot data required a log transformation of SSWS, we will assess the final SSWS 
outcome for normality and perform a transformation if necessary. All power estimates were conducted by 
a biostatistician (Dr. Ramakrishnan) using PASS 2008 (NCSS, Kaysville, Utah). Spaghetti plots and 
descriptive statistics regarding HR, BP, and RPE responses to INCLINE and DECLINE training will be 
reported prior to formal analyses. Patterns of attrition between the 2 groups will also be compared.  
Dr. Ramakrishnan will be the unblinded statistician who will track the trial to ensure adverse events are not 
disproportionately harmful to any one group of participants. After every adverse event, a report will be 
prepared by Dr. Ramakrishnan and shared with the team and the MUSC IRB. All serious adverse events 
will be analyzed by the investigative team and the MUSC Institutional Review Board. Serious adverse 
events are defined as 1) being unexpected; 2) related to a subject’s participation in research; and 3) that 
subjects are at greater risk of harm than was previously recognized. If > than 10% in each cell have a serious 
adverse event, we will evaluate the circumstances and decide if the event was caused by a particular 
treatment. If a majority of team or the IRB decides that the adverse event was related to intervention, 
subsequent randomizations will be stopped. 
 
 
 
12.0 Provisions to Monitor the Data to Ensure the Safety of Subjects (if applicable) 

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Informed consent will be obtained by the on-site R&D IRB approved VA research staff (i.e.  research 
therapist, research assistant, investigator, coordinator, or other associated trained staff) in a private room 
located at the Center for Rehabilitation Research in Neurological Conditions (CNNRC), Dept. of Health 
Sciences and Research, MUSC, 77 President Street, MSC 700, Charleston, SC.2nd Floor, Room C214 and 
213 (designated VA space through MOU between MUSC and VA). 
All hard copies of signed consent forms and associated data (intake form) will be stored in a locked office 
located on the 2nd floor, Room C213, north wall, in a badge access and secure building at the Medical 
University of South Carolina (77 President Street, Charleston, SC, designated VA space through a 
Memorandum of Understanding between MUSC and VA ). 
 
13.0 Risks to Subjects 
Potential Risks: There are no significant risks to the subjects in the proposed training methods. The risks 
to individuals participating in this study are no greater than the risks when providing conventional physical 
rehabilitation services to an individual after stroke. The same precautions and safety guidelines will be 
taken that are provided in patient care in rehabilitation settings. The rehabilitation program should not 
present a risk for the patient but could result in muscle soreness and/or joint stiffness but these symptoms 
should not persist more than a few days. There is a minimal risk for muscle strains during the testing and 
training. The locomotor assessments used in the proposed study are routine, clinical assessments of gait 
used in physical therapy clinics and rehabilitation facilities. The GAITRite system has been used to assess 
walking performance with no adverse reactions or report of discomfort. The experimental protocol to be 
used in this portion of the proposal involves minimal risk, and is considered standard clinical practice. 
During all treadmill walking trials and training sessions, a safety harness will be worn and a trained staff 
member will be present to provide assistance in the event of loss of balance. During training, individuals 
will be allowed to use a small amount of body weight support (≤ 20% of body weight) to facilitate 
independent walking.  The harness will be designed to eliminate the consequences of falling as the device 
“catches” the subject should they trip or stumble. The presence of this device affords comfort and 
diminishes the “fear of falling” in subjects.  
Dr. Ramakrishnan has been granted permission to break the blind of the data to ensure that randomization 
to each group is not harmful to the participants. This plan is thoroughly described in the Research Plan and 
Human Subjects sections.  All serious adverse events will be analyzed by the investigative team and the 
MUSC Institutional Review Board. Serious adverse events are defined as 1) being unexpected; 2) related 
to a subject’s participation in research; and 3) that subjects are at greater risk of harm than was previously 
recognized. If greater than 10% in each cell have a serious adverse event, we will evaluate the 
circumstances and decide if the event was caused by a particular treatment. If a majority of team or the 
IRB decides that the adverse event was related to intervention, Dr. Ramakrishnan will stop randomizing 
that patient profile into that group. 
Protection Against Risk: A licensed physical therapist will be present in the building during all treatment 
sessions. In addition, during all treadmill walking trials, a safety harness will be worn to provide assistance 
in the event of loss of balance. 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 a licensed physical therapist with over 22 years of experience 
in the development and implementation of exercise interventions. On-site medical services will be available 
in the event of adverse events to the subjects. Subjects will be able to terminate the training or testing 
sessions at their request at any time without prejudice. Minimization of risk will be accomplished by 
monitoring vital signs every 5 minutes within prescribed criteria for termination of the training session. 
We will follow the American College of Sports Medicine criteria for terminating an exercise session which 

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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).  
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 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 with who participate in this study may see improvements in their functional ability, but any benefit 
cannot be guaranteed. Others may benefit from advancement of scientific knowledge. Given the minimal 
risks involved and the potential for improved functional capacity, the potential benefits of participation 
make the potential risks reasonable 
 
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