Rehabilitation of Corticospinal Control of Walking Following Stroke
Phase: NA
Conditions: Stroke
Sponsor: VA Office of Research and Development

 
 
Protocol 
Page 1 of 14 
IRB version 03.09.04 
PI version: 4/16/2019 
Protocol 
1. Project Title 
Rehabilitation of corticospinal control of walking following stroke:  ABCs of Walking 
2. Investigator(s): 
David J. Clark, ScD (PI) 
 
Emily J. Fox, PhD PT (Co-I) 
Dorian K. Rose, PhD PT (Co-I) 
Stephen E. Nadeau, MD (Other) 
 
3. Abstract: 
Current approaches for rehabilitation of walking following stroke do not sufficiently restore 
mobility function. For instance, fewer than 50% of individuals with stroke-induced walking 
dysfunction recover the ability to walk independently in the community.  New breakthroughs in 
rehabilitation are needed that will target the motor impairments responsible for poor walking 
function in individuals post-stroke. Functional recovery can occur in response to task-specific 
neuroplasticity of damaged brain circuitry.  The corticospinal tract is an important target for 
neuroplasticity because it plays an important role for control of walking in humans.  We and 
others have shown that, compared to steady state walking, accurate gait modification (ACC) 
tasks are a potent behavioral stimulus for activating the corticospinal tract. Therefore, we 
propose that training with ACC tasks (e.g., obstacle crossing/avoidance, accurate foot 
placement, etc.) may be superior to training with steady state walking (SS) for eliciting 
corticospinal neuroplasticity and recovery of walking function.  Most rehabilitation paradigms 
have previously focused on SS training. This is largely because therapists consider it premature 
to progress to ACC tasks when persistent deficits of steady state walking still remain.  However, 
this reasoning might be counter-productive, because training only steady state walking may not 
sufficiently stimulate neuro-plasticity of the damaged corticospinal pathway. In contrast, ACC 
training is specifically designed to stimulate corticospinal neuroplasticity.  Importantly, since 
ACC training targets a central mechanism, its benefits are expected to generalize across 
walking conditions.  Furthermore, it is expected to benefit most stroke survivors who possess at 
least a minimal residual capability to activate the corticospinal tract.  ACC training also provides 
an opportunity to practice tasks that are analogous to challenges encountered in the home and 
community environments.  Accordingly, there is strong mechanistic and practical rationale for 
ACC training. 
A number of earlier studies including our own pilot training intervention have cumulatively 
established exciting preliminary evidence showing that walking function is enhanced by training 
with ACC tasks.  However, no prior study has been specifically designed and sufficiently 
powered to determine the extent to which the “accurate gait modification” ingredient is crucial for 
recovery of walking function.  Also not known is the extent to which ACC training reduces the 
neural impairments underlying poor walking function. The central hypothesis of this study is that 
ACC training will be superior to SS training for increasing walking function and for reducing 
underlying neural control of the paretic leg in adults with post-stroke hemiparesis.  Each 
intervention will involve twelve weeks of training, 3 days per week (36 sessions total), and will 
emphasize the motor learning principles of high intensity, repetition and task-specificity.  

 
 
Protocol 
Page 2 of 14 
IRB version 03.09.04 
PI version: 4/16/2019 
Assessments will be conducted immediately pre-intervention, immediately post-intervention and 
at a follow-up session 3 months later.  Walking function will be measured in the lab and in the 
“real world”.  Neural impairment measures will include electromyography-based measures of 
inter-muscular coordination and corticospinal drive.   
We expect that the benefits of ACC training will justify larger randomized controlled trials to 
optimize the use of ACC training, including timing relative to stroke, combination with other 
therapeutic approaches, and identifying individuals who are most likely to benefit from this 
approach. This research is expected to enhance walking function in stroke survivors, including 
for the 15,000 Veterans who suffer a stroke each year. 
4.  Background: 
The Veterans Health Administration (VHA) estimates that each year over 15,000 
Veterans are hospitalized for stroke. Stroke is the leading cause of serious long term 
disability in the United States. Approximately 600,000 individuals incur a stroke each 
year, with one quarter of those occurring in adults under age 65. The proportion of 
survivors among all age groups has increased in recent years due to improved acute 
medical care. This has resulted in a large cohort of survivors whose objectives are to 
resume their societal roles, including employment, leisure, and social activities. One of 
the most common goals in persons with post-stroke hemiparesis is to improve walking 
function and independence. Indeed, 93% of stroke survivors rate their ability to “get out 
and about” as being important or essential. It is therefore striking that less than 50% of 
stroke survivors regain the ability to walk in the community, limiting participation in a 
broad range of activities including employment, leisure, and social activities. Restoration 
of walking function is not sufficiently achieved by current rehabilitation approaches. The 
proposed project is important and significant because it may yield a breakthrough in 
restoration of walking function for stroke survivors. 
Walking is a complex sensorimotor task requiring coordinated activation of numerous 
muscles. The basic reciprocal pattern of walking is facilitated by pattern generating 
circuits in the spinal cord. For typical steady state walking, these circuits are activated by 
an indirect locomotor pathway believed to include the motor cortex, basal ganglia and 
brainstem locomotor centers as well as by signals from the cerebellum and the periphery 
(e.g., sensorimotor reflexes).  Also important to walking is the corticospinal tract, which is 
a direct pathway connecting the cerebral motor cortex to lower motor neurons. Recent 
evidence confirms an important link between functional/structural integrity of the 
corticospinal tract and recovery of walking ability after stroke. The corticospinal tract is 
believed to contribute to a variety of motor processes, including selective control of 
muscle activation and movement, modulation of spinal reflex sensitivity, and acquisition of 
new motor skills. And it is now clear that the corticospinal tract contributes to muscle 
activation during steady state walking throughout the gait cycle in humans, as evidenced 
by studies using electroencephalography, imaging and transcranial magnetic stimulation. 
The primary cause of hemiparesis following stroke is damage to the motor cortex, 
cerebral white matter and/or posterior limb of the internal capsule, all of which contribute 
to the corticospinal pathway. Given the important of the corticospinal pathway to control of 
walking, it is crucial to engage this damaged tissue during rehabilitation.  Compared to 

 
 
Protocol 
Page 3 of 14 
IRB version 03.09.04 
PI version: 4/16/2019 
steady state walking, walking tasks that involve accurate foot placement and/or gait 
modifications are known to require much stronger corticospinal activation. Accordingly, 
we propose that accurate gait modification tasks (ACC tasks) are a highly potent 
behavioral stimulus for activity-dependent plasticity of the corticospinal tract. This leads to 
an urgent question: Will an intervention that provides a more potent dose of corticospinal 
activation during walking, such as ACC training, yield even larger functional benefits than 
standard rehabilitation that uses steady state walking? 
5. Specific Aims: 
 
Specific Aim 1: Determine if ACC training is superior to SS training for improving walking 
function.  
Hyp. 1a-1d: ACC training will yield significantly larger improvements in walking function, as 
evidenced by: a) preferred walking speed; b) walking speed during obstacle crossing; c) total 
daily step activity; d) frequency of community ambulation.  
 
Specific Aim 2: Determine if ACC training is superior to SS training for improving neural control 
of walking.  
Hyp. 2a: ACC will yield significantly larger improvements in inter-muscular coordination, as 
indicated by the characteristics of EMG inter-muscular coordination patterns. 
Hyp. 2b: ACC will yield significantly larger improvements in corticospinal drive during walking, 
as indicated by EMG synchrony in leg muscles. 
6.  Research Plan: 
6.1. Recruitment and Screening 
We will recruit 64 participants with chronic post-stroke hemiparesis (6-48 months post-
stroke) to take part in rehabilitation of walking according to the following list of 
inclusion/exclusion criteria.  The Principal Investigator reserves the right to enroll 
participants who exhibit minor deviations from these criteria. 
 
Inclusion criteria 
 occurrence of a single unilateral stroke within the previous  6-48 months (verified 
by MRI or CT from medical record) 
 living in the community and able to travel to training and assessment sites 
 approval of participation by primary care physician 
 age 18 - 80 years 
 lower extremity paresis indicated by Fugl-Meyer Assessment Score < 30 
deficit in at least one “synergy” subcategory (II – IV) of the Fugl-Meyer 
Assessment 
 self-selected 10m gait speed of 0.4 – 0.8 m/s (with or without an ankle/foot 
orthosis or cane) 
 able to provide informed consent 
 willingness to be randomized to either intervention group 
 
Exclusion criteria 

 
 
Protocol 
Page 4 of 14 
IRB version 03.09.04 
PI version: 4/16/2019 
 neurological disorder or injury (other than stroke) such as Parkinson’ s disease or 
spinal cord injury 
 severe arthritis, such as awaiting joint replacement, that would interfere with 
study participation 
 cardiovascular disease (congestive heart failure, significant valvular disease, 
history of cardiac arrest, presence of an implantable defibrillator, uncontrolled 
angina) 
 myocardial infarction or major heart surgery in the previous year 
 cancer requiring treatment in the past three years, except for nonmelanoma skin 
cancers and other cancers having an excellent prognosis (e.g., early stage 
breast or prostate cancer) 
 lung disease requiring use of corticosteroids or supplemental oxygen 
 renal disease requiring dialysis 
 current diagnosis of schizophrenia, other psychotic disorders, or bipolar disorder 
 Mini-Mental State Examination (MMSE) score <23 
 significant depression (e.g., Patient Health Questionnaire score > 14) 
 severe obesity (body mass index > 40) 
 uncontrolled hypertension (systolic > 200 mmHg and/or diastolic > 110 mmHg) 
 uncontrolled diabetes with recent diabetic coma or frequent hypoglycemia 
 bone fracture or joint replacement in the previous six months 
 diagnosis of a terminal illness 
 current participation in physical therapy or cardiopulmonary rehabilitation 
 significant visual impairment affecting capability to gauge movement accuracy 
 previous enrollment in a clinical trial for recovery of walking function 
 current enrollment in any clinical trial 
 planning to relocate out of the greater Gainesville FL area during the study period 
 unable to communicate sufficiently with study personnel 
 clinical judgment regarding safety or noncompliance 
We will use a multi-pronged approach for recruitment, including: 
 Posting of flyers: Flyers advertising the study will be posted throughout the 
Malcom Randall VA Medical Center, Brooks Rehabilitation Hospital, and the 
Jacksonville VA Clinic. 
 Newspaper advertisements: We will run advertisements in regional and local 
newspapers in the Gainesville and Jacksonville areas. Advertisements will be 
designed to target Veteran enrollment. 
 Research Registries: The VA Brain Rehabilitation Research Center and the 
Brooks Clinical Research Center maintain IRB-approved registries of individuals 
who have experienced a neurological injury and who are interested in 
participating in research trials. The registries will be queried for individuals post-
stroke who have difficulty walking and who meet other specific criteria for this 
study. 
 Community Outreach: The VA Brain Rehabilitation Research Center and the 
Brooks Clinical Research Center each participate in approximately 4 community 
events per year. This includes VA Health Fairs, which is a good opportunity to 

 
 
Protocol 
Page 5 of 14 
IRB version 03.09.04 
PI version: 4/16/2019 
target Veteran enrollment. Flyers and post-cards will be distributed at these 
events. 
 Internet: The Brooks Clinical Research Center maintains a website dedicated to 
providing patients with information about the research being conducted 
(http://www.brookshealth.org/why-brooks/rehabresearch). 
 Inpatient Stroke Care: Each individual admitted to Brooks Rehabilitation is asked 
to sign a HIPAA Authorization to be contacted with information about research 
opportunities. Each person who provides authorization will be contacted to 
participate in the Brooks Research Registry. 
 Outpatient and Home Care: Brooks Clinical Research Center will recruit from the 
outpatient rehabilitation clinic and from Brooks Home Care Advantage Health 
Agency by providing research information postcards in each admissions packet. 
Home Care stroke admissions are approximately 180 per year. Outpatient clinics 
will have post cards and fliers in all 27 clinics. All post card inquiries will be 
followed up by the phone screening and consent to the registry. 
 
6.2 Preliminary screening of potential participants 
Volunteers who are interested in participating will be screened by telephone using an 
IRB approved script.  Those who pass the phone screen will be sent a form entitled 
“Authorization for disclosure of health information/patient request for access to patient 
health information”.  This form will allow us to contact the volunteer’s medical 
provider(s) in order to obtain information about the volunteer’s stroke and other medical 
information related to this study.  This information is being used for screening purposes 
to ensure that volunteers meet eligibility requirements.  The volunteer’s physician will 
also be asked to provide confirmation in writing that the volunteer is medically approved 
to participate in the rehabilitation intervention. 
 
6.3 Enrollment and on-site screening 
Volunteers who pass the preliminary screening will be invited to attend an on-site 
screening session.  Upon arrival, the individual will be consented for participation in on-
site screening only.  Assessments will include the Fugl-Meyer Assessment, walking 
speed, Mini-Mental State Exam, Patient Health Questionnaire, pain questionnaire, body 
mass index and blood pressure.  Criteria are listed above in Section 6.1.  Other clinical 
assessments/questionnaires may also be conducted including the Functional 
Independence Measure, Dynamic Gait Index, Environmental analysis of mobility 
questionnaire, Activities Specific Balance Confidence Scale, Satisfaction with mobility 
function and recovery (walking items from the Mobility and Self-Care (MOSES) 
Questionnaire) and clinical assessment of peripheral somatosensation. 
6.4. Assessments 
Participants who pass the on-site screening will invited to return to our research site for 
full enrollment in the rehabilitation trial and for baseline assessment.  At each time point of 
the study (baseline, post-intervention and follow-up), participants will undergo a battery of 
assessments. A physical therapist will perform all clinical assessments. The therapist 
performing the assessments will be blinded to group assignment. At the discretion of the 
Principal Investigator, any assessment listed here may also be performed during the 

 
 
Protocol 
Page 6 of 14 
IRB version 03.09.04 
PI version: 4/16/2019 
rehabilitation sessions in order to monitor the progress of rehabilitation and/or to address 
secondary research questions of interest.  
Primary Assessments 
Specific Aim 1a: Preferred overground steady state walking speed 
Methodology and Instrumentation: Participants will walk overground over a GAITRite 
instrumented walkway (CIR Systems Inc, Havertown, PA), which calculates walking 
speed. 
Protocol: Participants will begin walking 3 meters before the start of the walkway and 
continue to walk 3 meters after the end of the walking, in order to avoid acceleration and 
deceleration at each end of the walkway. Walking speed will be recorded three times at 
each assessment. 
Analysis: The median walking speed measured at each assessment will be used for 
subsequent analysis. An intent-to-treat analysis will be conducted to test the primary 
hypothesis using regression analysis, with the change of walking speed as dependent 
variable, the training group as independent variable, and accounting for covariates 
including baseline walking speed, severity of stroke (Fugl-Myer Assessment), co-morbid 
conditions (Charlson Index), and physical activity level (CHAMPS Questionnaire). 
Specific Aim 1b: Walking speed during obstacle crossing 
Methodology and Instrumentation: Participants will walk overground across a 20 foot 
course that has two obstacles (1” x 3” x 36” dimensions) placed at 6 and 14 feet into the 
course, as previously conducted by Shumway-Cook and colleagues. Time will be 
recorded using a stop watch, and speed calculated according to the known time and 
distance. 
Protocol: Participants will begin walking 3 meters before the start of the walkway and 
continue to walk 3 meters after the end of the walking, in order to avoid acceleration and 
deceleration at each end of the course. Walking speed will be recorded three times at 
each assessment. 
Analysis: The median walking speed measured at each assessment will be used for 
subsequent analysis. The change between pre-training and post-training (or follow-up) 
will be calculated. Between-groups difference of the change value will be assessed using 
a regression analysis similar to Aim 1a. 
Specific Aim 1c: Total daily step activity 
Methodology and Instrumentation: Step activity will be measure over a three-day interval 
using a Step Activity Monitor (SAM) that is worn at the lateral malleolus of the non-paretic 
leg. The device is safe, highly accurate, unobtrusive for the wearer, capable of 
continuously recording data in short time intervals, and capable of withstanding daily 
home and community use. Proper use of the device will be demonstrated to each subject 
at each assessment time point. Follow-up phone calls by study staff will be made during 
the 3-day intervals to enhance compliance and respond to any problems. 
Protocol: The following instructions will be provided to each participant: When you wake 
up in the morning, place the SAM on the outside of your less involved ankle. Make sure 
the arrow on the monitor is pointing upward. Go about your daily activities. You do not 
need to “pay attention” to it throughout the day. You will not want to get the monitor wet, 

 
 
Protocol 
Page 7 of 14 
IRB version 03.09.04 
PI version: 4/16/2019 
so take if off for bathing, showering, and/or swimming. Remove the SAM while you are 
sleeping at night, and put it back on in the morning. If you forget to put it on, call us and 
we will give you instructions about what to do. 
Analysis: The average daily step activity will be calculated across the three day interval. 
The change between pre-training and post-training (or follow-up) will be calculated. 
Between-groups difference of the change value will be assessed using a regression 
analysis similar to Aim 1a. 
Specific Aim 1d: Walking activity in the community 
Methodology: As previously conducted by Shumway-Cook and colleagues, participants 
will maintain a written log of trips taken away from home (i.e., into the community) and the 
number of walking-related activities performed on each trip. 
Protocol: Participants will complete the trip activity log for a one week interval at each 
assessment time point. Participants will be contacted by telephone in the middle of the 
week and end of the week to obtain results and for additional interviewing to ensure 
maximal accuracy of reporting. 
Analysis: The primary outcome will be the ratio of [total walking activities / total trips away 
from home] during the one week recording interval. The change between pre- and post-
training (or follow-up) will be calculated. Between-groups difference of the change value 
will be assessed using an analysis similar to Aim 1a. 
Specific Aim 2a: Inter-muscular coordination 
Methodology and Instrumentation: We will use the inter-muscular coordination 
measurement approach described in: 
Clark DJ, Ting LH, Zajac FE, Neptune RR and Kautz SA.  Merging of healthy motor modules 
predicts reduced locomotor performance and muscle coordination complexity post-stroke.  J 
Neurophys, 103(2): 844-57, 2010. 
Surface EMG will be recorded from tibialis anterior (TA), soleus (SO), medial 
gastrocnemius (MG), vastus medialis (VM), rectus femoris (RF), medial hamstrings (MH), 
lateral hamstrings (LH) and gluteus medius (GM) of both legs. Each skin site will be 
shaved and firmly rubbed with a sterile alcohol wipe prior to electrode placement. EMG 
signals will be detected by disposable surface gel electrodes placed on the skin over the 
muscles of interest. 
Protocol: Participants will walk at preferred steady state speed on the treadmill and 
overground. After participants are given ample opportunity to get familiarized with 
treadmill walking, we will record EMG during three 30-second bouts of walking. We will 
conduct ten 10-meter bouts of overground walking in order to provide sufficient data for 
analysis. 
Analysis: Data from treadmill and overground assessments will be analyzed separately. 
Data will be analyzed using custom data analysis programs created in Matlab (The 
Mathworks, Natick, MA), which have developed and implemented for our earlier research 
studies. The number of independent inter-muscular coordination patterns for each leg will 
be calculated using a non-negative matrix factorization (NNMF) algorithm. EMG from all 
eight recorded muscles of the paretic leg will be corrected for baseline offset (de-biased), 
rectified, and smoothed (4 Hz lowpass). The EMG data will be combined into an m x t 

 
 
Protocol 
Page 8 of 14 
IRB version 03.09.04 
PI version: 4/16/2019 
matrix, where m= # of muscles and t=time. This matrix will be entered into the NNMF 
algorithm, which extracts a smaller set of factors (i.e., inter-muscular coordination 
patterns, or ICPs) that identify the underlying common timing patterns among muscles. 
We will dichotomize the ICP response as either “increase” vs. “unchanged/decrease”. A 
chi-square test will be used to assess whether the two training groups have the same 
proportion of participants with ICP increase, i.e., whether ACC or SS training was more 
effective for restoring the characteristics of post-stroke ICPs (muscle groupings and 
timing) to those of healthy ICPs.  
Specific Aim 2b: Functional integrity of corticospinal tract during walking 
Methodology and Instrumentation: We will use the frequency-based EMG analysis 
approach described in: 
Clark DJ, Kautz SA, Bauer AR, Chen YT and Christou SA.  Synchronous EMG activity in the 
Piper frequency band reveals the corticospinal demand of walking tasks.  Ann Biomed Eng, 41(8): 
1778-1786, 2013. 
Surface EMG will be recorded from soleus (SO), medial gastrocnemius (MG), tibialis 
anterior (TA) and rectus femoris (RF) of both legs. EMG placement and data acquisition 
methodology is identical as described above for Inter-muscular Coordination. 
Protocol: Participants will perform ten trials of overground walking at preferred steady 
state speed over a 10 meter course. Participants will then perform a number of trials in 
which obstacles are placed of the course and the individual will need to step over. 
Participants will be instructed to step over the obstacle with as little foot clearance as 
possible but without striking the obstacle, in order to maximize the accuracy of the task. 
Analysis: Functional integrity of the corticospinal tract during walking will be quantified for 
each side as the difference between muscle-muscle synchrony during obstacle crossing 
versus during steady state walking. Data will be reduced using custom analysis programs 
created in Matlab (The Mathworks, Natick MA). The change in muscle-muscle synchrony 
between pre-training and post-training (or follow-up) will be calculated. Between-groups 
difference of the change value will be assessed using a regression analysis similar to Aim 
1a. 
6.5 Follow-Up Assessments at 3 months post-training 
For each participant, we will conduct a follow-up assessment session 3 months after the 
conclusion of the intervention. The objective is to determine the extent to which functional 
gains are retained in each group, including whether the gains experienced with ACC 
training exceeds that of SS training. The assessments and analysis will be essentially the 
same as what has been proposed in Specific Aim 1.  
6.6 Secondary Assessments 
It is possible that assessments other than our primary assessments may help us to 
explain certain study findings. Furthermore, these secondary assessments include 
measures that are common in clinical rehabilitation and research that will help us to 
communicate our research findings to the field. Each assessment will be conducted at 
pre-intervention, post-intervention and at the 3-month follow-up session (unless noted 
otherwise in the description below). 

 
 
Protocol 
Page 9 of 14 
IRB version 03.09.04 
PI version: 4/16/2019 
Functional Independence Measure (FIM locomotor subscale): We will assess the 
locomotor subscale of the FIM, which uses a 7-point ordinal scale to gauge the level of 
assistance required to walk on a flat surface and on stairs. 
Fugl-Meyer Assessment (lower extremity component): 34-point scale assessing lower 
extremity function through a progression of items examining more complex movements, 
speed, and coordination 
Dynamic Gait Index: evaluates dynamic balance and the ability to adapt to changes in 
task demands on eight different gait tasks including: gait on even surfaces, gait when 
changing speeds, gait and head turns, stepping over or around obstacles, and gait with 
pivot turns and steps. 
Environmental analysis of mobility questionnaire: The EAMQ is a self-report 
questionnaire, which consists of items that inquire about older adults tendencies to both 
encounter and avoid community mobility challenges that address several dimensions of 
community mobility. 
Mini-Mental State Examination: a 30-point questionnaire that is used to screen for 
cognitive impairment. 
Activities Specific Balance Confidence Scale: The ABCS is a 16-item questionnaire that 
gauges confidence (on a scale of 0-100%) when performing various balance and walking 
tasks relevant to household and community ambulation. 
Charlson Index of Comorbidity: contains 19 categories of comorbidity, and will be 
completed from chart records. Each category has an associated weight that is based on 
the age-adjusted risk of one-year mortality. Higher overall comorbidity scores indicate 
more severe burden. This index has been used successfully to predict stroke outcomes. 
CHAMPS Physical Activity Questionnaire: quantifies the approximate number of hours 
per week spent performing various types and levels of physical activity. It is designed to 
be appropriate for use with underactive individuals. We will administer the CHAMPS 
questionnaire at baseline and after weeks 4, 8 and 12 of the intervention. We will also 
administer the questionnaire at the 3-month follow-up session. 
Satisfaction with mobility function and recovery: walking items from the Mobility and Self-
Care (MOSES) Questionnaire will be rated on an ordinal scale to determine satisfaction 
pre- and post-intervention. 
Working Alliance Inventory: gauges both patient’s and therapist’s view on the quality of 
the patient-therapist interaction, such as sharing common goals, maintaining trust, and 
sharing a common approach to problem-solving. The inventory will be conducted during 
the post-intervention assessment. 
Quantitative assessment of walking (biomechanical, spatiotemporal and physiological 
parameters) will be conducted using our instrumented treadmill, motion analysis system, 
physiological measurement systems and GAITRite instrumented walkway. The 
instrumented treadmill acquires three-dimensional ground reaction forces under each foot 
(Bertec, Columbus OH). Kinematic data will be acquired by placing reflective markers on 
the participant using a modified Helen Hayes marker set and recording the movement of 
these markers at 100 Hz using a 12 camera motion capture system (Vicon Motion 
Systems).  Spatial data will also be acquired using pressure-sensitive shoe insoles.  
Physiological assessment will involve safe, non-invasive methods including muscle 
activity using electromyography (EMG), brain activity using functional near infrared 
spectroscopy (fNIRS) and/or electroencephalography (EEG) and stress/arousal level 

 
 
Protocol 
Page 10 of 14 
IRB version 03.09.04 
PI version: 4/16/2019 
using galvanic skin response (GSR). Participants may be asked to perform other tasks 
while walking, such as answering questions, memorizing information, carrying a 
tray/package, stooping to pick up an object, reaching overhead, walking over a soft mat, 
walking with dim lighting and/or wearing a weighted vest (not to exceed 15% of body 
weight or participant comfort, whichever is less). 
We will ask participants to perform some tasks outside of the lab, but still on VA-
approved property. These tasks may include walking on grass or other soft surface, 
walking up/down a wheelchair ramp, walking up/down stairs or curbs, walking in a busy 
corridor and walking on a concrete pathway. 
6.2 Retention and Adherence to Intervention 
All participants will have an initial face-to-face information session with Dr. Clark and/or 
Dr. Fox to foster a collaborative relationship, explain the intervention and answer 
questions. The importance of adherence to the intervention for optimizing therapeutic 
benefits will be reviewed with each participant. Monetary compensation of $20 will be paid 
for each therapy session attended (compensation will be tracked daily but paid on a 
monthly basis to minimize administrative burden). A primary purpose of this 
compensation is to offset expenses incurred for traveling to/from therapy sessions. If a 
participant misses a therapy session, a member of the study team will call him/her on the 
same day to schedule a make-up session. If a participant cannot complete the therapy, 
we will make every effort to follow him/her through the end of the trial and acquire all 
outcomes to the extent possible. 
A study coordinator will speak with participants about unsatisfactory adherence to the 
therapy sessions in order to determine if there are obstacles to participation that we can 
assist with. Participants who consistently miss exercise sessions will be subject to 
withdrawal from the study at the discretion of the Principal Investigator. 
6.3. Rehabilitation Interventions 
Overview 
The “accurate walking task” (ACC) training and “steady state walking” (SS) training 
interventions are designed to be similar in treatment frequency and duration, but with the 
distinction that ACC training will invoke a more potent, task-specific activation of the 
corticospinal tract due to the important role of the corticospinal tract for controlling limb 
placement accuracy. Both interventions will involve training on 3 days/week for 12 weeks 
(i.e., 36 sessions), with each session including 30 minutes of actual physical activity. Rest 
will be provided as needed, but will not count toward the 30 minute training time (the full 
session will last approximately one hour). 
Training will take place in both the treadmill and overground walking environments. We 
will use the treadmill with safety harness because it provides a safe environment in which 
participants can fully test and train their capabilities without fear of fall-related injury. This 
is important to maximizing the intensity of training throughout the intervention period. We 
will use overground walking to maximize the transfer of learned skills to the “real life” 
walking situation (i.e., specificity of training). 

 
 
Protocol 
Page 11 of 14 
IRB version 03.09.04 
PI version: 4/16/2019 
All training sessions will be supervised by a licensed physical therapist who has been 
extensively trained in our protocols, or by a study investigator.   Research assistants may 
also contribute to conducting training sessions under the direct supervision of the 
therapist or investigator.  Training will emphasize independent stepping with maximal load 
bearing on the paretic leg and appropriate movement strategies. Occasional light hands-
on cueing may be provided for tactile feedback or manual assistance to encourage 
appropriate movement and minimize compensatory movement. Verbal feedback will also 
be provided. 
Randomization 
We will use a stratified randomization approach, accounting for participant sex and 
severity of stroke. Severity will be gauged using the synergy sub-score of the Fugl-Meyer 
Assessment of Lower Extremity Motor Function. The synergy sub-score (0-22 points) 
reflects the extent to which limb control is constrained to synergistic joint movements. 
Stratification will ensure an even distribution of participants with higher (15-22) and lower 
(0-14) stroke severity in each intervention group. Randomization to an intervention group 
will be determined by the statistician, who will have no knowledge of the participant other 
than sex and Fugl-Meyer synergy score. 
ACC training 
This description is meant to provide an approximation of what will take place during 
rehabilitation. After a brief warm-up period of comfortable treadmill walking, participants 
will spend 15 minutes performing ACC tasks on the treadmill. They will then spend 15 
minutes performing ACC tasks overground.  During the first three weeks of the 
intervention, the ACC training tasks will be presented in a “block practice” format. That is, 
during a training session each task will be practiced for a few minutes before moving on 
to the next task. Weeks 4-6 will use a “variable practice’ format in which different ACC 
tasks are interspersed to make the training session less predictable and more 
challenging. The final six weeks of training will use a “combined practice” format in which 
multiple ACC tasks are performed simultaneously. For example, targeted foot placement 
while walking up/down from platforms and targeted foot placement during obstacle 
crossing. 
 
Over the course of the intervention, training intensity will be further increased by: 
1) reducing therapist assistance during ACC tasks 
2) increasing number of repetitions of each ACC (less rest or “down time” between 
repeated trials) 
3) increasing amount of limb excursion required during ACC tasks (i.e., larger obstacles, 
longer steps, etc.) 
4) increasing speed of walking during ACC tasks 
The perceived intensity reported by the participants will be quantified using the Borg 
CR10 Scale. Intensity and progression of training will be recorded by the therapist using a 
training log that will be updated throughout the training session. This log will also include 
overground preferred and fast walking speeds at the start of the session, treadmill speeds 
used during the session, description of each task, approximate number of trials performed 

 
 
Protocol 
Page 12 of 14 
IRB version 03.09.04 
PI version: 4/16/2019 
for each task and approximate success rate for each task.  ACC tasks include, but are not 
limited to: 
Walk over obstacles 
Treadmill: A foam block will be released on the front of the treadmill belt at different 
phases of the gait cycle. The participant will be asked to step over the obstacle but to 
keep the clearance distance as small as possible in order to increase the accuracy 
demands of the task. Task difficulty will be modulated based on the size of the obstacle 
and treadmill walking speed. 
Overground: Multiple foam block obstacles will be placed along walkway. The participant 
will be asked to step over the obstacle but to keep the clearance distance as small as 
possible in order to increase the accuracy demands of the task. Task difficulty will be 
modulated based on the size of the obstacles, number of obstacles and walking speed 
(preferred vs. fastest safe). 
Performance goal: Walk over obstacles without striking the obstacle or losing balance, 
without relying excessively on therapist assistance, and without using major 
compensatory movements. During overground walking, speed should remain fairly stable. 
Use of appropriate movement patterns will be emphasized. 
Walk around obstacles 
Treadmill: not applicable 
Overground: Obstacle will be placed along a walkway. The participant will be asked to 
walk around each obstacle, staying as close to the obstacle as possible without touching 
it. Task difficulty will be modulated based on the proximity of the obstacles and walking 
speed (preferred vs. fastest safe). 
Performance goal: Walk around obstacles at steady speed without striking the obstacle or 
losing balance, without relying excessively on therapist assistance, and without using 
major compensatory movements. Use of appropriate movement patterns will be 
emphasized. 
Walk up/down from platforms 
Treadmill: not applicable 
Overground: Task will be performed using a commercially available set of various sized 
platforms used in clinical practice (see photo to left). Participant will walk onto platform 
and then down from platform in the most smooth and continuous motion possible. Task 
difficulty will be modulated by changing the size and number of platforms that must be 
traversed. 
Performance goal: Walk over platforms at a steady speed without stopping to re-adjust 
foot position and without major compensatory movements. 
Step onto targets 
Treadmill: Targeted stepping on the treadmill will be accomplished by using a laser 
pointer or projector (mounted on a stand) to project a target onto the treadmill belt. 
Participant will be instructed to place the tip of their shoe as close as possible to the target 
(but without “touching” it) on each step. When participants become more skilled at the 
task, targets will be drawn onto the treadmill belt with chalk so that the target(s) appear 
quickly and at an unpredictable phase of the gait cycle as the belt rotates. Task difficulty 

 
 
Protocol 
Page 13 of 14 
IRB version 03.09.04 
PI version: 4/16/2019 
will be modulated by changing the number of targets, location of targets (in sagittal and 
frontal planes) and walking speed. 
Overground: Targeted stepping overground will be accomplished by placing targets made 
of non-slip material along a walkway. Participants will be instructed to place the tip of their 
shoe as close as possible to the target (but without touching it) on each step. Task 
difficulty will be modulated by changing the number of targets, location of targets (in 
sagittal and frontal planes) and walking speed. 
Performance goal: Accurate targeting of foot placement without major compensatory 
movements while walking at a steady speed. 
Foot placement ladder 
Treadmill: not applicable 
Overground: Task will be performed using a commercially available “foot placement 
ladder” that is used in clinical practice (see photo to left). The ladder has adjustable rungs 
that allow the therapist to modulate the difficulty of the task. Participant will walk through 
the ladder, stepping between rungs, in the most smooth and continuous motion possible. 
Task difficulty will be modulated by changing the number and orientation of rungs. 
Performance goal: Traverse the ladder without tripping, without stopping to re-adjust foot 
position, without major speed deviations, and without major compensatory movements. 
SS training 
This description is meant to provide an approximation of what will take place during 
rehabilitation. After a brief warm-up period of comfortable treadmill walking, participants 
will spend 15 minutes walking on the treadmill at steady state speed. Speed will be set 
such that the intensity level yields a perceived exertion of 5 (out of a maximum of 10) on 
the Borg CR10 Scale, which corresponds to “hard” exertion. Participants will then spend 
15 minutes walking overground at steady state pace at a similar exertion as treadmill 
training. Progression of training is inherently built into this protocol because, as walking 
ability improves, participants will be capable of walking faster at the same level of 
perceived exertion. Borg Scale ratings will be compared to those reported by the 
participants in the ACC training intervention to ensure approximate equivalence of 
intensity with SS training. If Borg Scale ratings are found to be non-equivalent as we 
conduct the interventions, we will modify the intensity of SS training to match ACC 
training. Intensity and progression of training will be recorded by the therapist using a 
training log that will be updated throughout the training session. This log will also include 
overground preferred and fast walking speeds at the start of the session, and treadmill 
speeds used during the session. 
6.7. Power analysis and sample size justification 
The primary objective of this study is to determine if ACC training yields a meaningful 
benefit over SS training for recovery of walking function in adults post-stroke. The primary 
outcome measure for this study is overground preferred walking speed.  We seek to 
detect a group difference in walking speed of at least 0.11 m/s. A group difference of this 
size indicates a substantial clinically meaningful difference. To determine the required 
sample size, we used alpha = 0.05 for a one-sided test (ACC>SS), power = 0.80, and 
inter-individual variability of training response = 0.16 m/s (according to prior work). We 
also assume that at least 85% of participants will be retained to the post-intervention 

 
 
Protocol 
Page 14 of 14 
IRB version 03.09.04 
PI version: 4/16/2019 
assessment. Earlier studies by our group have consistently exceeded this goal. Using 
these parameters, we will need to enroll 64 participants (32 per treatment group). This 
power estimate is conservative because within-group variability is expected to be reduced 
after accounting for baseline characteristics (walking speed, stroke severity, co-morbid 
conditions, physical activity). 
7. Possible Discomforts and Risks: 
This study involves exercise, which can be stressful to the body.  Exercise temporarily 
increases blood pressure and can temporarily increase the risk of heart attack or stroke.  
Exercise also can cause temporary shortness of breath, muscle soreness and a feeling of 
fatigue.  There is a risk of falling, which may cause serious injuries.  There is also a risk of 
muscle/joint injury. There is a slight risk of skin irritation due to the use of tape to secure 
sensors to the skin during the assessment visits.  The equipment used to measure brain 
activity can be mildly uncomfortable when worn for prolonged periods because the 
sensors are spring loaded and lightly press on the scalp.  To minimize discomfort we will 
limit the length of testing to about one hour, or will end the testing if the participant 
requests. Researchers will take appropriate steps to protect any information they collect.  
However there is a slight risk that personal information could be revealed inappropriately 
or accidentally.  Depending on the nature of the information such a release could upset or 
embarrass the participant.  This study may include risks that are unknown at this time 
8. Possible Benefits: 
Participating in this study may improve walking ability and physical fitness.  However, 
there are no guaranteed benefits. 
9. Conflict of Interest: 
There is no conflict of interest.