Post-Stroke Optimization of Walking Using Explosive Resistance: Concurrent Effects on Depression (POWER-D Trial)
Phase: PHASE2
Conditions: Stroke, Depression
Sponsor: Medical University of South Carolina

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PROTOCOL TITLE: 
Post-Stroke Optimization of Walking using Explosive Resistance: Concurrent effects on 
Depression (POWER-D Trial) 
 
PRINCIPAL INVESTIGATOR: 
Chris Gregory 
 
 

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1.0 
Objectives / Specific Aims 
The purpose of this project is to determine the efficacy of POWER training for treating 
post- stroke depressive symptoms. We will also determine if depression limits response to 
rehabilitation and the extent to which changes in depression are associated with 
improvements in functional performance post-stroke. The PI and Co-I’s have experience 
performing all of the proposed methodologies. Specifically, we have extensive experience 
implementing exercise programs in persons post-stroke; 13,31,32,36 performing assessments of 
post-stroke walking;13,36 and diagnosing and treating depression. 37,38,39,40 
Aim 1: Determine the efficacy of POWER training for treating PSD 
We hypothesize significant reductions in HRSD scores in both groups, with improvements 
following POWER greater than control. We also expect greater response and remission 
rates in the POWER group. 
Aim 2: Determine the influence of PSD on the rate and extent of response to POWER 
training 
We posit that POWER training-induced improvements will be attenuated, though still 
significant, in depressed subjects. In addition, we hypothesize that improvements in 
walking speed and lower extremity muscle power generation will be contingent upon 
improvements in HRSD and that a critical threshold will determine the point at which 
depression is reduced thereby facilitating functional improvements. 
2.0 
Background 
With a surviving cohort of nearly 7 million individuals, stroke is the leading cause of long-
term disability in the United States. Of the ~795,000 new strokes occurring in the U.S. each 
year, approximately two-thirds of survivors will have some degree of long term disability, 
18 and less than half will progress to independent community ambulation. 19 Even among 
those who do achieve independent ambulation, significant residual deficits persist, with 
more than 60% of persons post-stroke reporting limitations in mobility related to walking. 
20 Depression contributes directly to disability following stroke and is the single strongest 
predictor of quality of life. Importantly, improvement in depressive symptoms is associated 
with better functional recovery and return to activities of daily living. The prevalence of 
PSD coupled with the fact that returning to independent ambulation is the top priority for 
individuals in the first year post stroke 21 necessitates development of effective rehabilitation 
strategies to reduce disability and improve quality of life for the millions of stroke 
survivors, their families and caregivers. 
Post-stroke depression is common and treatment options are inadequate. 
Post-stroke depression (PSD) is the most common neuropsychiatric consequence of stroke. 
Four out of five individuals develop major depressive disorder within seven years of stroke 
onset and point prevalence estimates for PSD are ~30%. 3 Thus, more than 2 million 
individuals with PSD are presently living in the U.S. Current pharmacological treatments 
for depression in older individuals are generally ineffective (65-75% will not achieve 
remission) and often come at the cost of significant side effects (e.g. seizure, delirium and 
falls). 6,22 Importantly, a review of treatment options for PSD found no evidence to support 
the routine use of drugs or psychological treatments for PSD 5 and in a recent meta-analysis, 
23 of 25 prospective studies that met the criteria for inclusion indicated that anti-depressant 
treatments were a significant predictor of prospective falls, independent of reduced physical 

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and cognitive function. 23 These issues highlight the need for alternative (non-drug) 
treatments with fewer side effects to successfully reduce PSD symptoms. 
Individuals with PSD are largely ignored in rehabilitation research and limited data 
describe the effects of depression on rehabilitation outcomes. 
Depression is reported to interfere with functional outcomes. 7 Thus, clinical trials targeting 
recovery of walking have historically excluded depressed subjects. 8,9,10 As such, there is 
an absence of data describing how individuals in this large clinical cohort respond to 
rehabilitation training. Given the prevalence of PSD, specific information regarding how 
depressive symptoms can be effectively reduced is a critical first step toward optimizing 
treatment approaches for these individuals. Further, data describing how depression 
impacts response to treatment would be extremely valuable to rehabilitation science and 
the development of effective treatments for PSD would have a major impact on healthcare 
delivery. 
Resistance training can effectively improve post-stroke walking and emerging 
evidence supports its anti-depressant benefit 
Hemiparesis, strictly defined as a muscular weakness or partial paralysis of half of the 
body, is seen in three- quarters of individuals post-stroke. A primary disability associated 
with post-stroke hemiparesis is the failure to make rapid graded adjustment of muscle force 
within the context of purposeful movement patterns, such as are required during walking. 
Progressive resistance training is widely accepted as the most effective method for 
developing muscular strength and is currently prescribed by most major health organizations 
for improving health and fitness. 24 Resistance training improves lower extremity strength 
following stroke and, when delivered at appropriate intensities, can provide significant 
functional benefit. 25,26 In contrast, there exist studies in the post-stroke rehabilitation 
literature that report limited functional benefit of resistance type exercises, some of which 
fail to elicit significant gains in strength following this type of training. 82,83,84 We recently 
developed an innovative rehabilitation approach, Post-stroke Optimization of Walking 
using Explosive Resistance (POWER) training (VA RR&D RX000844). 13,31,32 A unique 
aspect of POWER training is the focus on high-intensity, high-velocity concentric and 
eccentric contractions to specifically target post-stroke deficits in muscle power generation. 
Interventions targeting muscle power (i.e. training at high-velocities) in the aged elicit an 
over two-fold greater improvement in peak power, when compared to slow velocity 
training, and explain more of the variability in functional performance. 27,28,29 Data from 
our trial of POWER training show significant improvements in muscular and locomotor 
function 13 and a recent pilot study suggest its potential to improve depression (see 
preliminary studies). The feasibility of resistance training to target depression has been 
shown in individuals following stroke and data from neurologically healthy subjects 
suggest the nature of POWER training may be key to its effectiveness for treating PSD. 12 
Specifically, trials in older (non-stroke) subjects show benefits of resistance training on 
depressive symptoms and walking are dependent on training at high intensities, with 
reduced depression associated with improvements in  muscle  strength  and  function. 11 
Similarly, high-intensity resistance training significantly improves depression in subjects 
at high risk for metabolic syndrome, with changes in depression correlated with change in 
muscle strength. 29 
INNOVATION 
Novel approach to treat PSD 

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The innovative approach proposed herein incorporates an extremely effective therapeutic 
intervention for post-stroke locomotor function that shows great potential as an anti-
depressant treatment, the effectiveness of which could represent a major paradigm shift in 
post-stroke rehabilitation. Resistance training has shown potential to be an effective stand-
alone treatment for non-stroke related depression, the efficacy of which is reportedly 
similar to antidepressant drugs. 12,13,41 Follow-up studies show the effects of other forms of 
exercise persist longer and achieve higher rates of remission than pharmacological 
treatments. Thus, there is a sound rationale to investigate the influence of POWER training 
on post-stroke depression. 
Conceptualizing depression as a state that limits neuroplasticity 
Our conceptual framework considers that depression may be associated with disruption of 
homeostatic mechanisms that regulate neuroplasticity such that rehabilitation may not 
produce the same brain changes that it does in non-depressed individuals. The concept of 
impaired neuroplasticity in individuals with PSD is supported by findings of reduced 
synaptic plasticity in the motor 17 and visual cortices 16 as well as other telencephalic 
regions such as the hippocampus 30 in depressed patients. Together, these deficits suggest 
a deficiency in synaptic plasticity that is widespread, and not merely in the limbic and 
frontal regions that are most closely associated with depression. Although these findings 
have not been extended to PSD, conceptualizing depression as a disease which 
fundamentally limits plasticity allows us to pose specific questions regarding how 
depression limits response to rehabilitation, as well as how effective treatment of 
depression may improve rehabilitation outcomes. Thus, an extremely exciting possibility 
is that effective treatment for PSD may result in a virtuous cycle where reducing depression 
up-regulates neuroplastic responses, thereby facilitating functional gains. That is, 
effectively treating PSD may actually make an individual better able to recover from stroke. 
The work proposed represents the first step in a longer line of investigation aimed at the 
development of appropriate therapeutic strategies to effectively ameliorate (attenuate) 
functionally limiting impairments in persons post-stroke. We believe that it will prove 
impossible to make substantial progress in patient-specific neurorehabilitation evaluation, 
treatment and outcomes without each being strongly based on a continually refined 
theoretical framework. Many contemporary neurorehabilitation strategies are based on 
assumed relationships between impairments of body structure & function, activity and 
participation; yet little evidence exists to define how these domains mechanistically relate 
to one another and the personal factors (e.g. depression) that may limit participation. The 
proposed studies would move this topic forward by elucidating the relationship between 
changes in depression and functional improvements following training as well as 
neuroplastic mechanisms of response to POWER training; thereby providing key data for 
future work to improve the a priori identification of fundamental barriers (and facilitators) 
to therapy. 
Preliminary Studies for Aim 1:  
POWER training is highly effective at improving post-stroke muscular and locomotor 
function: (J Rehab Research & Development. 52(1):77-84, 2015) 
Twelve subjects (6–60 mos. post-stroke) participated in 24 training sessions of POWER 
training with exercises including leg press, calf raises, and jump training, all performed at 
high concentric velocity, as well as trials of fast walking. We measured self-selected 
walking speed as well as knee extensor and plantar flexor strength and power at pre-
training, post-training, and at follow-up time points. Post-training improvements in lower 

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extremity muscle strength and power were accompanied by improvements in self-selected 
as well as fastest comfortable walking speeds. Specifically, strength increased by 25.0 and 
23.3 percent in the paretic and non- paretic plantar flexor (PF) muscle groups, respectively. 
Improvements    in knee extensor (KE) strength were not as large, with gains of 14.8 percent 
in the paretic side and 16.0 percent in the non-paretic side. Gains in KE peak power of 28.6 
and 30.7 percent in the paretic and non-paretic limbs, respectively, were also found post-
training. Self-selected walking speed increased from 0.71 to 0.92 m/s, exceeding the 
clinically meaningful difference reported for participants post-stroke. Fastest comfortable 
walking speed increased from 1.10 to 1.51 m/s. 
POWER training improves depressive severity:  
We have enrolled and trained 10 subjects to date with mild to moderate PSD in POWER 
training. We measured depression severity (HRSD), at pre-, mid- and post-training time 
points over the 12 week training period. HRSD scores prior to training (15.1 ± 7.5) 
decreased after 6 weeks (10.8 ± 4.3) and 12 weeks (8.5 ± 3.3) of training. In addition, 7 
subjects realized a >50% reduction in depression severity (i.e. response) and 8 were 
considered to have achieved remission (i.e. HRSD < 10). Although we did not have a 
comparison group with PSD in this pilot study, these data suggest the potential for POWER 
training to positively impact depression severity in individuals with PSD.  
3.0 
Intervention to be studied  
Emerging evidence suggests that resistance training is effective at reducing depressive 
symptoms. 11,12,27 We developed an innovative rehabilitation approach, Post-stroke 
Optimization of Walking using Explosive Resistance (POWER) training; a high-velocity, 
high-intensity lower extremity resistance training intervention that improves post-stroke 
muscular and locomotor function (RR&D RX000844). 13 Preliminary findings from this 
study suggest POWER training reduces symptoms in those with mild to moderate depression 
(Figure 1). We seek to build upon these findings to determine its efficacy (vs. control) in 
treating PSD. 
Chronic stroke survivors with mild to moderate depression (n=32) will be randomly assigned 
to the intervention (POWER) or attention control (stretching) group. POWER training will 
take place over a 12-week period (3 sessions/week) with exercises including leg press, calf 
raises, and jump training, all performed at high concentric velocity, as well as trials of fast 
walking. We will perform bi-weekly measurements of depressive severity using the 
Hamilton Rating Scale for Depression (HRSD). 
Chronic stroke survivors with mild to moderate depression (n=16) as well as age (± 5 yrs), 
gender and severity-matched (determined by walking speed) non-depressed stroke subjects 
(n=16) will complete 12 weeks of POWER training. We will perform bi-weekly HRSD 
measurements as well as comprehensive dynamometric assessments of paretic and non-
paretic knee extensor muscle power generation and self-selected walking speed at these same 
time points. Secondary assessments of locomotor function will be the six-minute walk test 
(6MWT) and the amount of community walking measured via step activity monitors (SAM).  
Stretching is being used as an attention control condition for POWER training.  Control 
subjects will participate in a stretching protocol for the same duration (i.e. 60 minutes per 
session) and frequency (3 days per week) for 12 weeks to ensure that they have equal 
interaction with the study staff and controlling for the effects of repeated social interaction 
on depressive symptoms. 
 

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4.0 
Study Endpoints 
The primary outcome for this trial will be the absolute change in depression using the HRSD from 
baseline to week 12 compared between AET+rTMS and AET+sham groups.  
 
 
5.0 
Inclusion and Exclusion Criteria/ Study Population 
Subjects (male and female), ages 18-85, will be screened and recruited for the study 6-60 
months following stroke. The pool of post-stroke candidates for the study will be recruited 
through the extensive recruiting mechanisms at the local VAMC as well as the Clinical and 
Translation Tools and Resources CTTR core at MUSC. All participants will have had a new 
ischemic stroke.  
Inclusion criteria will be: 1) age 18-85; 2) stroke at least 6 months prior, 3) residual paresis 
in the lower extremity (Fugl-Meyer LE motor score <34); 4) ability to walk without 
assistance and without an AFO during testing and training at speeds ranging from 0.2-0.8 
m/s; 5) no antidepressant medications or no change in doses of psychotropic medication for 
at least 4 weeks prior to the study (6 weeks if newly initiated medication); 6) HRSD question 
#9 regarding suicide <2; and 7) provision of informed consent. In addition, depressed 
subjects will screen for probable major depressive disorder (PHQ-9 > 10) and be diagnosed 
using the Structured Clinical Interview for Depression (SCID) according to the Diagnostic 
and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). All subjects who 
meet criteria for training must complete an exercise tolerance test and be cleared for 
participation by the study physician.  
Exclusion criteria will be: 1) Unable to ambulate at least 150 feet prior to stroke, or 
experienced intermittent claudication while walking; 2) history of congestive heart failure, 
unstable cardiac arrhythmias, hypertrophic cardiomyopathy, severe aortic stenosis, angina 
or dyspnea at rest or during ADL’s; 3) History of COPD or oxygen dependence; 4) 
Preexisting neurological disorders, dementia or previous stroke; 5) History of major head 
trauma; 6) Legal blindness or severe visual impairment; 7) history of psychosis or other Axis 
I disorder that is primary; 8) Life expectancy <1 yr.; 9) Severe arthritis or other problems 
that limit passive ROM;10) History of DVT or pulmonary embolism within 6 months; 11) 
Uncontrolled diabetes with recent weight loss, diabetic coma, or frequent insulin reactions; 
12) Severe hypertension with systolic >200 mmHg and diastolic >110 mmHg at rest; 13) 
attempt of suicide in the last 2 years or at suicidal risk assessed by SCID interview; 14) 
History of seizures or currently prescribed anti-seizure medications; 15) Current enrollment 
in a clinical trial to enhance motor recovery; 16) Pregnancy verified by urine pregnancy test. 
6.0 
Number of Subjects 
A total of 48 chronic stroke survivors will be accrued locally. 
7.0 
Setting 
Locomotor Energetics and Assessment Laboratory: This 1350 ft2 laboratory is a shared 
resource supported in part by the Department of Health Sciences and Research, and features 
equipment capable of collecting kinematic, kinetic, electromyographic data during walking. 
This laboratory is adjacent to a small workshop available for the construction, repair, and 
alteration of simple mechanical devices. 
Locomotor Rehabilitation Laboratory: This laboratory encompasses an 800 ft2 space and 
is also a shared resource.  Specialized equipment within the laboratory that is most relevant 
to the proposed work is a ZeroG mobile body weight support system as well as a Woodway 

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split-belt treadmill.  The focus of this laboratory is on a multi-faceted approach to locomotor 
recovery after neurological injury, initially targeting stroke. 
 
8.0 
Recruitment Methods 
Subject recruitment: The pool of candidates for the study will be recruited from 
rehabilitation programs at the Medical University of South Carolina; the Ralph H. Johnson 
VAMC; and Charleston area communities. The combination of MUSC Stroke Center and 
the Ralph H. Johnson provide a unique environment from which to recruit participants for 
this study and we have on-going collaborative relationships with both entities. The MUSC 
program holds Joint Commission's Certificate of Distinction for Primary Stroke Centers 
which recognizes centers that make exceptional efforts to foster better outcomes for stroke 
care. The Stroke Center research team will assist with recruitment by reviewing patient 
rosters and potential participants will be given information while inpatient and again when 
they are seen for follow up in the outpatient clinic. Rack cards and flyers with basic study 
information and study investigator contact information will be put on display in the MUSC 
CHP Research Center. Additionally, the rack cards and flyers with be distributed to area 
rehabilitation clinics.   
 The MUSC Stroke Center 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 stroke recovery it will be supported by 
the Clinical and Translation Tools and Resources (CTTR) Core of the NIH-funded Center 
of Biomedical Research Excellence (COBRE) in Stroke Recovery at MUSC. The CTTR 
Core provides subject recruitment resources through a bioinformatics-enabled database 
registry. Currently (November, 2017) there are 663 post-stroke subjects in our database 
registry and ongoing recruitment is expected to add 1-3 more subjects each week. Of these, 
157 have screened positive for PSD (PHQ-9 > 10), all of whom have agreed to be contacted 
for participation in research studies. As evidence of our ability to recruit subjects with PSD, 
we (Dr. Gregory and Dr. George) have been successfully recruiting subjects for a trial as 
part of the South Carolina Center for Stroke Recovery Research. Over the duration of this 
study (~26 months) we have successfully enrolled subjects with PSD at a rate that would 
meet the goals for the proposed study. Thus, we are confident that recruitment goals will be 
met without difficulty. 
9.0 
Consent Process 
Informed consent will be obtained from participants prior to participation. Participants will 
first be informed of the purpose of the experiments and possible risks. A member of the 
study staff with then review the Informed Consent form with the potential participant, 
ensuring they are given adequate time to review the document. The potential participant will 
be asked if they have any questions about the study, and asked if they agree to participate. 
The Informed Consent and HIPAA forms will be signed by the participant. Copies of the 
signed forms will be given to the participant. The consent process will take place in a private 
room in the MUSC College of Health Professions Building. There will be no set period 
between informing the prospective participant and obtaining the consent. In every session, 
participants will be reminded that they may end their participation in the study at any point. 
 
10.0 Study Design / Methods 

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Subject screening and clinical assessments: After enrollment, participants will be 
thoroughly evaluated for functional and cognitive impairments as well as physical 
performance. Descriptive physical performance testing will include the lower extremity 
Fugl-Meyer Assessment (FMA-LE), Stroke Impact Scale (SIS), Berg Balance Scale (BBS) 
and the NIH Stroke Scale. The FMA-LE is a 34-point scale assessing lower extremity 
function through a progression of items examining more complex movements, speed, and 
coordination. The SIS is a stroke-specific outcome measure that assesses physical function 
and other dimensions of health-related quality of life: emotion, communication, memory and 
thinking, and social role function. The physical functioning domain includes strength, hand 
function, mobility, and activities of daily living. 71,72,73 The NIH Stroke Scale measures 
stroke related impairments including level of consciousness, ability to respond to questions, 
ability to follow simple commands, deviation of gaze, hemianopsia, facial palsy, limb 
movements, limb ataxia, sensory loss, neglect, dysarthria, and aphasia. In addition, the 
Folstein Mini-Mental Status will be used as a screen of cognitive function. Specifically, we 
will use the three-step command item as a primary screen for study eligibility. All screening 
and clinical assessments will be performed by a staff physical therapist within the Center for 
Rehabilitation Research in Neurological Conditions who will be blinded to training group 
assignment. 
Clinical Assessments: The proposed assessments are standard to post-stroke intervention 
trials. Including these assessments strengthens our design by allowing us to make 
conclusions regarding the effects of our intervention that extend beyond the behavioral 
measures of walking. We feel that the proposed benefits of our training will be most 
significant if they are shown to impact behaviors other than that which is targeted as the 
primary outcome and relate to other domains of function suggested to put individuals post-
stroke at risk for disability.  
• 
Dynamic Gait Index (DGI): The DGI evaluates the ability to adapt to changes in task 
demands. The DGI rates performance from 0 (poor) to 3 (excellent) on eight different 
gait tasks, including even surfaces, changing speeds, head turns in a vertical or 
horizontal direction, stepping over or around obstacles, and gait with pivot turns, and 
steps. 42 The DGI examines complex walking tasks (e.g. accelerating, turning, head 
turns) and provides valuable information regarding dynamic balance (as opposed to 
static balance assessed using the BBS) and often reveals deficits that otherwise would 
not be identified. 
• 
Step Activity Monitor (SAM): The SAM is worn on the ankle to quantify daily step 
activity. The SAM is a microprocessor-driven accelerometer that permits the 
researcher to count strides and observe activity during predetermined time spans. The 
SAM is 98%-99% accurate and has a test-retest reliability post-stroke of 0.98. 43 The 
SAM will be worn for two consecutive days at a 6-second epoch, per the LEAPS 
protocol. 8 Information about the effects of POWER training on the amount of 
community stepping are critical as we attempt to generalize any improvements beyond 
the laboratory. 
• 
6-Minute Walk Test (6MWT): Timed walking tests are primarily a measure of 
functional capacity.44 The 6MWT tests populations who present with little functional 
walking capacity and has been validated against the Rivermead Mobility Index 
(r=0.75) and 10-meter walk time (r=-0.61). 46 The 6MWT has a high intra- and 
interrater reliability (ICCs = 0.82-0.95). 45 

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Assessment of depression severity: The Hamilton Rating Scale for Depression (HRSD) 
and the Montgomery- Åsberg Depression Rating Scale (MADRS) are the most widely used 
instruments for obtaining ratings of depressive symptoms. The HRSD samples a broader 
array of symptoms and is the primary outcome for this project. However, the MADRS is 
also sensitive to therapeutic change and includes more focus on vegetative symptoms. Thus, 
we will utilize a single structured interview that contains the questions necessary to complete 
both the HRSD and MADRS. The order of questions results in a more efficient interview, 
clustering material of similar content, thereby reducing repetition. Items that require patient 
observation (e.g., retardation, agitation) or spontaneous patient report (e.g., HRSD mood 
item) occur towards the end so scores are not contaminated by direct questioning on these 
topics. Items dealing with somatic symptoms (e.g., sleep) occur before items focusing on 
psychological state (e.g., guilt, suicide) so as to develop rapport during the earlier part of the 
interview leading to fuller disclosure of symptoms that are difficult to discuss. Critically, the 
rater administering the interviews will not be involved with any other aspects of the study. 
A trained psychiatry practitioner (Dr. George or one of his colleagues) will assess depression 
severity bi-weekly. Test-retest reliability for the HRSD is extremely high (0.94; 95% CI 
0.89-0.97) and thus appropriate to use for repeated measure of depression severity. 41 
Depression will be classified as mild (HRSD = 12-16) or moderate (HRSD ≥17) and 
diagnosed upon enrollment using the Structured Clinical Interview for Depression (SCID) 
according to the Diagnostic & Statistical Manual of Mental Disorders, 4th Edition (DSM-
IV). 
Assessment of cortical excitability and neuroplastic potential via PAS: A means of 
testing “neuroplastic potential”, without dependence on subject motivation and effort 
(frequently impaired in depression) is via a non- invasive brain stimulation protocol called 
paired associative stimulation (PAS). PAS uses repeated, timed and paired peripheral nerve 
stimulation and TMS of the contralateral motor cortex and induces consistent changes in 
excitability of the motor cortex in healthy subjects as demonstrated by changes in the 
amplitude of MEPs.  
Prior to PAS, all participants will be assessed for potential contraindications to TMS using 
a safety-screening questionnaire. This screen as well as the PAS assessments will be 
performed by personnel with experience utilizing this technique in individuals with PSD. 
Single pulse cortical stimulation will be delivered using a Bi-Stim module magnetic 
stimulator (The Magstim Company Limited; Whitland, UK) with a figure-of-eight coil 
(P/N 3190; 70mm outer diameter of each winding; maximal output of 2.2T). We will use a 
combination of on-line surface electromyography (sEMG) recordings to view peak-to-peak 
motor evoked potential (MEP) amplitude and a neuro-navigation system to identify the 
optimal coil position for stimulation of the abductor pollicus brevis (APB) muscle. The 
neuro-navigation system consists of a stereotaxic passive marker and camera system 
(Polaris Vicra P6, NDI, Waterloo, Ontario, Canada) and Brainsight software (Rogue 
Research Inc.; Montreal, Quebec, Canada), which will allow us to track the location of the 
figure-of-eight coil and ensure consistency during resting motor threshold (RMT) and 
SI1mV (stimulus intensity necessary to induce a 1-millivolt MEP response) assessments.  
In order to locate the APB muscle ‘hotspot’ we will use a suprathreshold stimulation 
intensity on the hand area of the primary motor cortex to elicit MEP’s of the APB muscle. 
The area on the hand knob of the motor cortex that produces the largest and most 
consistent MEP’s of the APB muscle will be marked as the ‘hotspot’ using the neuro- 
navigation system.  After locating the participant’s APB muscle ‘hotspot’ we will then 
assess the participant’s RMT. We define the RMT as the amount of TMS output 
(expressed in percentage of maximal stimulator output [%MSO]) necessary to induce an 

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MEP that exceeds or is equivalent to a peak-to-peak amplitude of 50μV (.05mV) in 50% of 
stimulations. To estimate RMT, we will utilize an automated version of a simple adaptive 
parameter estimation by sequential testing (SA-PEST) procedure developed at MUSC. 47 
Following RMT assessment, we will assess the participant’s SI1mV. The same ‘hotspot’ 
location and SA-PEST procedure will be used to determine the participant’s SI1mV, 
however the SA-PEST program will be set to search for MEP amplitudes of approximately 
1-mV. Once established, the SI1mV will be used as a primary measure of corticospinal 
excitability. Using the %MSO of the SI1mV we will then collect 20 test MEP’s at a rate of 
0.25Hz. Once MEP’s are collected, participants will be set-up for peripheral nerve 
stimulation. Stimulation of the median nerve of the non-dominant arm will be delivered via 
constant current stimulator (DS7A; Digitimer, Hertfordshire, UK). Bipolar electrodes will 
deliver a 200μs square wave pulse at an intensity equal to 300% sensory perceptual 
threshold. Perceptual threshold will be determined each session and will be defined before 
any stimulation protocols are commenced. Single pulse TMS will be applied to the APB 
muscle representation on the contralateral motor cortex 25ms (ISI25) after the delivery of 
median nerve stimulation. A train/delay generator (Digitimer, Hertfordshire, UK) will 
trigger paired peripheral nerve stimulation and brain stimulation. A total of 200 paired 
stimuli will be delivered at rate of 0.25 Hz, resulting in a total stimulation time of ~14 
minutes. The 20 test MEP’s will be reassessed immediately after PAS, and then every 15 
minutes for one hour.  
We will utilize the PAS measures at baseline, after 2,4,6,8,10 and 12 weeks of treatment 
(or control) as well as at the follow-up time point to assess whether the interventions 
change PAS measured neuroplastic potential. We will use PAS to assess cortical 
excitability (SI1mV) as well as neuroplastic potential (represented by mean normalized post-
stimulation MEP amplitude). We will compare PAS measures at baseline to after either 
POWER or control. We will also compare repeated PAS measures in patients with and 
without PSD (Aim 2) to determine whether PSD inhibits neuroplasticity, and if effective 
treatments reverse the impaired potential for plasticity. 
Electromyographic assessment: Surface electromyography (sEMG) will be collected 
using 2cm by 2cm surface recording electrodes and will be placed perpendicular to the 
orientation of the fibers of the APB muscle belly, on the participant’s non-dominant hand. 
Prior to sEMG placement the site of the APB muscle will be lightly abraded and cleaned 
with pre-packaged alcohol swabs. All EMG signals will be collected using Spike2 v7.12 
software (Cambridge Electronic Design; Cambridge, UK) and will be amplified (x1000) and 
bandpass- filtered (100-2000 Hz) using a CED 1902 amplifier (Cambridge Electronic 
Design; Cambridge, UK), and sampled at 5000 Hz using CED Micro 1401-3 data acquisition 
unit (Cambridge Electronic Design; Cambridge, UK). Data will be saved directly to a 
network drive for offline analysis. During all stimulation protocols sEMG activity will be 
continuously monitored in order to ensure that the APB muscle is not voluntarily active. 
Exercise Tolerance Testing: Prior to training, a bicycle ergometry protocol modified from 
the LEAPS trial 8 will be used to assess exercise tolerance prior to study inclusion. The 
protocol will be overseen by a physician and will commence with the subject seated quietly 
for two minutes. Exercise will begin with the subject pedaling at ~60 revolutions per minute 
(RPM) and 0 Watts (W) of workload, with workload will be increased by ~15 W every 3 
minutes. If the pedal cadence drops below 50 RPM, additional reminders will be given. 
Testing continues until maximal effort is achieved. The test will be terminated prior to 
achieving maximum effort for predefined symptomatic, clinical, and electrocardiographic 
criteria. Symptom-related reasons for termination include angina, dyspnea, and fatigue. 

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Fatigue is defined as either voluntary exhaustion or inability to maintain a minimum cycling 
cadence of 40 RPM. Clinical criteria for termination include: 1) Hypertension: ≥ 220/120 
mmHg, or 2) Hypotension: a drop in diastolic blood pressure >20 mmHg, and O2 saturation 
<85%. Electrocardiogram criteria include: 1) ≥ 1 mm horizontal or down sloping ST segment 
depression, 2) sustained paroxysmal ventricular tachycardia (>30 beats), and 3) sustained 
paroxysmal supraventricular tachycardia (>30 beats). If the test is terminated because of 
electrocardiographic findings, the subject will be managed medically as needed, referred for 
care, and disapproved for participation. Resting blood pressure and heart rate will be 
obtained prior to initiation of exercise as well as after the subject has been sitting on the 
stationary bicycle for 1 minute. During the exercise test, blood pressure readings will be 
obtained every 3 minutes. Heart rate will be obtained from the 12-lead EKG. Maximal heart 
rate will be recorded as the highest heart rate achieved during the exercise tolerance test. 
Subject monitoring during testing and training: Blood pressure (BP) and heart rate (HR) will 
be monitored prior to, during, and at completion of each session. Subjects’ resting diastolic 
BP must be <100 mmHg, systolic < 200 mmHg, and heart rate <110 beats/min to begin the 
testing. 74 Criteria for termination 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). 
Experimental protocol for walking data collection: At the beginning of the first training 
session of every other week (bi-weekly), subjects will walk on a 10m. long gait mat 
(GaitRite) to measure self-selected and fastest comfortable walking speed and other 
spatiotemporal parameters. Subjects will be permitted a practice trial, and then be asked to 
complete three trials at each speed. For all trials, subjects will wear their own shoes and be 
asked to walk without an assistive device or ankle-foot orthosis. 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. A physical therapist will be present for all testing sessions as needed. 
Post-stroke Optimization of Walking using Explosive Resistance (POWER) training: 
Individuals with chronic post-stroke hemiparesis will undergo training to improve muscle 
power generation for 12 weeks (3 times/week) that includes both resistive and task-specific 
elements. Session duration will be ~60 minutes (inclusive of rest intervals) although the total 
time will depend on the amount of rest needed for a given individual. Training will include 
five distinct resistance activities aimed at improving muscle power-- each previously 
reported to contribute to improved walking (Table 1). Sit to stand and leg press exercises are 
elements of programs shown to be effective in improving strength and walking performance 
in the post- stroke population. 48 Repeated step-up training using a single riser targets both 
eccentric and concentric training in both the sagittal and frontal planes. As possible for 
individual subjects, we will utilize a step height higher than standard community steps (10”) 
to further challenge neuromuscular requirements of the task. Calf raises (i.e. plantar flexion) 
will be performed on a small step so as to allow for adequate range of motion. In addition, 
our pilot data demonstrate that jump training, focused on lower extremity muscle power 
generation, is part of a comprehensive program that improves gait speed in people with post-
stroke gait deficits. Sit to stand, step-up and calf raise activities will be performed within the 
novel overground body-weight support (BWS) environment enabled by the Zero-G (ZeroG, 
Bioness Inc., Valencia, CA), whether receiving support or not, to provide the maximum 
safety possible. 
During the initial training session, subjects will perform the individual component tasks 
beginning with least amount of BWS (or highest load) required for successful completion of 

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the required number of repetitions in order to match the participant’s ability to the difficulty 
of the task. 49 BWS will be progressively reduced to determine the minimum support 
necessary to complete each task. Participants will be progressed within each task by 
decreasing BWS by 5% of body mass (or adding 5% load for leg press) upon successfully 
meeting the goals for progression (see Table 1). An adjustable weighted vest will be utilized 
to increase mass by 5% during training once support is not required for successful task 
completion. Subjects will not be permitted to use assistive devices and physical assistance 
will not be provided during training. 
Sit to stand, leg press, step-up and calf raise activities will be performed under two conditions 
within each training session. Condition 1 will include performing two sets of ten repetitions 
with the targeted amount of resistance for the given session and based on rate of progression 
throughout training. Condition 2 will require the participant to perform as many repetitions 
as possible during a 20 second period utilizing either 80% of the resistance from Condition 
1 or an increase in BWS of 20%. This condition is designed to encourage high velocity and 
hence high-power output contractions. Given our focus on muscle power generation, all 
participants will be instructed to perform the concentric portion of each exercise at maximum 
velocity regardless of the prescribed condition, followed by a controlled eccentric 
contraction. This approach is adapted from programs specifically targeting power training 
in aging populations with mobility deficits and shown to result in significant increases in 
peak power generation when compared to slower velocity training, while achieving similar 
gains in strength. 50,51,52 
For jump training, subjects will be familiarized with the equipment and, during the initial 
training session, will complete a total of 30 (3 sets of 10) bilateral ground contacts (jumps). 
We will begin the first session at a resistance of ~20% of body mass.  Based on individual 
subject ability, external resistance will be increased (or decreased) and resistance 
documented. The number of 
jumps will be increased to 45 in 
week two and to 60 thereafter 
(the goal being to complete the 
prescribed # of jumps in ≤ 3 
sets). 
Upon 
successful 
completion of at least 60 
ground contacts (e.g. complete 
clearance from foot plate; 
Figure 5), resistance will be 
increased in increments of 5 lbs. or 5% body mass, whichever is greatest.   As subjects feel 
comfortable, and no later than week 4, unilateral jump training will be performed using each 
leg, the goal being to progress to a reciprocating jumping pattern (i.e. alternating legs each 
jump for a total of 60 jumps per leg). Throughout the training protocol, a minimum of two 
sessions at a given resistance will be required before load is increased and resistance will be 
held consistent between limbs throughout the training program. Session intensity will be 
systematically progressed and modified by changing either the applied resistance or the 
number of ground contacts. 
Progressive loaded overground fast walking: As part of each training session, subjects will 
perform 10 trials of fast walking (10 meter per trial). These trials are intended to emphasize 
the task-specific lower extremity power generation required to accomplish increased 
walking speeds. Subjects will be asked to complete all trials without an assistive device or 
ankle-foot orthosis at speeds ≥ 125% of self-selected overground velocity. Although we will 
Figure 5: Exercise apparatus used for jump training 

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not allow the use of an AFO, subjects will be permitted to wear an ankle brace for medial-
lateral support (AirCast®) that allows for plantarflexion and dorsiflexion voluntary 
movements. Subjects will walk over our instrumented walkway (GaitRite) so as to provide 
real time feedback of speed as well as spatio- temporal parameters of walking for each trial. 
These trials will also be performed in the ZeroG harness to protect the subject in the case of 
a loss of balance as well as to provide body-weight support as needed to facilitate walking 
at the required speeds. After each session, the average speed will be calculated and compared 
to the self-selected speed. When the average speed exceeds 125% of self-selected speed, we 
will decrease BWS by 5% for the next training session. At the point when subjects are able 
to successfully exceed 125% of self-selected speed without body-weight support, a weighted 
vest will be worn and mass systematically added to allow progression. Note that in order to 
provide the optimal stimulus for increasing propulsion, we will provide an amount of BWS 
to offset to the added mass. This has been shown to engage the muscles most responsible for 
generating propulsion to a greater extent 53 and should optimize the power training stimulus 
for the muscles generating propulsion. 
It is important to point out that progression for muscle power training and overground 
stepping will be accomplished via reduction in BWS (or added mass) as tolerated, allowing 
for increased “resistance” and graded exercise. The overground permissive environment 
allows safe training without assistive devices or and allows determination of the precise 
ability level of the individual for a task. In creating a constant permissive environment, we 
are able to identify precisely how much support is required for independent completion of 
the task while simultaneously eliminating falls risk. This environment allows the participant 
to engage in therapy at a consistently more challenging level than is allowed in conventional 
rehabilitation. This approach is based on a philosophy known as the “challenge point 
framework”, which theorizes that one’s ability level is defined by the level of difficulty at 
which one has an equal (50%) chance of success or failure, 49 a level of difficulty that is 
rarely matched in clinical rehabilitation due to increased potential for falls. 
Attention Control (Stretching): Stretching is being used as an attention control condition 
for POWER training.  Control subjects will participate in a stretching protocol for the same 
duration (i.e. 60 minutes per session) and frequency (3 days per week) for 12 weeks to ensure 
that they have equal interaction with the study staff and controlling for the effects of repeated 
social interaction on depressive symptoms. The stretching program is a modified protocol 
previously implemented in a post-stroke population and designed for individuals 50 years of 
age and older and will include activities targeting upper and lower extremity flexibility. 54 
Specifically, subjects in this group will perform traditional stretching movements targeting 
flexors and extensors of the knees, ankles and hips bilaterally. In addition, low back 
rotations, bridging, prone extensions and hip abduction will also be performed.  Upper 
extremity movements will include shoulder flexion, horizontal flexion/abduction, internal 
and external rotation as well as wrist flexion and extension.  As individual levels of 
flexibility increase, the level of difficulty will be increased accordingly. Heart rate responses 
to the stretching program will be intentionally kept below 40% heart rate reserve. The 
stretching will be overseen by a licensed physical therapist or exercise physiologist and 
consistently monitored throughout the period of training. 
*** To provide the best care possible, those initially randomized to the control group will 
be offered the opportunity to re-enroll into POWER training should they still meet criteria 
for depression at the follow-up time point.  
Dynamometric Assessment: Isometric and isotonic assessments will be performed for knee 
extension and ankle plantar flexion at bi-weekly intervals throughout POWER using a 

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Biodex isokinetic dynamometer (Biodex Corp., Shirley, NY). Prior to testing, each subject 
will go through a period of familiarization and warm-up consisting of 5 minutes of cycling 
and three sub-maximal contractions. During isometric testing, maximum voluntary isometric 
contraction (MVIC) will be defined as the highest torque achieved during 3 maximal 
contractions (~3 sec contractions separated by a minimum of 60 seconds rest). If MVIC 
values during the three trials differ by more than 5%, additional contractions will be 
performed.  During isotonic testing, peak power will be assessed using 40% of MVIC. 
Differences in lower extremity maximal velocity are shown to occur at relatively low 
external forces (e.g. 40% 1 RM) and are most closely associated with gait velocity in older 
individuals. 51 To optimize reliability of the testing, each test will be repeated 3 times. If the 
coefficient of variation among the 3 highest powers is > 10%, additional contractions will 
be performed. Power-angle curves will be plotted and the peak powers recorded. During all 
dynamometric testing, subjects will be instructed to (1) develop torque as fast as possible 
and (2) produce a maximal contraction. Subjects will be given an auditory cue and receive 
continuous visual feedback. All contractions will be performed with subjects positioned in 
the dynamometer and the axis of the dynamometer aligned with the joint axis of rotation. 
Proximal stabilization will be achieved with straps at the chest, hips, and knee as appropriate. 
In order to increase sensitivity, the force transducer signal will be amplified and fed into a 
data acquisition unit (Lab View Inc.) and corrected for the effects of gravity. 
11.0 Specimen Collection and Banking 
 
N/A 
 
12.0 Data Management  
Data Analysis Plan: We will compare the effects of POWER training (vs. control) on HRSD 
scores. We will also determine response (≥50% reduction in symptoms) and remission 
(HRSD < 10) rates following training and at a six-month follow-up. We will utilize repeated 
measures mixed effects models to assess significant changes in outcomes between groups. 
Time and group will serve as dependent variables, as well as their interactions. A random 
intercept term will be included in the model to account for clustering within subjects. Various 
error structures associated with the repeated measures will be considered (e.g. compound 
symmetry vs. auto-regressive). 
We will determine if PSD limits response to treatment by making between group 
comparisons of change (post-pre) in outcomes in depressed vs. non-depressed subjects 
utilizing repeated measures mixed models. Time (seven occasions), group (depressed vs. 
non-depressed) and their interaction will serve as dependent variables.  Three primary 
dependent variables of interest here are, self-selected walking speed (SSWS) and paretic leg 
power generation. A random intercept term will be included in the model to account for 
clustering within subjects. Various error structures associated with the repeated measures 
over time will be considered (e.g. compound symmetry vs. auto-regressive). Analyses 
incorporating differences in outcomes as dependent variables will examine whether changes 
over time are more pronounced in depressed versus non-depressed subjects as well as 
whether changes are more pronounced in depressed subjects with the greatest improvement 
in HRSD. These models will also incorporate random subject effects to account for within-
subject dependence. To determine associations between changes in outcomes, we will look 
at the relationships between outcomes using Pearson or Spearman correlations, depending 
on the distribution of the data. Further, we will use segmented (joint-point) regression to 
estimate if specific thresholds exist that mark in individual subjects where HRSD starts 
improving (decreases) and other outcomes start to improve (increase) to help us understand 

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if there is a critical point of change in HRSD that is important for facilitating functional 
improvements. The purpose of using the segmented regression is to see if HRSD scores 
either plateau or change direction at a given point. The segmented regression model will 
essentially fit two linear models that have different slopes and intercepts but meet at a point 
of time. This will be achieved through inclusion of a dummy variable and its interaction with 
time in the model. The dummy variable will take the value 0 for time points below the 
threshold and 1 above. The threshold, namely the time, at which the model changes direction 
will be assumed unknown. Therefore, this model will be a non-linear regression model. We 
have written a macro in SAS to fit such models. This macro also allows for higher-order 
polynomials. Our intention is to fit random effects models, calling PROC NLMIXED in our 
macro. Other covariates can also be included in this approach. The purpose of the segmented 
regression model is to identify the earliest time at which there is maximum effect. 
All efforts will be taken to minimize dropouts. If dropouts occur, we will attempt to 
determine the reason for dropout. If the dropouts occur at random, the mixed effects model 
can account for the missing data. However, if the dropouts are found to be treatment related, 
they will be treated as non-ignorable missing data and appropriate missing data methods will 
be applied and multiple imputations considered. 
Sample size determination and Statistical Approach: A total of 50 post-stroke subjects 
will be recruited.  For Aim 1, 32 subjects with PSD will participate in either POWER training 
or control intervention (n=16 per group). These analyses will rely on longitudinal measures 
and we assume (based on experience with this intervention) that no more than 15% will fail 
to complete all assessments. This is an extremely conservative approach in that none of the 
subjects in our pilot trial withdrew from treatment.  With 16 subjects enrolled per group and 
a 15% attrition rate over time (resulting in complete data on 13 subjects per group), we would 
have at least 80% power to detect a minimum difference in the change in HRSD from 
baseline to the end of the study of 2.94 (change in pilot data = 6.6) with a s.d. of 5.3 (at 5% 
significance level). Since this is a longitudinal study, we also incorporated an autocorrelation 
(AR(1)) of 0.5 for 10 measurements within individuals. The published studies report 
treatment effect sizes ranging from 0.6 to 0.9, which are more conservative. In our 
preliminary data, we observed an effect size of 1.19 (95% CI 0.98 to 1.36) for improvement 
in depression severity. To detect this effect we will have more than 90% power. For Aim 2, 
with baseline data from n=26 subjects, we will have 80% power to detect a minimum 
difference (pre-post) of 0.13 m/s for SSWS (s.d. = 0.2 m/s) and 17.88 ft/lb for muscle 
strength (s.d=31.9 ft/lb) using a longitudinal approach with an autocorrelation (AR (1)) of 
0.5 for 10 measurements within individuals. In the statistical analysis for both aims, we will 
summarize the longitudinal data using Spaghetti plots. If the spaghetti plots suggest linear 
or quadratic trend we will include these in the model along with appropriate interactions and 
random effects. We will perform appropriate model diagnostics and, if needed, consider 
transformations to achieve normality.  To reduce potential heterogeneity in the data, 
secondary analysis will adjust for covariates such as depression level.  
13.0 Provisions to Monitor the Data to Ensure the Safety of Subjects 
 
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 

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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. 
Adverse events: An adverse event will be defined as any expected or unexpected harmful event 
observed in subjects enrolled in the approved project.  Adverse events do not necessarily have a 
causal relationship with aspects of the treatment or be related to study procedures. A serious adverse 
event is any event that results in death, a life-threatening situation, hospitalization or prolonged 
hospitalization, persistent or significant disability/incapacity or a congenital anomaly/birth defect or 
requires medical intervention to prevent one of the outcomes listed above.  Serious adverse events 
require prompt reporting to the sponsor and the IRB.  Important medical events that may not result 
in death, be life-threatening, or require hospitalization may also be considered serious adverse events 
when, based on appropriate medical judgment of the study physician, they could jeopardize the 
patient and may require medical or surgical intervention to prevent one of the outcomes in this 
definition. The data and safety monitoring plan for this study will include subject monitoring for 
adverse events, review of these events by the study team, study physician and IRB. 
Subject monitoring. At each study visit, subject voluntary reporting of potential adverse events will 
be encouraged and events of interest will elicit specific follow-up to include: falls, orthopedic 
injuries and new or exacerbating pain. During training, safety monitoring will include HR, blood 
pressure, and continuous observation for other signs or symptoms of cardiorespiratory insufficiency, 
worsening neurologic impairments or orthopedic injury.  In addition, any adverse responses to TMS 
will be closely monitored.  Adverse events will be followed until resolution determined by a 
physician according to type, severity and need for treatment.  Any causal relationship with the 
intervention or impact on the study intervention, whether anticipated or not will be specifically 
documented. 
Data Safety & Monitoring Plan: 
Trial Management: The proposed study will be managed through the Department of Health Sciences 
& research at the Medical University of South Carolina (MUSC). All data will be collected and 
tracked using only the assigned study ID of each participant and the cross-walk linking the study ID 
to each participant’s personal identifying data will be kept confidential and locked in a secured 
location.  All study data will be collected by the appropriate individual (research staff, PIs, Co-Is). 
Data will be collected using standardized paper and electronic forms and will be securely transferred 
to the data entry location. Research staff will transcribe any paper data into a REDCap data capture 
system (Research Electronic Data Capture), a secure, web-based application designed exclusively 
to support data capture for research studies. REDCap provides: 1) an intuitive interface for data 
entry (with data validation); 2) audit trails for tracking data manipulation and export procedures; 3) 
automated export procedures for seamless data downloads to common statistical packages 
(SAS/STAT and SPSS); 4) procedures for importing data from external sources; and 5) advanced 
features, such as branching logic and calculated fields. These procedures are effective in minimizing 
data entry errors (e.g., missing or errant data).  
Data Quality Assurance: Validity and data integrity will be checked on an ongoing basis through 
the use of data audits. The study statistician (Ramakrishnan) will supervise quarterly data quality 
assessments (i.e., examination of the outcomes database(s) for missing data, unexpected 
distributions or responses, and outliers) performed by the study research staff. Accuracy and 
completeness of the data collected will be ensured by bi-weekly review. A 10% random sample of 
the primary source document will be cross-checked with the database on a quarterly basis. If 

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inaccuracies exceed 2%, then a second 10% will be randomly chosen for audit. Should data 
discrepancies be discovered, they will be resolved using original source documents. The REDCap 
system does not accept outliers, illogical response patterns, etc. The PI will have bi-weekly meetings 
with the research staff to discuss qualitative comments received during treatments and data 
collection sessions as well as any problems in data collection or entry. The statistician will 
periodically examine the database to look for irregularities. Initial data analyses will examine 
distributions of variable scores and comparability of baseline characteristics across conditions in 
case analyses need to be adjusted for these. 
All serious adverse events will be reported to the MUSC Institutional Review Board (IRB) within 
24 hrs. Follow-up of all serious adverse events will be reported as well. Based on our previous 
studies involving exercise and/or TMS in individuals post-stroke, we anticipate the serious adverse 
event rate to be extremely low.  
Adverse Event Monitoring and Trial Safety: The proposed methodologies are all non-invasive and, 
as such, involve minimal physical risk to participants. However, adverse events will be monitored 
throughout the study and all events will be followed to resolution or stabilization. Adverse events 
will be coded on a weekly basis and the research staff will prepare a summary of all adverse events. 
The PI will review this during weekly study meetings (or before if more urgent). Serious adverse 
events are defined as events, related or unrelated, that require or prolong hospitalization or result in 
congenital defects, death, disability, cancer, overdose, development of drug dependency or abuse, 
or any other life-threatening event. The Institutional Review Board (IRB) of the Medical University 
of South Carolina (MUSC) will be immediately informed of any serious adverse events as soon as 
the PIs, Co-Is, or study staff are made aware of it and a written report will be filed within 72 hours. 
The research staff will be instructed not to reveal whether a person is a participant in the study and 
will report to the PIs any outside requests for information about a participant or any breaches in 
confidentiality. All requests by participants’ physicians and other medical providers will be referred 
directly to the PIs.  
Data Safety & Monitoring and Study Implementation: The PI (Chris Gregory, Ph.D., P.T) will be 
responsible for monitoring the trial. The PI will perform biweekly evaluations of the data safety by 
examining adverse events summary prepared by research staff. Specifically, the PI will work with 
the study statistician and IRB to define acceptable frequency of adverse events and serious adverse 
events. 
 
14.0 Withdrawal of Subjects (if applicable) 
 
Participation in this study is completely voluntary and participants may decide to stop taking part 
in this study at any time. In addition, there may be circumstances where the investigators and/or 
the sponsor may stop your participation in this study at any time if they decide it is in the best 
interest of the participant.  Examples of such circumstances include those that represent a 
perceived health risk to the individual (e.g., chronic elevation in resting blood pressure or 
significant unexplained increase in depressive symptoms). If such a circumstance does occur, 
participants will be notified by the research staff of the decision and recommendations for follow-
up will be provided to the individual.  If the decision if made for a participant to withdraw 
(whether by the individual or the research staff) no further data will be collected.  However, data 
collected to date will still be analyzed using intent-to-treat analyses. 
 
 

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15.0 Risks to Subjects 
A licensed physical therapist will be present 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 several years of experience in the development and 
implementation of exercise interventions. Any adverse events will be recorded and 
monitored as required by the IRB. 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 within prescribed criteria for termination of the 
training session. We will follow the American College of Sports Medicine criteria for 
terminating an inpatient exercise session which includes: subject complaints of light-
headedness, confusion, or dyspnea; onset of angina; excessive blood pressure changes 
(systolic BP greater than 220 mmHg, diastolic BP greater than 110 mmHg); and 
inappropriate bradycardia (drop in heart rate >10 beats per minute). 
At any point during the study, should a participant complete the HRSD and answer questions 
indicating very severe depression (>22) or answer any questions on the HRSD or PHQ-9 
indicating any suicidal ideation, thoughts, or plan, they will be immediately referred for 
clinician evaluation.  This includes those patients whose symptoms may worsen during the 
course of the study.  A licensed psychiatrist (Dr. George or one of his colleagues) will be 
available during all depression assessments if further evaluation is necessary. In the event of 
an incident during treatment or training that a clinician is not immediately available, the 
participant will be escorted to the emergency department for further evaluation. 
 
16.0 Potential Benefits to Subjects or Others 
Subjects who participate in this study may see improvements in their own mood or 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. 
A better and more specific scientific understanding of effects of PSD and its impact on 
rehabilitation may ultimately lead to a better understanding of neuroplasticity and the extent 
to which training restores psychological and locomotor function. Given the minimal risks 
involved and the potential to add to the limited base of scientific knowledge describing this 
population, the potential risks are reasonable 
17.0 Sharing of Results with Subjects 
None of the individual data collected as part of this study will be shared.  However, 
aggregate data generated for the purpose of scientific publication will be made available to 
participants once the final data analyses are completed.   
 
 

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18.0 Drugs or Devices (if applicable)  
 
N/A 
 
 
 

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