Using Transcranial Direct Current Stimulation to Jump Start Gait Training in Chronic Stroke Patients
Phase: NA
Conditions: Stroke, Cerebral Vascular Accident
Sponsor: University of Arkansas

Original 10/29/2012 
Version 10 Revised  11/21/2014 
Study Title: 
Using tDCS to Jump Start Gait Training in Chronic Stroke 
Patients 
 
Principal Investigator:  
Mark Mennemeier, PhD 
Room 1113 Stephens Neuroscience Institute 
University of Arkansas for Medical Sciences 
4301 W. Markham Street, Slot 826 
Little Rock, AR 72205 
Telephone:  501.526.7773 
Email:  MSMennemeier@uams.edu 
 
 
Sub-Investigator(s): 
Chad Lairamore, PT, PhD 
 
201 Donaghey Avenue 
 
University of Central Arkansas  
 
Conway, AR  72035 
Telephone:  501.450.5597 
 
Kevin Garrison, PT, PhD 
201 Donaghey Avenue 
University of Central Arkansas 
Conway, AR  72035 
Telephone:  501.450.5597 
 
Study Physician: 
Timothy Kimbrell, M.D. 
Department of Psychiatry 
University of Arkansas for Medical Sciences 
Little Rock, AR  72205 
Phone:  501 257-3496 
 
Biostatistician: 
David Keith Williams, PhD 
 
University of Arkansas for Medical Sciences  
 
4301 W. Markham 
 
Little Rock, AR 72205 
 
Telephone:  501.526.6721 
Medical Monitor:  
John Dornhoffer, M.D. 
 
 
 
 
University of Arkansas for Medical Sciences  
 
 
 
 
4301 W. Markham 
 
 
 
 
Little Rock, AR 72205 
 
Study locations  
1. University of Arkansas for Medical Sciences  
 
Transcranial Magnetic Stimulation and Human Electrophysiology 
Core Research Facility, Center for Translation Neuroscience,UAMS 
 
 
 
2. University of Central Arkansas  
 
Movement Analysis Laboratory, Department of Physical Therapy, 
UCA 

Title:  Using tDCS to Jump Start  Gait Training and in Chronic Stroke Patients 
PI:  Mark Mennemeier, PhD  
 
Version 10 Revised  11/21/2014 
 
Original   Date:  10/02/2012  
Page 2 
 
Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization to tDCS 
conditions 
Consent, Screen, MRI 
Abbreviations:  tDCS= transcranial direct current stimulation, GA= gait assessments (performed 
at UCA), SIS= Stroke Impact Scale (performed at UCA), TMS=transcranial magnetic stimulation 
(performed at UAMS). MEP= motor evoked potential 
 
GA and SIS-16 assessments will occur at 1 week (± 5 days) and 1 month (± 
10 days) following treatment 
 
 
TMS assessments will occur at 1 week (± 5 days) and 1 month (± 10 days) 
following treatment.  fMRI will be repeated between weeks 5 & 8. 
Sham tDCS 
Anodal tDCS 
20 minutes of 
sham tDCS  
20 minutes of 
tDCS @ 2mA  
Baseline Assessments: (GA, SIS-
16, and TMS) 
 
Gait training 3 times per week for 4 weeks 
GA will be performed weekly during the gait training timeframe 

Title:  Using tDCS to Jump Start  Gait Training and in Chronic Stroke Patients 
PI:  Mark Mennemeier, PhD  
 
Version 10 Revised  11/21/2014 
 
Original   Date:  10/02/2012  
Page 3 
 
Table of Content 
Contents 
Study Schema ................................................................................................................. 2 
Abbreviations ................................................................................................................ 45 
Protocol Summary ......................................................................................................... 56 
Background and Rationale ............................................................................................ 57 
Hypothesis and Specific Aims ..................................................................................... 911 
Study Interventions...................................................................................................... 912 
Study Design and Procedures ................................................................................... 1013 
Study Schedule ......................................................................................................... 1316 
Study Population ....................................................................................................... 1316 
Outcome Measures ................................................................................................... 1518 
Risks ......................................................................................................................... 1620 
Benefits ..................................................................................................................... 2126 
Data Safety and Monitoring ....................................................................................... 2226 
Adverse Events ......................................................................................................... 2226 
Data Handling and Recordkeeping ........................................................................... 2428 
Data Analysis ............................................................................................................ 2428 
Ethical Considerations ............................................................................................... 2530 
Dissemination of Data ............................................................................................... 2731 
References ................................................................................................................ 2731 
 
 
 
 

Title:  Using tDCS to Jump Start  Gait Training and in Chronic Stroke Patients 
PI:  Mark Mennemeier, PhD  
 
Version 10 Revised  11/21/2014 
 
Original   Date:  10/02/2012  
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Abbreviations 
ANOVA=Analysis of Variance 
Botox=botulinum toxin 
CNS=central nervous system 
The control group (C)=the group receiving sham tDCS. 
tDCS = transcranial direct current stimulation  
anodal tDCS = positive charge associated with cortical activation  
cathodal tDCS = negative charge associated with cortical inhibition 
EMG = electromyography  
FAC=Functional ambulation category 
ECT= electroconvulsive therapy 
EEG=Electroencephalography 
EMG=Electromyography 
Hz=Hertz 
The intervention group (I) = the group receiving active tDCS 
IRB=UAMS Institutional Review Board 
LED=Light-emitting diode 
mA = milliamp 
MEP = motor evoked potential 
MEPmax=Motor evoked potential maximum 
MRI=Magnetic Resonance Imaging 
MT=motor threshold 
MVC=maximum volitional contraction 
NICE=UAMS New Investigation Consult and Education 
NINDS=national institute of neurological disorders and stroke 
NIH=National Institutes of Health 
NMES=neuromuscular electrical stimulation 
SIS=Stroke Impact Scale 
TA=tibialis anterior muscle 
TASS=Transcranial Magnetic Stimulation Adult Safety Screen 
TMS = transcranial magnetic stimulation  
rTMS = repetitive tanscranial magnetic stimulation 
ORC=UAMS Office of Regulatory Compliance 
UAMS=University of Arkansas for Medical Sciences 
UCA=University of Central Arkansas  
 
 
 
 
 
  
 
 
 

Title:  Using tDCS to Jump Start  Gait Training and in Chronic Stroke Patients 
PI:  Mark Mennemeier, PhD  
 
Version 10 Revised  11/21/2014 
 
Original   Date:  10/02/2012  
Page 5 
 
Protocol Summary 
Rationale:  Approximately one third of stroke patients with hemiparesis are unable to 
walk without assistance.  Mobility limitations exert a huge physical, financial, and 
emotional burden on stroke survivors.  Costs associated with decreased mobility are 
estimated to be in the tens of billions of dollars. Conversely, regaining mobility greatly 
improves the quality of life of stroke survivors.  Consistent with directives of the National 
Institute of Neurological disorders and Stroke (NINDS), this project uses 
neuromodulation as a treatment to enhance gait recovery in chronic stroke patients.  
Specifically, we will examine whether transcranial direct current stimulation (tDCS) can 
augment the beneficial effects of a gait training program.   
As stroke can reduce a patient’s capacity for increased cortical excitation, we aim to use 
anodal tDCS to increase cortical excitability during gait training.  tDCS is a noninvasive 
neruomodulatory device that passes a low voltage current across the scalp and 
underlying brain tissue and can either increase or decrease cortical excitability 
depending on how it is applied.   
Study:  We will block randomize 88 chronic stroke patients to two treatment arms.  
Persons will be block randomized into anodal and sham tDCS conditions.  Persons in 
the anodal tDCS condition will receive 20 minutes of stimulation and persons in the 
sham condition will receive 20 minutes of sham stimulation.  All patients will receive gait 
training using a body weight supporting treadmill.  In over ground assessments at 
baseline, weekly during gait training sessions, and one week, and one month post 
treatment, we will measure 1) gait velocity and spatiotemporal gait parameters using the 
GAITRite electronic walkway and 2) ankle,knee, and hip angles using  motion analysis 
to gauge changes in the gait pattern.  Cortical excitability will be measured at baseline, 
one week, and one month post treatment using transcranial magnetic stimulation 
(TMS).  Functional MRI will be measured at baseline and after treatment between 
weeks 5-8. Additionally, we will measure change in physical function and social well-
being using the Stroke Impact Scale and we will define patient characteristics that are 
associated with response to treatment.   
Significance:  If successful, this study will augment gait recovery and potentially 
increase the number of patients who benefit from gait training. Our methodological 
innovations will have application to a wide variety of neurological conditions. 
Background and Rationale 
 
Stroke is the leading cause of disability in the United States affecting 13 million people 1, 
2.  Up to two thirds of stroke survivors have significant limitations impairing their ability to 
walk3 including slow gait speed4 and changes in the quality of the gait pattern5. 
Additionally, individuals with a stroke and limited mobility are at high risk for 
susbsequent complications including falls6, fractures7, and a further decline in mobility8. 
In contrast, recovering the ability to walk greatly improves quality of life and can return 
individuals to a previous level of productivity 9-12. Our proposal aims to use tDCS to 

Title:  Using tDCS to Jump Start  Gait Training and in Chronic Stroke Patients 
PI:  Mark Mennemeier, PhD  
 
Version 10 Revised  11/21/2014 
 
Original   Date:  10/02/2012  
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“jump start” the beneficial effect of gait training.  This proposal is responsive to research 
priorities of the NINDS.  
 
An NINDS Stroke Progress Review Group (PRG) first convened in 2001 to prioritize its’ 
unmet scientific needs and research opportunities.  The group reconvened in 2011 to 
issue an updated report (http://www.ninds.nih.gov/find_people/groups/stroke_prg/2012-
stroke-prg-full-report.htm#RR).  In this report, neuromodulation technologies like tDCS 
and TMS, with potential for rapid restoration of lost function, were listed among the main 
advances in recovery and rehabilitation since 2007; citing evidence that CNS 
neuromodulation may promote motor recovery particularly when combined with the 
patient’s attempt to perform an impaired activity.  The three top priorities were studies 
designed to 1) understand and harness clinical brain plasticity, 2) develop measures of 
neuroplasticity in the lesioned brain with relevance to important clinical outcomes, and 
3) assess functional recovery and return to daily activities.  Finally, the report stated that 
translating restorative post-stroke therapies should focus on matching the right patients 
with the right therapies.  Our proposal addresses all of these objectives. 
 
Gait Training.  Improving the ability to walk is one of the primary goals of physical 
therapy treatments for individuals with a stroke, and walking speed can be predictive of 
level of disability.  The ability to walk at speeds greater than 0.8 meters / second is 
predictive of the ability to walk freely in the community, walking at speeds of 0.4 – 0.8 
metets per second is predictive of limited community mobility, while walking at speeds 
of less than 0.4 meters / second is indicative of being able to walk only in the home.13 A 
recent review of gait treatment approaches has demonstrated improvements in gait 
speed when different methods of training are performed; however, not all individauls 
post stroke are able to improve walking ability and gait velocity to a level allowing 
community mobility.14 We aim to enhance the beneficial effects of gait training with 
tDCS. 
 
tDCS is an inexpensive and readily available device 
that can be used to facilitate stroke recovery by 
inducing changes in brain  plasticity 15. In tDCS, a 
constant current stimulator, with surface electrodes, 
provides a steady flow of low voltage, direct current 
(e.g., 0-4 mA) across the scalp and underlying brain 
tissue.  Current shifts the resting membrane potential 
towards hyper or depolarization. The direction of the 
current determines its’ effect on brain excitability 
(figure right).  Anodal tDCS increases, and cathodal 
tDCS decreases the excitability of cortical tissue for 
periods of time that outlast stimulation for about 30 to 
90 minutes. When switched on, the stimulator 
produces a transient tingling sensation under the 

Title:  Using tDCS to Jump Start  Gait Training and in Chronic Stroke Patients 
PI:  Mark Mennemeier, PhD  
 
Version 10 Revised  11/21/2014 
 
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electrode which fades in 30 to 60 seconds.  An advantage of tDCS is that sham 
stimulation can be achieved without detection, simply by turning the stimulator off after 
the initial sensory experience.  Prolonged effects of tDCS are attributed to persistent 
bidirectional modification of post-synaptic connections similar to those described for 
long-term potentiation and long-term depression effects15. Functionally, tDCS can 
improve performance on both sensorimotor and cognitive tasks in normal subjects 16.  In 
stroke patients, a recent meta-analysis of 8 studies on the effects of anodal tDCS has 
shown benefit for upper extremity motor recovery 17.  One study used TMS-evoked 
recruitment curves to measure cortical excitability 18 and found that improved hand 
function correlated with increases in cortical excitability.  Whereas few studies have 
used tDCS to improve lower extremity function in stroke patients 19; one study found 
that anodal tDCS applied to the lesioned hemisphere enhanced voluntary control of the 
paretic ankle 20 and our preliminary study found tDCS-induced improvement in gait 
velocity and physical function in patients with chronic stroke (see preliminary results 
below). 
 
Hypothesized mechanism.  Stroke damages brain tissue and it deafferentiates intact 
tissue in functionally linked regions both within and between hemispheres. Both factors 
alter cortical excitation and inhibition in neural networks that carry out motor functions 21, 
22 and both can reduce a patient’s capacity for increased cortical excitation 15. We 
hypothesize that increasing cortical excitability with anodal tDCS prior to gait training will 
augment recovery. 
 
Preliminary studies conducted by Dr. Mennemeier and the Investigational Team 
Feasibility of obtaining valid TMS evoked recruitment curves for the TA muscle.  In 
attempts to obtain recruitment curves for the TA muscle using a standard TMS coil, this 
study frequently exceeded stimulator output before the curve could become fully 

Title:  Using tDCS to Jump Start  Gait Training and in Chronic Stroke Patients 
PI:  Mark Mennemeier, PhD  
 
Version 10 Revised  11/21/2014 
 
Original   Date:  10/02/2012  
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established (i.e., plateau).  In a series of normal subjects, this study overcame this 
limitation. First, by using a double cone coil which achieves deeper penetration of the 
magnetic field so TMS can be delivered at a lower intensity and, secondly, by having 
subjects make partial, isometric contractions of the TA muscle ipsilateral to stimulation 
(i.e., 20% of the maximum, volitional contraction: MVC).  Contracting the ipsilateral limb 
enhances MEPs recorded from the contralateral limb (representative subject shown in 
Figure A, above).  This method was then tested in normal subjects before, immediately 
following, and one hour after receiving active tDCS (10 minutes @ 1.4mA anodal) or 
sham tDCS delivered over motor cortex. (representative subjects shown in B and C).  
MEP maximums increased after active tDCS for up to 1 hr and the recruitment curves 
became steeper indicating a lower threshold (i.e., an increase in cortical excitability).  
Similar changes were not seen for sham tDCS. During testing of our initial participants 
with stroke we found this technique to work for only one of three individuals.  We will 
thus attempt to establish a motor threshold over the lesioned brain hemisphere for 
placement of tDCS electrodes and to establish participant characteristics for the 
exploratory regression analysis.  Then we will obtain recruitment curves from stroke 
patients’ intact hemishphere – having them contract the non-paretic, ipsilesional TA 
muscle at 20% MVC while a recruitment curve is obtained for the non-paretic, 
ipsilesional TA muscle.  Additionally, we will assess the responsiveness of MEPs from 
the ipsilesional TA muscle after the administration of anodal tDCS to the lesioned cortex 
during our baseline assessments.  
 
Feasibility of using tDCS with treadmill training in chronic stroke. 
In a pilot study investigating pairing locomotor 
training with transcranial direct current 
stimulation in patients with chronic stroke23, our 
research collaborator at the University of 
Kentucky, Dr Sawaki, conducted a double-blind, 
randomized trial of active and sham tDCS (20 
min at 2mA anodal stimulation over motor 
cortex) delivered just prior to locomotor training 
using a robotic gait orthosis treadmill.  Eight 
participants (4 men, mean age=67.8; range=44-
80) with chronic left hemisphere stroke (mean 
years post-stroke=4; range=1.1-11.6) were 
tested.  Performance on a 10-meter walk test 
was the primary outcome measure, and 
assessments of functional ambulation category 
(FAC), timed up and go, balance, and the 16 item Stroke Impact Scale (SIS 16) were 
secondary measures. Improvement on the 10-meter walk test and the SIS 16 following 
active tDCS are shown in the figure - right. Active tDCS lead to greater improvement 
than sham tDCS on the FAC (p=0.028) and similar trends were evident for the SIS 16 
(p=0.062) and the timed up and go test (p=0.066). This study shows that active tDCS 
augments gait training and function.  The data were also used for power calculations.   

Title:  Using tDCS to Jump Start  Gait Training and in Chronic Stroke Patients 
PI:  Mark Mennemeier, PhD  
 
Version 10 Revised  11/21/2014 
 
Original   Date:  10/02/2012  
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Hypothesis and Specific Aims 
Hypothesis:  Increasing cortical excitability with active anodal tDCS prior to gait training 
will augment recover from a stroke. 
Specific Aims: 
 
1. Determine if active tDCS augments gait.   Gait speed is a primary outcome 
measure.  Spatiotemporal and kinematic gait assessment are secondary 
measures of gait.  Over ground laboratory assessments of gait will measure 
1) gait velocity and spatiotemporal gait measures using the GAITRite 
electronic walkway 2) ankle, knee, and hip angles using the SIMI motion 
analysis system.  Changes in gait parameters will be expressed as difference 
scores from baseline.  Difference scores will be compared between the active 
and sham groups to determine if tDCS augments gait parameters. 
2. Determine if active tDCS augments cortical excitability after gait training.  
Cortical excitability will be defined by a cortical recruitment curve, a primary 
outcome measure, derived from plots of motor evoked potentials (MEPs) 
recorded from the ipsilesional TA muscle.  MEPs are elicited by single pulse 
transcranial magnetic stimulation (TMS) delivered at increasing intensity over 
motor cortex.  Changes in the slope of the recruitment curve signal change in 
cortical excitability.  Difference scores from baseline will be compared 
between active and sham groups to determine if tDCS augments cortical 
excitability after FESAGT.  A repeat fMRI will be performed to assess change 
in cortical excitability after gait training. 
 
3. Determine if active tDCS augments physical function and social wellbeing.  
The Stroke Impact Scale-16 (SIS-16), a primary outcome measure, will be 
used to assess ADL/IADL, mobility, and social and occupational engagement 
at baseline and post treatment assessments.  Difference scores from baseline 
will be compared between active and sham groups to determine if tDCS 
augments physical function and social well-being. 
Exploratory Aim 
Identify patient characteristics that predict response to treatment. Patients will 
be classified empirically based on their response to treatments.  Regression 
analyses will examine whether and how initial impairment, functional level, 
and cortical excitability predict a treatment response.   
Study Interventions 
 
tDCS and gait training will be conducted at UCA three times a week for 4 consecutive 
weeks 
 

Title:  Using tDCS to Jump Start  Gait Training and in Chronic Stroke Patients 
PI:  Mark Mennemeier, PhD  
 
Version 10 Revised  11/21/2014 
 
Original   Date:  10/02/2012  
Page 10 
 
tDCS.  tDCS will be applied using a Soterix constant current stimulator with 5 x 5 cm 
(25cm2) carbon rubber electrodes (Covidien 664 REFX 2x2) applied to the scalp with 
10-20 conductive paste. The anodal electrode will be placed over the lower extremity 
representation of primary motor cortex of the lesioned hemisphere [established during 
TMS motor threshold testing (Baseline Testing) and the functional MRI assessment].   
The cathodal electrode will be placed over the contralateral motor cortex.  During 
anodal tDCS, participants will receive 20 min at 2mA over motor cortex (with 30 
seconds of ramp-up and ramp-down).  The highest current density for the electrodes is 
.08 (mA/cm2) and and the total charge per session is 2.4 C. These values are well 
below the safety margins outlined in Nitsche 24.  During sham tDCS, current will be 
ramped-down and turned off after 30 seconds 25. Both active and sham tDCS will be 
administered during the gait training protocol. 
 
 
 
Gait Training.  Dr. Lairamore will supervise the gait training sessions.  The gait training 
protocol is a modified version of the LEAPS protocol26 where participants will be 
progressed from gait training phase 1 to a higher intensity of training in phase 2.  All gait 
training will be performed on a treadmill and participants will wear a safety harness.  
Unlike the LEAPS protocol, participants in this study will not have a percentage of their 
body weight supported with the harness during gait training sessions.    
Study Design and Procedures 
 
Recruitment: 
 
Stroke subjects will be recruited via advertisement and from participants in past stroke 
studies who indicated a willingness to be contacted for additional studies.  We will 
recruit participants > 3 months post unilateral, stroke to minimize confounding effects of 
spontaneous recovery. Subjects who participated in previous versions of the study will 
be re-contacted if they indicated they were willing to be contacted for additional studies.  
Table 1.  Gait training protocol. 
 
Phase 
Sessions 
Gait training 
priorities 
Treadmill Speed 
Intensity 
Manual Assistance 
Phase 1  
(1-6) 
 
Independence 
at the paretic 
leg  
 
   speed 
 
0.8 mph minimum 
(goal of 1.4 mph) 
Four 5 minute 
sessions 
 
As needed at trunk, 
paretic and non-paretic 
legs. 
 
    Assist to paretic leg. 
Phase 2 
(7-12) 
 
Independence 
at the paretic 
leg  
 
   speed 
 
1.0 mph minimum 
(goal of >1.8 mph) 
1b:      session 
duration and 
   number of 
sessions as 
tolerated 
 
 
Assist first to paretic 
leg, then to trunk/pelvis 

Title:  Using tDCS to Jump Start  Gait Training and in Chronic Stroke Patients 
PI:  Mark Mennemeier, PhD  
 
Version 10 Revised  11/21/2014 
 
Original   Date:  10/02/2012  
Page 11 
 
If they are willing to participate in the revised study they will be re-consented and re-
enrolled under the new protocol. 
 
Screening Procedures 
All screening procedure will be conducted at either UAMS or UCA  
 
For women of childbearing years a free pregnancy testing (urine dip stick test) will be 
required. 
 
Administration of NIH Stroke Scale: administered and scored by study personnel who 
interview the participant.  Severe language communication difficulties would preclude 
participation. 
 
Administration of mofied Rankin Scale: administered and scored by study personnel 
who interview the participant. 
 
Administration of TMS Adult Safety Screening (TASS, determine study eligibility): by 
study personnel. 
 
Medical records will be reviewed to evaluate participant’s study acceptability and to 
obtain clinical studies including neuroradiological imaging studies. 
 
MRI procedures 
 
Prior to the MRI scan, subjects may have a training session in the MRI simulator to help 
habituate and train them to the MRI environment.  Per the MRI Policies and Procedures, 
the decision of who will be acclimated in the MRI Simulator will be made by the 
Research Coordinators and PI on a case-by-case basis.  The PI for the study will have 
final say in this decision.  Before the MRI scan, participants will be given an explanation 
of the study’s procedures and screened with the MRI Safety Form for metal objects and 
claustrophobia.  Participants will also be screened with the SAFESCAN® ferromagnetic 
detector according to MRI Policy and Procedures. The participant will then lie supine in 
the scanner. Participants will wear noise-cancelling headphones for communication and 
view visual stimuli through a mirror attached to the imaging head coil. Participants will 
undergo an anatomic scan to facilitate alignment of electrodes. Participants will also 
have a resting state scan in which they will be told to simply let their mind wander while 
they lay still in the scanner. Participants will also complete a scan measuring TA 
contraction. Subjects will be asked to contract the TA muscle in their right and left legs 
periodically depending on stimuli presented to them. Participants will have an identical 
repeat fMRI scan after completing the gait training protocol.  Total scan time will be 
approximately 20-30 minutes per scan.  
 
Randomization Procedures 
After consenting, screening, and obtaining an MRI, participants will be block 

Title:  Using tDCS to Jump Start  Gait Training and in Chronic Stroke Patients 
PI:  Mark Mennemeier, PhD  
 
Version 10 Revised  11/21/2014 
 
Original   Date:  10/02/2012  
Page 12 
 
randomized into groups (20 minute tDCS group + gait training or sham tDCS + gait 
training).   
 
Baseline Procedures 
The TMS motor threshold (MT) will be established 27 and the best location for eliciting 
MEPs from the contralesional TA muscle will be tracked on the subject’s CT or MRI 
scan,  or on a template MRI scan if clinical studies are not available, using Brainsight.  
Gait assessment (details provided in Outcome Measures) and the Stroke Impact 
Scale-16 will be performed for all participants at UCA.  Motor evoked potentials and 
Recruitment curves (developed by the TMS procedure) will be performed at UAMS.  
  
Intervention Procedures (Study Weeks 1 through 4) 
Study interventions will be conducted 3 times a week for 4 continuous weeks.  tDCS, 
and gait training will be performed at Movement Analysis Laboratory, Department of 
Physical Therapy, UCA as described above (Study Interventions).   
 
Post-Intervention Procedures (Study Weeks 5(± 5 days) and 8 (± 10 days) : 
During Study Weeks 1-5, and 8 Gait assessment (details provided in Outcome 
Measures) and the Stroke impact Scale 16 will be performed at UCA.  During Study 
Weeks 5 and 8 TMS will be performed at UAMS and participants will complete a repeat 
fMRI scan.  Details of TMS procedure used to establish recruitment curves are located 
in the Outcome Measures. 
 
Reduction of Study Bias: 
Dr. Lairamore will supervise delivery of interventions, and so, he will not be blinded to 
tDCS condition; however, Drs. Mennemeier and Garrison who collect and analyze data 
will be blinded to condition.   
 
Study Locations: 
tDCS, gait training,SIS-16, and the assessments of gait will take place in the Motion 
Analysis Laboratory at UCA; motor evoked potentials and recruitment curves developed 
from TMS are measured in the TMS and Human Electrophysiology core facilities at 
UAMS. Subject burden is reduced by requiring only four trips to UAMS over two - three 
months.  (Subjects are informed that scheduling conflicts could result in an extra visit.) 
UAMS will be the IRB of record and Sponsor of the IDE. 
 
 

Title:  Using tDCS to Jump Start  Gait Training and in Chronic Stroke Patients 
PI:  Mark Mennemeier, PhD  
 
Version 10 Revised  11/21/2014 
 
Original   Date:  10/02/2012  
Page 13 
 
Study Schedule 
 
 
Screening 
Baseline 
Study  
Weeks 1 -4 b 
Study 
Week 5 
Study 
Week 8 
Consent 
X 
 
 
 
 
Screening 
X 
 
 
 
 
NIH Stroke Scale 
X 
 
 
 
 
Modified Rankin Scale 
X 
 
 
 
 
TASS 
X 
 
 
 
 
Medical Record 
Review 
X 
 
 
 
 
MRI 
X 
 
 
X 
 
Pregnancy 
Assessment 
X 
 
 
 
 
Randomization 
X 
 
 
 
 
Assessments 
 
 
 
 
 
Gait assessments 
 
X 
X 
X 
X 
RC & SIS 
 
X 
 
X 
X 
Interventions 
 
 
 
 
 
tDCS 
 
 
X 
 
 
Sham tDCS 
 
 
X 
 
 
Gait training 
 
 
X 
 
 
Definitions: TASS= Transcranial Magnetic Stimulation Adult Safety Screen, MRI=magnetic resonance 
imaging, RC & SIS-16=recruitment curve established using transcranial magnetic stimulation (TMS) and 
Stroke Impact Scale . bThree times a week for four weeks participants will receive active or sham tDCS 
and gait training interventions at UCA for a total of 12 treatment periods. 
Study Population 
Up to 100 stroke patients will be enrolled to obtain 88 who meet entry criteria and 
complete study procedures (i.e., 44 participants in each of the active or sham tDCS 
groups).   Attrition, estimated at about 15%, will be handled by replacement. 
Participants will be ≥21 years old to better represent the general stroke population. All 
participants will complete the NIH Stroke Scale, have evidence of gait impairment, and 
will be able to fully and safely participate in treatment. 
Inclusion Criteria 
 
Stroke survivors > 3 months from most recent unilateral, stroke based on 
clinically or experimentally obtained MRI brain scans and behavioral evidence of 
stroke (e.g., risk factors, hemiplegia, unilateral sensory impairment, or localized 
higher cortical dysfunction) by report or in the medical record. 
 
Age: >21 years of age. 
 
Complete NIH Stroke Scale. 
 
Assements performed at screening include the following: 
o Sufficient endurance, motor ability and balance to ambulate at least 10 

Title:  Using tDCS to Jump Start  Gait Training and in Chronic Stroke Patients 
PI:  Mark Mennemeier, PhD  
 
Version 10 Revised  11/21/2014 
 
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meters continuously with moderate or less assistance. 
o Demonstrate a gait impairment during ambulation such as gait instability 
or inefficient gait pattern  
 
Pass the Transcranial Magnetic Stimulation Adult Safety Screen (TASS) except 
for items related specifically to stroke and the treatment for stroke,  i.e., 
neurologic injury, having a seizure related to stroke, or having a crainiotomy for 
treatment related to stroke such as to relieve intracranial pressure. 
Exclusion Criteria 
 History of potentially fatal cardiac arrhythmias, such as ventricular tachycardia, 
supraventricular tachycardia, and rapid ventricular response atrial fibrillation with 
hemodynamic instability. 
 Demand pacemakers or any other implanted electronic systems. 
 Pregnant women, uncontrolled seizure disorder, Parkinson's Disease, Spinal 
cord injury, Traumatic brain injury with evidence of motor weakness, Multiple 
sclerosis. 
 Documented episode in the medical record of a seizure occurring 1 month or 
more post stroke for which the patient received consultation or treatment for said 
seizure.  Seizures occurring with in the first month following a stroke are not 
exclusionary unless followed by another seizure.  
 Fixed ankle plantar flexor contracture, peroneal nerve injury at the fibular head as 
the cause of foot-drop. 
 History of dementia, severely impaired cognition, communication or 
comprehension deficits. 
 Presence of severe or frequent headaches 
 History of Botulinum toxin (Botox) injection to either of the lower extremities 
within the 3 month period preceding study entry. 
 
Have other medical conditions or are taking medications that compromise 
ambulation or balance. 
 Failure to meet established screening criteria for TMS or tDCS (i.e., TASS - 
except as noted under inclusion criteria) 
 Principal Investigator’s or Medical Monitor’s discretion not to include a participant 
 
Additional Exclusion Criteria for MRI Scan 
 Claustrophobia, or the inability to lie still in a confined space  
 Major medical disorders (e.g., HIV, cancer) 
 Medications which may affect image quality (e.g., water pills)  
 Magnetic metallic implants (such as screws, pins, shrapnel remnants, aneurysm 
clips, artificial heart valves, inner ear (cochlear) implants, artificial joints, and 

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vascular stents), as these may heat, pull, or twist in the strong magnetic field of 
the MRI scanner  
 Non-removable dental implants, such as braces or permanent retainers, as these 
will distort the MRI images we collect (note: filings, crowns, and silver or gold 
teeth are OK)  
 Permanent makeup or tattoos with metallic dyes  
 A positive pregnancy test (for females), since the effect of strong magnetic fields 
on the developing fetus remains unknown and inconclusive. (We will conduct a 
pregnancy test for all female participants on the day of the MRI scan.)  
 Psychotic disorders (e.g.,  schizophrenia) 
 Any other condition that the investigator believes might put the participant at risk 
 
Outcome Measures 
 
Study Aim 1:  Gait analysis (Dr. Garrison).  Over ground laboratory assessments of gait: 
1) Gait velocity and spatiotemporal gait parameters will be measured with the GAITRite 
system (CIR Systems, Inc., Havertown, PA) 28-35.    2) Hip, ankle, and knee angles 
during gait will be measured using the  Simi Aktisys gait analysis system (Simi Reality 
Motion Systems; Postfach, Unterschleissheim Germany). LED markers are placed on 
the participant’s lower extremity.  Ankle, knee, and hip angle data is obtained 
simultaneously to evaluate motor strategies for overcoming gait impairments. Both 
types of data will be collected simultaneously as participants walk 10 meters across the 
GAITRite walkway at a self-selected speed for 5 repetitions.   
 
Study Aim 2:  Recruitment curves.  A Magstim 200 super rapid2 stimulator with a 110 
mm double cone coil will deliver stimulation.  First, the TMS motor threshold (MT) will be 
established 27 and the best location for eliciting MEPs from the contralesional and 
ipsilesional TA muscle will be tracked on the subject’s MRI scan in Brainsight.  EMG will 
be recorded from the TA muscles of both limbs.  The MT will be determined by placing 
the TMS coil over the cortical motor area and delivering single pulses of increasing 
intensity until the optimal area of stimulation is found.  Threshold will be defined as the 
percentage of the maximum stimulator output necessary to elicit a motor evoked 
potential (MEP) of 50 volts recorded from the tibialis anterior muscle of the 
contralateral leg in 3 of 6 stimulus trials. Motor thresholds for both the lesioned and non-
lesioned brain hemispheres will be recorded.   
 
Second, recruitment curves will be obtained as follows:  1) delivering ten, single TMS 
pulses beginning at 70% of MT, 2) increasing TMS intensity by 10% and repeating the 
process up to 160% of the MT or until a plateau in the recruitment curve is reached, 3) 
offline data processing will be performed with the Matlab curve fitting toolbox and 4) the 

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threshold, slope, and MEPmax, and the goodness of fit (R2) will be calculated.  A 
change in the slope of the recruitment curve will indicate change in cortical excitability. 
   
Study Aim 3:  Functional and social assessments.  The Stroke Impact Scale-16 (SIS-16, 
completed by study team) is a standardized instrument 36-38 that assesses 3 functional 
domains in stroke patients including ADL / IADL, mobility, and social and occupational 
engagement. 
Compensation 
Participants will be remunerated  $200 for completing the entire study protocol.  They 
will be remunerated $75 dollars for partial completion.  
Risks  
 
A potential risk for study participation is the potential loss of confidentiality.  Measures to 
protect the confidentiality of study participants will implemented as described in the Data 
Handling and Recordkeeping section below. 
 
Device Risks: 
Potential risks associated with tDCS include the following: 
 A weak electrical current is applied to the brain via the scalp during tDCS using 
two surface electrodes. Current evidence shows that tDCS applied to motor and 
non-motor areas according to the present tDCS safety guidelines produces only 
minor adverse effects in healthy humans and patients with varying neurological 
disorders.  One published safety study of tDCS, using stimulation parameters 
similar to this study, evaluated 103 subjects 25, and found no adverse effects on 
cognitive and psychomotor measures, nor EEG changes during or after 20 min of 
treatment. In a double-blind, sham-controlled study 39 it has been shown that 
comparing tDCS and sham stimulation of the motor cortex elicited minimal 
discomfort and difference in the duration of tingling sensations. Another study 
summarized adverse effects of 567 tDCS sessions over motor and non-motor 
cortical areas (occipital, temporal, parietal) in 102 subjects who participated in 
tDCS studies 40.  
 active tDCS intervention causes a sensation of mild tingling and itching 
under the electrodes that lasts for 10 to 30 seconds.  Less frequently, a 
burning sensation or a burn is reported.  Headache, visual sensations, 
difficulty concentrating, nervousness or overexcitability during procedure, 
unpleasant sensations, dizziness, fatigue, insomnia, and nausea are 
infrequently reported after tDCS.  Because 10-20 conductive paste is 

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added to the electrodes to deliver tDCS, subjects will get paste in their 
hair. 
 Risk will be minimized by the following steps: 
o First subjects are fully informed of all risks during the informed 
consent process.   
o For tDCS we use stimulation parameters that are well below the 
maximum levels that are considered safe.  We will ensure there is 
no skin breakdown or lesions in the vicinity of electrode placement.  
The electrodes have connectors on their back to eliminate the 
possibility of contact with scalp which could cause a burn.  We 
monitor electrode impedances during stimulation to ensure good 
conductance of current to scalp. 
o For TMS, we use stimulation procedures that fall within the 
guidelines recommended at the conclusion of the NIH Panel on 
TMS (see Wasserman 41). Patients will be fully informed of the 
possibility of seizure, the plan for care in event of a seizure, and 
any foreseeable financial or medical consequences resulting from a 
seizure. 
o All subjects will wear ear plugs during testing sessions.  TMS will 
be stopped if an ear plug falls out during a session. 
o A study physician trained in rescue procedures, will be on call when 
a subject is receiving single pulse TMS in this study.  The study 
physician will be called by study personnel in the event of muscle 
contractions persisting after TMS (possible seizure) or complaints 
of dizziness, nausea, shortness or loss of breath, or loss of 
consciousness (possible syncope).  Study personnel will note body 
parts that might be affected (e.g., the left arm or leg after right 
hemisphere stimulation) and/or other symptoms that might occur 
and report them to the study physician.  [Should these be observed, 
the session will be terminated, and the subject will not be tested 
again].   
o If a subject were to have a seizure or syncopal episode during or 
immediately following TMS, the following precautions will be 
performed by study personnel: 
o The stimulator will be stopped and the coil will be removed from the 
subject's head. 
o The subject will be supported to physically guard against injury. 
o The subject will be placed on his/her side on a flat surface away 
from sharp edges. 
o The study physician will be called. 
o Emergency services will be called by study personnel to transport 
the subject to the emergency room if so directed by the study 

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physician. 
o Emergency services will be called if the study physician cannot be 
reached.  
o Either the study physician or the PI or subinvestigators will 
accompany the subject to the ER and explain the recommended 
post-event assessment which is as follows:   
o It is recommended that after the seizure is over, the subject will be 
examined thoroughly for injuries and a complete neurological exam 
will be completed.  Routine studies, including calcium, magnesium, 
and prolactin, will be completed and urine will be sent for a drug 
screen.  An MRI scan of the head will be performed to rule out 
underlying epileptogenic pathology.  An EEG will be performed with 
hyperventilation and anterior temporal leads.  The subject will be 
advised that following a seizure provoked by TMS, the likelihood of 
further spontaneous seizures is not significantly increased unless 
other pathology is discovered.  The subject will be scheduled for a 
neurology consultation. The subject will not be allowed to drive 
himself/herself home.  Transportation would be arranged for the 
subject. 
o The PIs and study physician would provide documentation that the 
seizure happened during a TMS session, that it does not constitute 
epilepsy, and that seizures caused by TMS have not resulted in 
future seizures. Seizures induced during electroconvulsive therapy 
(ECT) for depression, for example, do not cause driving privileges 
to be revoked in the state of Arkansas.  Like ECT, a seizure 
occurring after TMS would not cause driving privileges to be 
revoked.  
Potential risks concerning MRI scan: One potential safety concern is participant internal 
metal during MRI scanning, which can be painful and dangerous. Screening procedures 
administered prior to the scan will be used to rule out any participants who may 
potentially be at risk for harm as a result of internal metal objects. Another potential risk 
involved with imaging procedure is claustrophobia. Participants are able to quit the scan 
at any time by indicating to the technician that they wish to do so. 
 
Other risks: 
Potential risks associated with TMS must be considered in light of the duration and 
frequency of stimulation 41. Most of the risks which are listed below have been 
associated with repetitive TMS subjects in this study ARE NOT RECEIVING 
REPETITIVE TMS.  Rather, subjects in this study are receiving single pulses of TMS. 
Single pulses delivered in the fashion described above involve significantly less risk and 
discomfort than repetitive TMS (rTMS) where 100s to 1000s of pulses are delivered in 
succession.  Adverse events rarely associated with single pulse TMS would include the 
following:  1) Vasodepressor (neurocardiogenic) syncope is a common reaction to 

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anxiety and psycho-physical discomfort.  Syncope may occur more often than seizure 
during TMS testing and treatment and suspected seizure associated with TMS might 
actually be syncopal episodes rather than seizure 27  2) Animals have shown permanent 
increases of the auditory threshold after high intensity single-pulse TMS 42 and humans 
have shown transient increases.  Subjects wear earplugs to protect hearing during 
TMS.  3) Human subjects have rarely experienced seizure following single pulses of 
TMS 27.  In two cases, they were not healthy, normal subjects.  In one case, the seizure 
may have been associated with brain lesions due to multiple sclerosis and with the use 
of olanzapine.  In the second case, seizure was associated with the use of 
chlorpromazine and lithium and a family history of epilepsy.  As mentioned above, a 
seizure or syncopal episode occurred during single pulse TMS in one normal subject 
who did not have identifiable risk factors for seizure or syncope 43.  A study physician 
experienced in TMS will be on call in case of an adverse event.  A thorough plan is in 
place to contact emergency services if necessary and to follow up if a subject went to 
emergency services.  Subjects are fully informed of risks during the informed consent 
process. 
Risk factors that pertain to TMS studies (but have greater relevance to rTMS than single 
pulse TMS) are listed below. These risk factors are assessed via the TMS adult safety 
screen and the exclusion/inclusion criteria for this study. 
 Likely: Subjects may feel anxious about participation.  Subjects may 
experience minor discomfort associated with scalp muscle twitching. 
 Less likely: Head pain related to stimulation of underlying muscle and 
nerves occurs in approximately 10% of subjects. The incidence and 
severity is a function of stimulus site and intensity.  The symptoms are 
typically limited to the time of stimulation and can be treated with minor 
over-the-counter analgesics if necessary. 
 Rare:  The following have rarely been identified with TMS: 
o Syncope (as described above). 
o Seizure induction represents the most serious known risk of rTMS 
41. Seizures have been reported more frequently in subjects with 
brain lesions (e.g., stroke) but have rarely been reported in subjects 
with no history of seizures or neurologic disease. 
o Single pulse TMS has been associated with seizure in two persons 
who had risk factors for seizure such as taking medications that 
lower the seizure threshold and having a relative with epilepsy. One 
normal subject who did not have risk factors for seizure and who 
was not taking medication either had a seizure or a syncopal 
episode during a single pulse TMS study27, 43. 
o A seizure caused by rTMS could place subjects at financial risk 
secondary to cost of medical care.  Having a seizure might also 
influence driving privileges, employment, and the ability to obtain 

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insurance.  Subjects are informed of these risks in the consent 
process. 
o Effects on Cognition: Few adverse effects of rTMS on cognition 
have been reported 44 and there is a trend for performance to be 
better on measures such as delayed story recall.  Using rTMS, two 
studies, reported possible adverse effects lasting up to one hour. 
Greenberg et al. (cited in Wasserman 41) reported that task 
switching was impaired after 20-Hz stimulation of the right 
compared to the left dorsolateral frontal lobe 45.  Flitman et al 46 
reported a significant decrease in logical memory one hour after 
testing after extensive stimulation using parameters that exceed 
guidelines for inter-train interval (150 trains of rTMS at 15 Hz, 750 
msec duration, and 1.2 times the MEP). 
o Effects on Mood: Dysphoria with crying has been induced after left 
prefrontal stimulation 47. In contrast, high-frequency stimulation of 
the right prefrontal cortex may transiently improve mood as rapid-
rate rTMS has been shown to be a safe and effective treatment in 
patients with depression. 
o Effects on Hearing: Foam earplugs were effective in avoiding 
changes in the auditory threshold in a safety study of TMS 44.   
 
Protection Against Risks:  Repetitive Transcranial Magnetic Stimulation 
Transcranial magnetic stimulation will be delivered by fully trained study personnel.  
The following steps will be taken to minimize the risks discussed above. Additionally, 
subject exclusion criteria should eliminate subjects for whom risk is greater. 
1. First subjects are fully informed of all risks during the informed consent 
process.  We use stimulation procedures that fall within the guidelines 
recommended at the conclusion of the NIH Panel on TMS (see Wasserman 41). 
Patients will be fully informed of the possibility of seizure, the plan for care in 
event of a seizure, and any foreseeable financial or medical consequences 
resulting from a seizure. 
2. All subjects will wear ear plugs during testing sessions.  TMS will be stopped if 
an ear plug falls out during a session. 
3. A study physician trained in rescue procedures, will be on call when a subject is 
receiving single pulse TMS in this study.  The study physician will be called by 
study personnel in the event of muscle contractions persisting after TMS 
(possible seizure) or complaints of dizziness, nausea, shortness or loss of 
breath, or loss of consciousness (possible syncope).  Study personnel will note 
body parts that might be affected (e.g., the left arm or leg after right hemisphere 
stimulation) and/or other symptoms that might occur and report them to the 

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study physician.  [Should these be observed, the session will be terminated, 
and the subject will not be tested again].   
4. If a subject were to have a seizure or syncopal episode during or immediately 
following TMS, the following precautions will be performed by study personnel: 
a. The stimulator will be stopped and the coil will be removed from the 
subject's head. 
b. The subject will be supported to physically guard against injury. 
c. The subject will be placed on his/her side on a flat surface away from 
sharp edges. 
d. The study physician will be called. 
e. Emergency services will be called by study personnel to transport the 
subject to the emergency room if so directed by the study physician. 
f. Emergency services will be called if the study physician cannot be 
reached.  
g. Either the study physician or the PI or subinvestigators will accompany 
the subject to the ER and explain the recommended post-event 
assessment which is as follows:   
   
It is recommended that after the seizure is over, the subject will be examined thoroughly 
for injuries and a complete neurological exam will be completed.  Routine studies, 
including calcium, magnesium, and prolactin, will be completed and urine will be sent for 
a drug screen.  An MRI scan of the head will be performed to rule out underlying 
epileptogenic pathology.  An EEG will be performed with hyperventilation and anterior 
temporal leads.  The subject will be advised that following a seizure provoked by TMS, 
the likelihood of further spontaneous seizures is not significantly increased unless other 
pathology is discovered.  The subject will be scheduled for a neurology consultation. 
The subject will not be allowed to drive himself/herself home.  Transportation would be 
arranged for the subject. 
The PIs and study physician would provide documentation that the seizure happened 
during a TMS session, that it does not constitute epilepsy, and that seizures caused by 
TMS have not resulted in future seizures. Seizures induced during electroconvulsive 
therapy (ECT) for depression, for example, do not cause driving privileges to be 
revoked in the state of Arkansas.  Like ECT, a seizure occurring after TMS would not 
cause driving privileges to be revoked. 
Benefits  
Potential benefits to subjects participating in the study include the following:  
 The potential benefits to participants include personal satisfaction knowing 

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they have helped further research that could benefit patients with stroke 
and education about research studies. 
 Further stroke patients could benefit from the treatment intervention in 
terms of increase ambulation and social well-being. 
 Participants are not guaranteed a benefit from this study. 
Data Safety and Monitoring 
 
Data safety and monitoring will be performed in two ways.  First, independent study 
monitoring will be performed by the Research Support Center at UAMS after the first 1-
2 participants are enrolled.  Thereafter, independent study monitoring will be performed 
by the Research Support Center at UAMS.  Monitoring would occur according to the 
RSC monitoring plan.  The Data and Safety Monitoring Plan describes operating 
procedures that will be in place to monitor compliance, study data validity and integrity, 
participant safety, individuals and/or entities (e.g., IRB) that will be involved in 
monitoring these procedures, and the frequency/regularity of this monitoring. 
Adverse Events  
 
Eliciting and Reporting Adverse Events: 
Subjects will be monitored for the occurrence of adverse events throughout the study 
procedures.   
 
Adverse Events Reporting and Evaluation:  
All adverse events occurring during the course of the clinical study, whether device- 
related or otherwise, will be recorded on the Adverse Event CRF. For all adverse 
events, the study physician will provide an assessment of the adverse event, its 
treatment and resolution, and its relationship to the investigational device. All adverse 
events will be reported to the Sponsor and/or IRB in accordance with applicable 
institutional and federal regulatory guidelines. 
 
Identification of Adverse Events: 
An adverse event is defined as any new medical problem, or exacerbation of an existing 
problem, experienced by a subject while enrolled in the study, whether or not it is 
considered device-related.  
 
Relationship of Adverse Events to the Study Device: 
The study physician will assess the relationship of the adverse event to the 
investigational device. The relationship will be assessed using the following categories: 
 Definitely Related: A direct cause and effect relationship between the 
investigational device and the adverse event exists. 

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 Possibly Related: A direct cause and effect relationship between the 
investigational device and the adverse event has not been clearly demonstrated, 
but is likely or very likely. 
 Unlikely Related: A direct cause and effect relationship between the 
investigational device and the adverse event is improbable, but not impossible. 
 Unrelated: The adverse event is definitely not associated with the investigational 
device. 
 
Unanticipated Adverse Device Effects: 
An unanticipated adverse device effect is defined as “any serious adverse effect on 
health or safety, or any life-threatening problem, or death caused by, or associated with, 
a device; if that effect, problem, or death was not previously identified in nature, 
severity, or degree of incidence in the investigational plan, or application (including 
supplementary application), or any other unanticipated serious problem associated with 
a device that relates to the rights, safety, or welfare of subjects.” 
 
In the event unanticipated adverse effect occurs, the investigator will report the event(s) 
according to federal and institutional  policies.  
 
Serious Adverse Events: 
Each adverse event will be assessed for its seriousness using the criteria outlined 
below. The term serious adverse event is not synonymous with a “severe” adverse 
event, which may be used to describe the intensity of an event experienced by the 
subject. An adverse event will be classified as serious if it meets any of the following 
criteria: 
 Results in, or contributes to, a death 
 Life-threatening (i.e., the subject was, in the opinion of the investigator, at risk 
of death at the time of the event, but it does not include an event that, had it 
occurred in a more severe form, might have caused death) 
 Results in permanent disability or incapacity (i.e., permanent impairment of a 
body function or permanent damage to a body structure) 
 Requires in-subject hospitalization or prolongs hospitalization 
 Necessitates medical or surgical intervention to preclude a permanent 
disability or incapacity  
 Results in a congenital anomaly or birth defect 
Non-serious adverse events are all events that do not meet the criteria for a “serious” 
adverse event. 
 
Severity: 
Each adverse event will be assessed for its severity, or the intensity of an event 
experienced by the subject, using the following. 
 Mild: Discomfort noticed, but no disruption to daily activity. 
 Moderate: Discomfort sufficient to reduce or affect normal daily activity. 
 Severe: Inability to work or perform normal daily activity. 
 

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Anticipated Adverse Events and Pre-existing conditions: 
 
Pre-existing conditions will not be reported as an adverse event unless there has been 
a substantial increase in the severity or frequency of the problem which has not been 
attributed to natural history. 
Data Handling and Recordkeeping 
Each subject’s name, birth date, address and phone number will be obtained for 
purposes of follow-up.  We will ask for each subject’s drug use history, medical history, 
and current drug use. Experimental data and questionnaire data will be collected.  This 
information will be coded into the Microsoft Excel.  Each subject’s personal information 
will be de-identified in the database by using codes comprising the subject number and 
date and time the subject was tested.  The PIs and study personnel at UAMS and UCA 
will have access to subject identities in order to arrange follow-up and to call them as 
part of the research project, such as follow-up contact. If subjects prefer e-mail 
correspondence research personnel will send e-mails for scheduling, follow-up, and 
research-related communication.  
Data Analysis 
Aims 1-3.  Difference scores from baseline will be calculated for each outcome 
measure.  A mixed model ANOVA with group (active tDCS groups versus sham tDCS) 
as the between subjects factor and time of assessment (pre, weeks 1-4, & one week 
andone month post) as the within subjects factor will be used to test all aims. A 
significant group effect, with active tDCS > sham tDCS, for any of the outcome 
measures would indicate that anodal tDCS augments gait training.  A significant main 
effect of time would be evaluated using planned contrasts where we expect post 
treatment assessments to be improved relative to baseline. Interim analyses will be 
completed at critical stages during the protocol.   
   
Power analysis: We aim to determine whether tDCS can augment the beneficial effect 
of gait training. Our preliminary study using tDCS to improve gait velocity and the SIS16 
score yielded very large effect sizes for walking speed (2.95) and the SIS16 (1.32). In 
real terms, patients who received active tDCS reduced their time to walk 10 meters by 
about one minute (this could shave 5 minutes off a task, like getting mail, so it is 
functionally significant); whereas those who received sham reduced their time by only 
10 seconds. Power calculations indicate that sample sizes = 11 will yield power of .95 
and .80, respectively, to detect a tDCS-induced improvement gait velocity and physical 
function. However, assuming a very large effect size of greater than 2 is likely 
unrealistic. Therefore, we based our power analysis on determining a substantial 
meaningful change in gait speed (0.1 m/s) as determined by Perera et al.48  Using a 
2 x 3 mixed MANOVA with interaction and an estimated effect size of (cohn’s d = 

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0.39)37, a conservative r = 0.6049 and an alpha of 0.05 we will need 37 subjects per 
group to achieve a power of 85%. Therefore, we set our sample size at 88, so our study 
has sufficient power to detect meaningful changes in gait speed for individuals with 
chronic stroke.  
We set our primary study sample size at 88, so our study has sufficient power to detect 
a benefit of gait training and to determine if tDCS augments improvement. 
Exploratory Aim.  We will classify patients as “likely responsive” and “likely 
unresponsive” to tDCS based on the magnitude of difference scores and compare them 
to determined patient characteristics that predict a treatment response.  Predictors for 
88 subjects include 1) NIH Stroke Scale score, 2) initial levels of impairment, 3) initial 
MT of the contralateral TA muscle (and recruitment curve parameters form the 
ipsilateral TA muscle), 4) initial SIS-16 total and subscale scores, 5) stroke laterality, 
and 6) modified Rankin Scale scores.  A series of regression analyses will be conducted 
to reduce the overall number of predictors and to build an initial model, which assess 
the predictive value or weight of remaining variables, and to cross-validate predictors. 
To determine which stroke related variables are associated with a response to 
treatment, brain lesions will be mapped onto templates and analyzed using lesion 
subtraction techniques with the public domain MRIcro and MRIcron software programs 
(see Core B).  Lesion subtraction will identify the lesion sites that are common to 
treatment responders and not common to nonresponders. 
Ethical Considerations 
This study will be conducted in accordance with all applicable government regulations 
and University of Arkansas for Medical Sciences research policies and 
procedures.  This protocol and any amendments will be submitted and approved by the 
UAMS Institutional Review Board (IRB) to conduct the study.   
The PI or designated staff will discuss the informed consent form with the subject 
volunteer.  The consent process will take place in a quiet and private room.  Subjects 
may take as much time as needed to make a decision about their trial participation and 
may take the document home if desired.  The person obtaining consent will thoroughly 
explain each element of the document and outline the risks and benefits, alternate 
treatment(s), and follow-up requirements of the study.  Participation privacy will be 
maintained and questions regarding participation will be answered.  No coercion or 
undue influence will be used in the consent process.  No research related procedures 
will be performed prior to obtaining informed consent.  All signatures and dates will be 
obtained.  A copy of the signed consent will be given to the participant.  The informed 
consent process will be documented in each subject’s research record. 
Vulnerable populations:  Stroke patients can have cognitive deficits that could render 
them vulnerable.  Patients for this study will not be entered if there is evidence of 
preexisting dementia or if they exhibited language comprehension or other cognitive 
deficits that precluded understanding of instructions or of the informed consent. 

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Dissemination of Data 
 
Results of this study may be used for presentations, posters, or publications. The 
publications will not contain any identifiable information that could be linked to a 
participant.  This study will be registered on http://www.ClinicalTrials.gov.  
References 
1. 
Prevalence of stroke--United States, 2005. Mmwr 2007;56(19):469-74. 
2. 
Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K et 
al. Heart disease and stroke statistics--2009 update: a report from the American Heart 
Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 
2009;119(3):e21-181. 
3. 
Jørgensen HS, Nakayama H, Raaschou HO, Olsen TS. Recovery of walking 
function in stroke patients: the Copenhagen Stroke Study. Arch Phys Med Rehabil 
1995;76(1):27-32. 
4. 
von Schroeder HP, Coutts RD, Lyden PD, Billings E, Nickel VL. Gait parameters 
following stroke: a practical assessment. J Rehabil Res Dev 1995;32(1):25-31. 
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