Synergistic Effect of Combined Transcranial Direct Current Stimulation/Constraint Induced Movement Therapy in Children With Hemiparesis
Phase: NA
Conditions: Pediatric Hemiparesis
Sponsor: University of Minnesota

Synergistic Effect of Combined tDCS/CIMT in Children with Hemiparesis 
 
 
 
Synergistic Effect of Combined tDCS/CIMT in Children with Hemiparesis 
 
Regulatory Sponsor: 
Bernadette Gillick 
Medical School- PM&R 
420 Delaware Street SE, MMC 388 
Minneapolis, MN 55455 
612.626.3121 
612.625.4274 
gillick@umn.edu 
 
Funding Sponsor: 
CTSI K01 Grant 
University of Minnesota 
Clinical and Translational Science Institute 
717 Delaware St SE, Minneapolis, MN 55414 
612.625.2874 
 
Cerebral Palsy International Research Foundation (CPIRF) 
186 Princeton Hightstown Road; Building 4, 2nd Floor 
Princeton Junction, NJ 08550 
609-452-1200 
 
Foundation for Physical Therapy 
Magistro Family Foundation Research Grant 
1111 North Fairfax Street 
Alexandria, Virginia 22314-1488 
 
Study Product: 
Transcranial Direct Current Stimulation 
Transcranial Magnetic Stimulation 
Stereotactic Neuronavigation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 37 

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Synergistic Effect of Combined tDCS/CIMT in Children with Hemiparesis 
 
Version History 
 
Version # 
Approval 
Date 
Significant Changes from Previous Version 
Version   1 
9/11/14 
Original Protocol Version 
Version 2 
1/6/15 
Addition of Typically Developing Subjects 
Version 3 
3/13/15 
Addition of Pregnancy Test/MRI at Follow-up 
Version 4 
10/22/15 
Addition of ECG and Cuff Vitals Monitoring 
Version 5 
3/6/2017 
Addition of bimanual therapy and alteration in tDCS 
dosage 
Version 6 
4/13/17 
Consent form for Eligibility Screening and Dosage 
Version 7 
5/9/17 
Change in MRI pre-testing 

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Synergistic Effect of Combined tDCS/CIMT in Children with Hemiparesis 
 
Table of Contents 
 
 
 
Study Summary 
p. 4 
 
List of Abbreviations 
p. 6 
 
1 
Introduction 
p. 7 
2 
Background and Rationale 
p. 7 
3 
Study Objectives 
p. 7 
4 
Study Design 
p. 12 
5 
Study Procedures 
p. 16 
6 
Data Analysis 
p. 25 
7 
Safety and Adverse Events 
p. 26 
8 
Data Handling and Record Keeping 
p. 32 
9 
Study Monitoring, Auditing, and Inspecting 
p. 34 
10 
Ethical Considerations 
p. 34 
11 
Study Finances 
p. 34 
12 
Publications Plan 
p. 35 
13 
List of Reference Documents 
p. 35 
14 
References 
p. 36 

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Synergistic Effect of Combined tDCS/CIMT in Children with Hemiparesis 
 
Study Summary 
 
Title 
Synergistic 
Effect of 
Combined tDCS/CIMT 
in Pediatric 
Hemiparesis due to Stroke 
Short Title 
tDCS/CIMT in Pediatric Stroke 
Principal 
Investigator 
Bernadette Gillick, PhD, MSPT, PT 
Study Design 
Exploratory pre-test post-test follow up 
Study Duration 
September 2013-December 2017 
Study Center(s) 
University of Minnesota, Medical School, 420 Delaware Street 
SE, Minneapolis, MN 55455; Gillette Children’s Specialty 
Healthcare, 200 University Avenue E. St. Paul, MN 55101 
Objectives 
Evaluate the safety and determine the efficacy of combined 
tDCS/rehabilitation in children with hemiparesis. Examine the 
influence of combined tDCS/CIMT on brain excitability and 
reorganization. 
Number of 
Subjects 
30 
Main Inclusion / 
Exclusion Criteria 
Primary inclusion criteria: 
Children ages 8-21 years with congenital hemiparesis due to 
hemispheric stroke or Periventricular leukomalacia; no evidence 
of    seizure    activity    within     the     last     2     years. For 
Bimanual therapy: Children must display a motor evoked potential 
on the lesioned hemisphere. Primary exclusion criteria: 
Other neurologic disorder unrelated to stroke (disorders of 
cellular migration and proliferation, acquired traumatic brain 
injury), Metabolic disorders, neoplasm, epilepsy, expressive 
aphasia, pregnancy, indwelling metal or incompatible medical 
devices, skin disease or skin abnormalities and botulinum toxin or 
phenol intramuscular block within the preceding five months 
from scheduled tDCS application.  For Bimanual therapy: Children 
who do not display a motor evoked potential on the lesioned 
hemisphere. 
Study Device 
Transcranial Direct Current Stimulation (tDCS) 
Duration of Device 
Exposure 
Ten 20-minute tDCS sessions over ten days during concurrent 
rehabilitation sessions. 
Reference Therapy 
Control transcranial Direct Current Stimulation with built- 
in placebo feature.  For bimanual therapy: Period of time 
without intervention.  
Endpoints 
Safety and Efficacy 

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Synergistic Effect of Combined tDCS/CIMT in Children with Hemiparesis 
 
Statistical Methods Descriptive analyses of baseline characteristics and outcomes will 
include means and standard deviations for continuous variables 
with frequencies and percentages for categorical variables. 
Analysis Populations: There are 3 analysis populations planned. 
Intent-to-treat (ITT), Per-protocol (PP), and the Safety population. 
We do not anticipate these groups to differ. 
Aim #1: Safety analyses will use the safety population and be 
primarily descriptive, reporting the number and percentage of 
adverse events. 
 
 
 
Aim #2: The primary analysis will use the Intent to Treat 
population to compare logit-based AHA units between the 
intervention and control groups adjusting for baseline values of 
AHA and presence of MEP for precision. Supportive analyses 
using the PP population will also be conducted. Secondary 
endpoints of Canadian Occupational Performance Measure 
(COPM), TOKEN test, Stereognosis and Finger force 
measurements will be analyzed in a similar fashion. The 
association of improved logit-based AHA units with DTI derived 
fractional anisotropy (FA) and MEP will be evaluated across all 
patients using generalized linear regression. Secondary analyses 
will evaluate these associations also adjusting for age and sex due 
to potential confounding influence though may be limited by 
sample size. 
 
Aim #3: Associations between changes in cortical excitability and 
the primary and secondary outcomes will be evaluated across all 
patients using generalized linear regression as in Aim #2. 
 
Power  and  Sample  Size:  The  sample  size  and  power  was 
primarily driven by the primary analysis of Hypothesis #1 of Aim 
#2. Power calculations for the primary outcome of logit-based 
AHA units were based on 10 patients in each. Based on previous 
studies, we will have 81% power to detect a difference of 5 logit- 
based AHA units at a significance level of 0.05. This study is 
intended to determine feasibility and explore preliminary efficacy 
results to inform the design of a future, larger RCT should 
promising results be found. 
 
 
 
 
 
 

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Synergistic Effect of Combined tDCS/CIMT in Children with Hemiparesis 
 
List of Abbreviations 
 
AE 
Adverse Event 
AHA 
Assisting Hand Assessment 
CDC 
Centers for Disease Control 
CFR 
Code of Federal Regulations 
CIMT 
Constraint-Induced Movement Therapy 
CMRR 
Center for Magnetic Resonance Research 
COPM 
Canadian Occupational Performance Measure 
CRF 
Case Report Form 
CTSI 
Clinical and Translational Science Institute 
CWH 
Children with Hemiparesis 
DSMB 
Data and Safety Monitoring Board 
DSMP 
Data and Safety Monitoring Plan 
DTI 
Diffusion Tensor Imaging 
EEG 
Electroencephalogram 
EMG 
Electromyograph 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMFCS 
Gross Motor Function Classification Scale Score 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
IDE 
Investigational Device Exemption 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
MACS 
Manual Ability Classification System 
MEP 
Motor Evoked Potential 
MPRAGE 
Magnetization Prepared Rapid Acquisition Gradient Echo 
MPSOM 
Modified Pediatric Stroke Outcome Measure 
MRI 
Magnetic Resonance Imaging 
NIBS 
Non-invasive Brain Stimulation 
PHI 
Protected Health Information 
PP 
Per-Protocol 
RCT 
Randomized Controlled Trial 
REPA 
Report of External Professional Activities 
rTMS 
Repetitive Transcranial Magnetic Stimulation 
SAE 
Serious Adverse Event 
SNN 
Stereotactic Neuronavigation 
tDCS 
Transcranial Direct Current Stimulation 
TMS 
Transcranial Magnetic Stimulation 
UADE 
Unanticipated Adverse Device Effect 
UPIRTSO 
Unanticipated Problems Involving Risk To Subjects or Others 

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1 
Introduction 
 
This document is a protocol for a human research study. This study will be conducted 
according to US and International standards of Good Clinical Practice, applicable 
government regulations and Institutional research policies and procedures. 
 
All individuals responsible for the design and conduct of this study have completed 
Human Subjects Protection Training and are qualified to be conducting this research prior 
to the enrollment of any subjects. 
 
This document is confidential and the property of the University of Minnesota. No part 
of it may be transmitted, reproduced, published, or used by other persons without prior 
written authorization from the study sponsor. 
 
 
2 
Background and Rationale 
Cerebral palsy affects an estimated 800,000 people in the United States. The lifetime cost 
of caring for a person with cerebral palsy is approximately $1 million dollars.(CDC, 
2013) The neurologic deficits associated with this condition can take a variety of different 
forms though one of the most common manifestations affects movement on one side of 
the body (hemiparesis). Hemiparetic cerebral palsy influences motor function in children 
during development and throughout their lifetime. The deficits one sees are the result both 
of the congenitally induced brain lesion and the subsequent plasticity that can impair 
function of the surviving neurons in the damaged brain. 
 
Unfortunately, many current treatments have limited influence on children’s 
neurorecovery. Constraint-induced movement therapy (CIMT) involving constraining the 
unaffected limb to encourage use of the affected limb has shown promise, yet with new 
technology revealing the potential to directly influence the brain, there is an urgent need to 
study the synergy of combined techniques.  Another rehabilitation technique is bimanual 
therapy. Bimanual therapy is a treatment in which the child works on using two hands for 
everyday tasks. 
 
Non-invasive brain stimulation (NIBS) as a direct neuromodulatory intervention has the 
potential to act synergistically with CIMT or bimanual therapy to influence neurorecovery. 
 
tDCS is a novel form of painless, noninvasive brain stimulation. In contrast to other 
forms of NIBS, tDCS has produced no reported seizures, is less than 1/10th the cost, and 
is more portable, allowing simultaneous use with rehabilitation interventions. Although 
motor improvements have been found using tDCS in adult hemiparesis, the potential 
benefits of this technique in children have not been tested. 
 
Combining behavioral therapies, constraint-induced movement therapy (CIMT) or 
bimanual therapy with a novel form of neuromodulation, transcranial direct current 
stimulation (tDCS), we will investigate the influence of this intervention on improved 
motor outcomes in children with cerebral palsy. 
 
Children with hemiparesis often exhibit reorganization of the area of the brain responsible 

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for movement (specifically the corticospinal tract of the primary motor cortex).  Children 
with hemiparesis may exhibit contralateral reorganization (meaning the lesioned 
hemisphere influences movement of the contralateral more-affected hand) or ipsilateral 
reorganization (meaning the non-lesioned hemisphere maintains control of the 
contralateral more-affected hand).  One method to determine reorganization patterns is our 
existing neuroimaging and Transcranial Magnetic Stimulation (TMS) testing protocols.  
 
Research Question and Hypothesis 
The central hypothesis is that combined tDCS/CIMT or combined tDCS/Bimanual 
Therapy will be safe and result in greater improvement in hand function than CIMT alone 
in congenital hemiparesis.  Secondary analysis will explore for predictive biomarkers 
based on baseline measures of clinical characteristics and excitability measures, as well as 
diffusion tensor imaging (DTI). TMS testing for excitability measures will also determine 
neuroplastic response to the intervention. CIMT Design: Two-group randomized 
controlled preliminary trial, 20 children ages 8-21 with hemiparesis, one group receiving 
active tDCS with CIMT (intervention) and one receiving sham tDCS with CIMT 
(control), for 10 daily sessions.  Bimanual Therapy Design:  One-group open-label 
repeated measures preliminary study, 10 children ages 8-21 with hemiparesis with all 
children receiving the active tDCS with bimanual therapy (intervention) for 10 daily 
sessions. 
 
Aim 1.  Establish the safety profile of combined tDCS/CIMT in congenital 
hemiparesis. 
Our previous pilot revealed safety with no adverse events surrounding a one-time 
application of tDCS. We will now explore the safety of 10 serial sessions of tDCS 
combined with CIMT. 
Hypothesis 1: No seizure activity or other serious adverse event will occur in either 
group. 
Hypothesis 2: No decline in paretic or nonparetic hand function will occur in either 
group. 
Preliminary results from the 20 children who have participated in our tDCS/CIMT study 
totaling 260 neuromodulatory sessions has resulted in no serious adverse events.  We will 
now explore the safety of 10 serial sessions of tDCS combined with Bimanual therapy.  
Hypothesis 1: No seizure activity or other serious adverse event will occur. 
Hypothesis 2: No decline in paretic or non-paretic hand function will occur. 
 
Aim 2.  Determine the behavioral efficacy of combined tDCS/CIMT in congenital 
hemiparesis. We will assess hemiparetic upper extremity behavioral motor function 
changes and responsiveness to interventions. 
Hypothesis 1: The intervention group will show greater improvement in paretic hand 
function than controls. 
Hypothesis 2: The degree of difference in the integrity of the ipsilesional and 
contralesional corticospinal tracts as characterized by Diffusion Tensor Imaging, and 
the presence of ipsilesional motor evoked potentials (MEP), will be associated with 
improved hand function. 
For Bimanual Therapy:  Determine the behavioral efficacy of combined tDCS/Bimanual 
Therapy in congenital hemiparesis. We will assess hemiparetic upper extremity 
behavioral motor function changes and responsiveness to interventions. 

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Hypothesis 1: The intervention group will result in greater improvement in paretic hand 
function than the non-intervention period. 
Hypothesis 2: The degree of difference in the integrity of the ipsilesional and 
contralesional corticospinal tracts as characterized by Diffusion Tensor Imaging, and 
the presence of ipsilesional motor evoked potentials (MEP), will be associated with 
improved hand function. 
 
Aim 3.  Determine the influence of combined tDCS/CIMT on cortical excitability in 
congenital hemiparesis. Cortical excitability will be tested using single-pulse 
Transcranial Magnetic Stimulation (TMS). 
Hypothesis 1: Changes in cortical excitability will be associated with improved 
behavioral outcomes. 
Hypothesis 2: The intervention group will show greater changes, compared to 
controls, in contralesional primary motor cortex (M1) cortical excitability (i.e. ↑ 
motor threshold and ↓ motor evoked potential area) 
Hypothesis 3: When an ipsilesional MEP is present, the intervention group will show 
greater ipsilesional M1 cortical excitability changes (↓ motor threshold and ↑ motor 
evoked potential area) compared to controls. 
For Bimanual Therapy: Determine the influence of combined tDCS/Bimanual Therapy 
on cortical excitability in congenital hemiparesis. Cortical excitability will be tested 
using single-pulse Transcranial Magnetic Stimulation (TMS). 
Hypothesis 1: Changes in cortical excitability will be associated with improved 
behavioral outcomes. 
Hypothesis 2: The intervention period will result in changes in the contralesional 
primary motor cortex (M1) cortical excitability (i.e. ↑ motor threshold and ↓ motor 
evoked potential area) 
 
Preliminary Data 
Combining electrophysiologic and behavioral methods, we have recently found promising 
results in pediatric hemiparesis using a synergistic intervention of constraint- induced 
movement therapy (CIMT) and a form of NIBS- repetitive transcranial magnetic 
stimulation (rTMS).1   Of paramount importance, the study determined that alternating 5 
treatments using 6-Hz primed low-frequency rTMS with 5 treatments of CIMT applied to 
the non-stroke hemisphere was safe; without serious adverse events. The most common 
minor adverse events included headache and cast irritation. As to efficacy, our primary 
outcome variable, the Assisting Hand Assessment (AHA), revealed a significant 
difference in hand function between the control and treatment groups. (p=0.007) Although 
significance was not achieved for our secondary outcome measures of the Canadian 
Occupational Performance Measure (COPM), Stereognosis and Finger Extension force 
there were within-group improvements. 
 
These recent results demonstrate safety and reveal significant improvements in hand 
function using rTMS combined with CIMT. However, it is currently very difficult to 
incorporate the use of rTMS at the same time as performing therapy with the affected 
upper extremity due to machine size and application challenges. tDCS may be more 
feasible.  Applying tDCS/CIMT concurrently could optimize neuroplastic principles of 

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concurrent firing of neurons and strengthening of neuronal networks. Also, TMS/rTMS 
can be ten times the current cost of tDCS and thus cost may be prohibitive when using 
TMS/rTMS. Furthermore, if the application of tDCS reduces the need for additional 
therapies or concurrent therapies, a cost savings could be realized. Last, albeit rare, use of 
rTMS has resulted in reports of adverse events such as seizures and syncopal episodes, 
both in adults and children.2   In addition to its cost and portability, tDCS resulted in 
functional improvements in motor function in adults with and without the concurrent use 
of CIMT. 3   The important rationale for the investigation of tDCS in this population is 
that the use of non-invasive brain stimulation could translate into clinical applications, 
thus improving the quality of life for children with hemiparesis. 
 
After the rTMS study, we completed a tDCS pilot safety study of a one-time application 
in pediatric hemiparesis.4  Analysis of 11 subjects, children with congenital hemiparesis, 
revealed no serious adverse events including seizure. We included a physician evaluation 
using a modified Pediatric Stroke Outcome measure, and cognitive and behavioral testing 
with no significant differences from baseline or between groups in level of function.  This 
study established the feasibility and safety of this application. 
Bimanual therapy allows for a child to practice tasks with two-hands allowing for motor 
learning of both hands and mimicking the natural environment.  Bimanual therapy is a 
common therapy approach in the clinical setting.  Review of goal setting data suggests 
that the majority of children with hemiparesis identify and prioritize bimanual tasks as 
goals (e.g. tying their shoes, putting books in a backpack).  Evidence suggests that 
children with congenital hemiparesis benefit equally from CIMT or two handed, or 
bimanual, therapy.5,6   
Device Description 
Non-Invasive brain stimulation has been recently investigated for benefits in recovery of 
motor function in adults7 and more recently in children1,8   One form, Transcranial 
Magnetic Stimulation (TMS), can be used in specific protocols either to test cortical 
excitability or as an intervention to attempt to influence cortical excitability. In this study 
we are using TMS only as a test to assess cortical excitability in the area of the brain 
known as the motor cortex or M1.  Recent evidence suggests that 1.0mA and 2.0mA is 
well-tolerated and results in motor learning both for children with typical development9 
and 1.0 mA in children with hemiparesis.10  Safety of tDCS is further confirmed in a 
recent evidence based update with no reports of major adverse events following tDCS.11  
Transcranial Direct Current Stimulation (tDCS) will be used as an intervention, applying 
stimulation continuously over a period of 20 minutes. 
 
Testing for Cortical Excitability: Transcranial Magnetic Stimulation (TMS): We will use 
a Magstim Rapid2 TMS stimulator with a flat 70 mm figure-of-eight coil. TMS is a non- 
invasive method for assessing the excitability of the brain.  The TMS stimulator is a non- 
significant risk device. The technique involves placing a special electrode on the head. 
The electrode we will use is a flat figure-of-eight coil with a 70-mm diameter for each 
loop of the figure-of-eight. The center of the coil is hand held on the scalp over the 
desired region to be stimulated. An electrical current is pulsed through the electrode, 

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which creates a magnetic field.  This magnetic field, in turn, creates an electric field in the 
surrounding area, including inside the skull, which induces an ionic current to flow on the 
surface of the brain.  Depending on the parameters of the stimulation and the 
excitability of the underlying cortex, the stimulation may or may not depolarize the nerve 
membrane to threshold.  If it does depolarize, an action potential is generated and 
conducted to spinal motor neurons, which, depending on their own excitability, may 
transmit an action potential to muscle.  Ultimately, the response is recorded as a motor 
evoked potential (MEP) with EMG electrodes located over the target muscle. 
 
Intervention: Transcranial Direct Current Stimulation (tDCS): Soterix Medical 1x1 
stimulator. This device is intended for the noninvasive stimulation of the cortex via 
transcranial current stimulation (TCS). The device is capable of direct current 
stimulation and has a built-in sham condition setting. This sham stimulation feature 
allows for consistent application of the sham setting with ramp-up, extinguish and ramp- 
down modulation. As an added measure of safety, we will be using the LTE device which 
provides built-in adaptation to resistance and current. This device is for investigational 
research only in the United States.  An instructional video from the Harvard Berenson- 
Allen Center for Noninvasive Brain Stimulation describes the use of Soterix tDCS in 
detail. http://www.jove.com/video/2744/electrode-positioning-and-montage-in-  
transcranial-direct-current-stimulation 
 
All investigational devices used in this study will have the following label statement: 
CAUTION – Investigational Device. Limited by Federal law to investigational use. 
 
Stereotactic Neuronavigation: In order to verify our exact location over the motor cortex 
we will be using a computerized method of location called Stereotactic Neuronavigation 
(SNN). (Brainsight Stereotactic Neuronavigation, Rogue Research, Montreal, Canada) 
Through the use of a locator situated atop the TMS device and a comparative subject- 
specific MRI image on a computer screen which shows the locator position, we will be 
able to specify the TMS hotspot location and placement of the tDCS electrodes. 
 
3 
Study Objectives 
Primary Objective 
Determine the safety of contralesional  cathodal  transcranial Direct 
Current Stimulation combined with Constraint-Induced Movement  
Therapy in children with hemiparesis. 
 
For Bimanual Therapy: Determine the safety of contralesional  cathodal  
transcranial Direct Current Stimulation combined with Bimanual   
Therapy in children with hemiparesis. 
 
Secondary Objectives 
Assess behavioral status after combined transcranial Direct Current 
Stimulation/Constraint-Induced Movement in children with hemiparesis. 
 

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For Bimanual Therapy: Assess behavioral status after combined 
transcranial Direct Current Stimulation/Bimanual Therapy in children 
with hemiparesis. 
 
4 
Study Design 
 
 
 
Figure 1a-tDCS/CIMT 
 
 
 
 
 
 
 
 
Figure 1b-tDCS/Bimanual Therapy 
 
Overview of Study Design 
The study will use a randomized, sham-controlled, blinded, repeated-measures design. 
(Figure 1a above) Twenty total children with congenital hemiparesis and unilateral 
infarct as confirmed by MRI will be randomized into one of two groups: active tDCS 
with CIMT (intervention) or sham tDCS with CIMT (control). Randomization will be 
1:1 between intervention and control groups stratified on the presence of an 
ipsilesional MEP  and using randomly permuted blocks of size 2 and 4. The children 
will receive 10 weekday sessions of daily tDCS and CIMT at Gillette Children’s 
Specialty Healthcare – St. Paul, MN. The study will be conducted biannually in a 
camp-style format, anticipating 3-5 children participating in each camp.  This format 
is constructed thusly due to the extensive personnel and resources required to safely 
and effectively run this  trial. This study intends to determine feasibility and explore 
preliminary efficacy results to inform the design of a future, larger RCT, should 
promising results be found. 
 
For Bimanual Therapy: This group will be studied with a repeated-measures design 
(Figure 1b above).  Ten total children with congenital hemiparesis and unilateral 
infarct as confirmed by MRI will receive (active tDCS with bimanual therapy).  The 
children will receive 10 weekday sessions of daily tDCS and bimanual at UMN 
Center for Neurobehavioral Development. The study will be conducted in a camp-
style format, anticipating 3-5 children participating in each camp.  This format is 
constructed thusly due to the extensive personnel and resources required to safely and 
 

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effectively run this study. This study intends to determine feasibility and explore 
preliminary efficacy results to inform the design of a future, larger RCT, should 
promising results be found. 
 
Anticipated Duration of the Clinical Investigation 
 
The anticipated duration of study is as follows: Submission of all indicated applications is 
presumed to occur over a 4-month period of time, with the potential for revisions 
within this timeframe. Recruitment of children will be based over a 1 year period of 
time, running the camps during optimal time off from school, holidays and vacations 
when children are most readily available. Recruitment accrual rates will vary greatly 
due to the variation in a child’s school and after school activities. 
 
For Bimanual Therapy: The anticipated duration of study is as follows: Submission of all 
indicated applications is presumed to occur over a 2-month period of time, with the 
potential for revisions within this timeframe. Recruitment of children will be based over 
a 6-month period of time, running the camps during optimal time off from school, 
holidays and vacations when children are most readily available. Recruitment accrual 
rates will vary greatly due to the variation in a child’s school and after school activities. 
 
If the trial ends prior to the study completion, all scheduled subjects will be notified and 
study visits will be terminated.  The CTSI will be notified and all future reserved dates 
for use of the CTSI will be canceled.  All research investigators on the study will be 
notified.  The CTSI funding agency will also be notified. 
 
Action—tDCS/CIMT 
Anticipated 
Duration 
Award Notice 
Start date 9/1/13 
Confirm protocol and consent/assent with 
Gillette Team, Establish full Gillette UMN 
Team 
6 months 
Scientific Merit CMRR//IRB/CTSI 
Applications, Reviews and Approvals 
6 months 
Recruit Subjects/Study Enrollment and 
Intervention 
18 months 
Database Queries and Data Cleaning 
1 month 
Database Lock and Analysis 
1 month 
Final Reports and Manuscript Preparation 
1 month 
 
Action—tDCS/Bimanual Therapy 
Anticipated 
Duration 
Award Notice 
Start date 9/1/13 
Confirm protocol and consent/assent with 
Gillette Team,  
6 months 
Scientific Merit CMRR//IRB/CTSI 
Applications, Reviews and Approvals 
4 months 

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Recruit Subjects/Study Enrollment and 
Intervention 
6 months 
Database Queries and Data Cleaning 
1 month 
Database Lock and Analysis 
1 month 
Final Reports and Manuscript Preparation 
1 month 
 
Primary Clinical Endpoint 
The following measures will be used to create a safety profile: 
• Demographics 
• Manual Ability Classification System Score 
• TMS motor threshold 
• Vital Signs 
• Electromyograph (EMG) Activity of Ipsilateral and Contralateral Musculature, 
• Subject Report of Symptoms 
• Ipsilateral Hand Function 
• Physician Evaluation 
• 
Specific to Bimanual Therapy: Physician involvement will remain as reviewer of 
medical records for inclusion/exclusion, Medical Director, Medical Monitor.  No 
physician evaluation will be conducted. 
 
We will use counts and percentages of adverse events to establish the data for this 
endpoint. 
 
Study Population 
 
Sample Size: 20 children with hemiparesis and unilateral infarct as confirmed by MRI. 
Sample Size (Bimanual):  10 children with hemiparesis and unilateral infarct as confirmed by MRI. 
 
35 children will be enrolled and 20 final subjects will meet all criteria and be able to 
proceed with the study. The sample size of n=20 was based on practical and clinical 
considerations.  Information gleaned from this initial study will be used for development 
of intervention studies with the results dictating the defined direction of optimal usage of 
tDCS. 
 
For Bimanual Therapy: An additional 20 children will be enrolled and 10 final 
participants will meet all criteria and be able to proceed with the study.  The sample size 
of n=10 was based on practical and clinical considerations.  Information gleaned from this 
initial study will be used for development of intervention studies with the results 
dictating the defined direction of optimal usage of tDCS. 
Subject Recruitment: The recruitment subject pool for children with hemiparesis will 
include children who participated in previous studies, children from an IRB-approved 
database of families that have expressed interest in Dr. Gillick’s research, as well as 
children from the clinical practices of this study’s  Medical Director, Dr. Tim Feyma, 
and Co-investigator, Dr. Marcie Ward. Upon IRB  approval, we will further recruit 
through advertising on the Gillick Pediatric Neuromodulation Research Lab website 
(z.umn.edu/gillicklab), recruitment newsletters,  emails, letters to colleagues, various 
media outlets as applicable, ResearchMatch.org and  on the Children’s Hemiplegic and 

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Stroke Association website (http://www.chasa.org/). Typically developing children 
needed for a mock walk-through of the logistics of the study will be recruited from the 
database of children who participated in a previous study and have requested to be 
notified of other research participation opportunities. Recruitment of typically developing 
children will also include reaching out to families who have expressed interest in Dr. 
Gillick’s research in response to community presentations and her involvement in 
community service activities (i.e., elementary school science fair judge). 
 
Subject Screening: In addition to the phone screen, the physician medical records screen, 
and the on-site screen, all female subjects will need to take a urine pregnancy test.  If the 
test is positive the subject will be excluded from the study as the safety of use of tDCS 
and TMS during pregnancy has not been established. If the pregnancy test is negative, the 
subject can proceed into the treatment component of the study. 
 
Prior and Concomitant Therapy 
• Permitted- Behavioral therapies including occupational, physical or speech 
therapies will be allowed. 
• Not permitted- Implantable ongoing therapies such as intrathecal baclofen 
pumps. 
 
Inclusion Criteria 
Subjects will be eligible to participate in the study if the following conditions exist: 
1. Hemispheric Stroke or Periventricular Leukomalacia confirmed by most 
recent MRI or CT radiologic report with resultant congenital hemiparesis 
2. ≥ 10 degrees of active motion at the metacarpophalangeal joint 
3. Receptive language function to follow two-step commands as evidenced 
by performance on TOKEN test of intelligence 
4. No evidence of seizure activity within the last 2 years 
5. Presence of a motor evoked potential from at least the 
contralesional hemisphere if not both hemispheres 
6. Ages 8-21 years 
7. Able to give informed assent along with the informed consent of the 
legal guardian 
8. Children who have had surgeries, which may influence motor function 
e.g.- tendon transfer, will be included, yet surgical history will be 
documented and included in any publication within a participant 
characteristics table. 
9. For Bimanual Therapy: Children who display a motor-evoked potential 
from the lesioned-hemisphere as elicited by TMS single pulse testing. 
Exclusion Criteria 
Subjects  will  be  excluded  from  participation  in  the  study if  any  of  the  following 
conditions exist: 
1. 
Metabolic Disorders 
2. 
Neoplasm 
3. 
Epilepsy 
4. 
Disorders of Cellular Migration and Proliferation 
5. 
Acquired Traumatic Brain Injury 
6. 
Pregnancy 

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7. 
Indwelling metal or incompatible medical devices 
8. 
Evidence of skin disease or skin abnormalities 
9. 
Botulinum toxin or Phenol block within [six-months] preceding the study.  Children 
who are within the 5th month following botulinum toxin injections who desire to 
participate in the study, will be reviewed individually by the PI and Medical 
Director of the study.  A determination of inclusion will be based on the child’s 
typical period of efficacy of injections.  
10. For Bimanual Therapy: Children who do not display a motor-evoked potential from 
the lesioned-hemisphere as elicited by TMS single pulse testing. 
 
 
Exit/Discontinuation Criteria 
Subjects will exit the study if any of the following conditions exist: 
1. 
Subject voluntarily withdraws from the study. 
2. 
Subject death. 
3. 
Subject acquires any of the listed exclusion criteria. 
4. 
Subject completes the protocol. 
5. 
Subject is non-compliant with the protocol. 
6. 
Subject’s well-being,  in  the  opinion  of  the  Investigator,  would  be 
compromised by study continuation. 
7. 
Subject experiences a serious adverse event or seizure. 
8. 
Medical monitor and/or IRB recommendation 
 
 
5 
Study Procedures 
 
Eligibility Screening Consent 
To determine eligibility for participation, caregivers will be asked screening information using the 
Medical History Survey (version 3.6.17).  Prior to the collection of screening information that is 
identifiable, an Eligibility Screening consent form will be offered to caregivers by email, fax, 
mail, or waived.  If a caregiver chooses to waive the consent for the eligibility screening, we will 
proceed with the eligibility screening at the time of the caregiver’s study inquiry. The waiving of 
the eligibility screening consent will be documented.  
 
To further protect identifiable information, if the caregiver reports their child is not within the age 
range of 8-21 years old and does not have a diagnosis of congenital hemiparesis (meaning the 
stroke occurred within the first year of life), the caregiver will be informed their child does not 
meet the study enrollment criteria and no further screening questions will be asked of the 
caregiver.   
 
Informed Consent 
For subjects ages 8-17, each legal guardian and subject for this study will be provided a 
consent and assent form describing this study and the opportunity to discuss the study 
with the study personnel. (Subjects ages 18-21 will be provided a non-minor consent 
form only).  Information will be provided for an informed decision about their 
participation in this study. The consent, assent, and Addendum to Assent for Female 
Minors forms will be submitted with the protocol for review and approval by the IRB. 
The formal consent/assent of a subject, using the IRB-approved consent/assent form, 

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must be obtained before that subject undergoes any study procedure.  This consent form 
must be signed by the legal guardian(s) and the assent/addendum assent form(s) must be 
signed by the subject along with the signature on both forms of the investigator- 
designated research professional obtaining the consent/assent.  The IRB-approved form 
must be kept on-site and by the sponsor-investigator. 
 
Assent must be obtained from all minor subjects deemed capable by the IRB (between 8 
and 17 years old, inclusive) in addition to the Informed Consent of the legal guardian in 
accordance with Federal Regulations and/or the qualifying Institutional Review Board 
(IRB). 
 
tDCS/CIMT Randomization Scheme 
Each child will be randomized to either the real or sham tDCS arm of the study. The 
randomization will be done by sealed envelopes constructed by the study biostatistician 
using a random number generator.  The study coordinator will assign envelopes, in 
numerical order, to the subjects upon their enrollment. The envelopes will in turn be 
shared by the study coordinator and the research personnel involved in the intervention 
component of the study. 
 
tDCS/CIMT Blinding 
The investigator who performs the testing, and the physician who does the evaluations 
will be blinded to the treatment arm as well as the child/caregiver/family.   The following 
procedure will be employed: 
1. The study coordinator and biostatistician will meet and a sealed envelope will be 
given to the study coordinator. 
2. The study coordinator will share the group assignment with theprincipal investigator 
in a secure private room, in the absence of the physician, research tester, subject legal 
guardian and subject.  The Medical Monitor to the study will have access to the group 
assignment. 
3. Interventionist will, during the intervention, switch the setting on the tDCS device to 
the designated placebo setting, hidden from view of the subject.  Blinding is applied 
through the designation of the setting on the tDCS machine of sham or real tDCS. 
For the first 30-seconds of either setting, a gradual “ramp-up” sensation of the 
stimulation occurs. This is built into the machine for both settings. However, for the 
sham stimulation, the sensation then abates, and not until the end of the 20-minute 
session does the subject receiving the 30-seconds of “ramp-down” sham once again 
experience the sensation. The sensation then occurs and “ramps-down” the amperage 
until the machine turns off. 
4. Information on subject group assignment will be logged and stored in a designated 
locked cabinet at the study coordinators office. 
 
tDCS/Bimanual Therapy: 
As this is an open-label design, all children will complete multiple baseline assessments to serve 
as their comparison period without intervention.  All children will then participate in the real 
tDCS/Bimanual Therapy intervention.  Children, caregivers, and investigators will not be blinded 
to intervention.  Study collaborators assisting with the scoring of assessments will be blinded to 
the child’s progress during the intervention phase.  
 

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Laboratory Testing Procedures 
Specimen Preparation: For females, urine samples will be obtained on site at the CTSI 
with use of private bathrooms. The subject and legal guardian will be instructed on how 
to obtain the urine specimen by the study PI. The urine sample will then be obtained in a 
screw-top urine cup and handed to the PI who will be wearing latex gloves. 
 
Specimen Handling and Storage: Immediate assessment of pregnancy status will occur as 
the PI, in the assignment laboratory specimen assessment room, will utilize the allotted 
amount of sample required for adequate assessment. Once the testing has occurred, the 
sample will be flushed in a designated CTSI urinal or disposal sink. No storage of urine 
material will occur. If pregnancy test is positive, the child will be excluded from the 
study, and a recommendation to follow-up with their primary care physician will be 
enacted. 
 
No shipment of specimens will occur in this study. 
 
Clinical Procedures 
Phone Screen: All interested subjects are screened by phone for a review of inclusion and 
exclusion criteria, to obtain general health history of potential subject, and to give 
opportunity for family to ask questions and have those questions answered. 
Study Visit 
HIPAA consent is obtained in order to perform a medical record review.  Information for 
all subjects will be collected and managed in accordance with HIPAA policies. This 
review is completed by the study physicians for review of inclusion/exclusion by history 
and MRI/CT radiographic reports of the brain. Eligibility will be verified by the principal 
investigator after this review. Eligibility is then discussed with the legal guardian and a 
formal schedule is established. The family will be sent a detailed itinerary outlining their 
visit. Families interested in future study participation will be provided with the 
“HIPAA For Future Study” form.  Informed consent/assent will be completed on the 
day of enrollment. 
 
 
tDCS/CIMT:  
ASSESSMENTSANDMEASUREMENTS 
Pre-Test Interim Test Post-Test Follow-up 
MRI/DTI 
x 
X 
TMS 
x 
x 
x 
Vital Signs 
x 
x 
x 
Subject Report of Symptoms 
x 
x 
x 
x 
Physician Evaluation - MPSOM 
x 
x 
x 
X 
Behavioral and Cognitive Testing to include: 
TOKEN, goal review, , AHA, 
x 
x 
x 
Behavioral Testing: Hand Dynamometer 
X 
X 
X 
X 
Behavioral Testing: Participation of activities 
X 
X 
Classification Systems: MACS/GMFCS 
X 
tDCS Survey 
x 
Study Feedback 
x 
 

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tDCS/CIMT Pre-Test 
Location: Center for Magnetic Resonance Research (CMRR) 
Time: 1 hour 
• Consent/Assent will be obtained and a pregnancy test for female subjects will be 
administered. 
• Subjects will be scanned on a Siemens 3T system. The scan protocol will include 
both a T1-weighted structural Magnetization Prepared Rapid Acquisition Gradient 
Echo (MPRAGE) scan and Diffusion Tensor Imaging (DTI). 
Location: Clinical and Translational Science Institute (CTSI) 
Time: 2 hours 
• Cardiovascular Measurements: Subjects will be instrumented with a 3 or 12- 
Lead ECG for measurement of heart rate and a non-invasive blood pressure 
measuring device that will be placed on a finger of their hand. (AD Instruments, 
Colorado Springs, CO). Subject Report of Symptoms survey will be completed. 
• The testing researcher will perform an assessment of cortical excitability using 
Transcranial Magnetic Stimulation. The subject will be comfortably seated in a 
reclining chair. Surface EMG electrodes will be attached over the extensor digitorum 
muscle serving the nonparetic hand, which will record the MEPs resulting from the 
magnetic stimulation to the contralesional M1. Next, the threshold for TMS activation 
of the target muscle will be determined. Subjects will wear a tight-fitting Lycra 
(Invista, Inc., Wilmington, DE) swim cap to allow measurement and drawing of the 
region where the optimal scalp position (“hotspot”) should be located. We will use a 
70-mm figure-eight TMS coil connected to a Magstim 200 machine. The coil will be 
handheld on the swim cap over the approximate hotspot area tangential to the scalp 
and oriented with the handle pointing posterolaterally at a 45° angle to the sagittal 
line. It will be moved systematically to find the true location of the hotspot. Single- 
pulse magnetic stimuli will be delivered manually at approximately 0.1 Hz starting at 
an intensity of 60% of the stimulator maximum. This level will be adjusted 
systematically until the resting motor threshold is found, defined as the minimum 
intensity required to elicit MEPs >50 µV peak-to-peak in at least 5 of 10 trials with 
the target muscle at rest. 
• The testing researcher will perform an assessment of cognitive and behavioral 
function using: a TOKEN test of intelligence, Assisting Hand Assessment, a 
measure of the child’s goals, ,Hand Dynamometry, the Gross Motor Function 
Classification Scale Score (GMFCS),  the Manual Ability Classification System 
(MACS), and a measure of the child’s general activity level. 
Location: Gillette Children’s Specialty Healthcare 
Time: 15 minutes 
• The physician will assess the subject with the Modified Pediatric Stroke Outcome 
Measure (MPSOM). 
 
Intervention 
Location: Gillette Children’s Specialty Healthcare – St. Paul, MN 
Time: 2 hours/day for 10 (business) days with interim testing after Day 5 
 

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• Subject will be randomized into active vs. sham group 
• Before the tDCS session, skin under the electrode region will be assessed for lesions 
and evidence of skin disease or abnormalities which could cause potential irritation. 
tDCS is not administered if there is any skin damage, rash or other skin lesion under 
the electrode sites. 
• Skin is lightly cleaned with an alcohol swab, taking care NOT to abrade the skin in 
any manner.  Move hair away as best as possible from the site of stimulation in order 
to increase conductance. 
• Sanitized and disinfected rubber electrodes with clean, single-use sponges dampened 
with normal saline are placed over the stimulation sites and held against the head with 
wide rubber bands which cover the entire surface of the electrodes. Care is taken to 
ensure contact with the skin is firm and even over the entire surface of the electrode. 
• The static impedance measurement is checked- stimulation does not proceed unless 
levels are within limits recommended by the tDCS device manufacturer. 
• Active tDCS with CIMT group (intervention) Stimulation is commenced and 
subjects are advised to report immediately if the stimulation feels painful, or anything 
other than low-level itchy or tingling sensations, common yet consistently reported at 
any time during the period of stimulation.  tDCS continues with a weak electrical 
current of 0.7 mA applied across the scalp for 20 minutes in a single experimental 
session. 
• After the first 2 minutes, the subject is questioned about pain at the electrode sites. If 
the stimulation is painful, a small amount of additional saline (approximately 4 mL) is 
added to the sponge, taking care to avoid wetting adjacent hair and thereby increasing 
the electrode area, and the tightness and placement of the band are checked.  If pain 
persists, the stimulation is stopped and the electrode sites are checked. This procedure 
is repeated twice (every 5 minutes during tDCS) with a small amount of saline 
solution being routinely applied at these times. 
• During this 20 minute tDCS session and then continuing for the next 1 hour and 40 
minutes, the child will be involved CIMT for the paretic hand and arm using a mitt. 
The mitt will therefore be applied for the 2-hour total period which incorporates this 
20 minute tDCS session. The CIMT will be administered to the child on an 
individual basis for these 2 hours each CIMT day by a CIMT-trained and licensed 
therapist.  Individualized activities will be created by the supervising treatment 
therapist investigator for shaping and repetition activities. Additionally, children will 
continue to use their paretic limb during functional activities at home and during a 
daily parent-supervised and documented home program. 
• Sham tDCS with CIMT group (control). These children will receive 10 daily 
sessions of both CIMT and sham tDCS. Children will receive the same procedures as 
the active tDCS with CIMT group (intervention), yet the device will be set to an 
integrated placebo setting which extinguishes the current after a 30 second to 1 
minute ramp-up phase and gradually reintroduces the ramp-down at the end of the 20 
minute session. 
• At the end of stimulation, the electrode site is checked for redness or skin damage. 
The rubber electrodes and headbands are cleaned with a disinfectant solution. 
• Vital signs measurements and Subject Report of Symptoms will be conducted before 
and after each daily session. 
• Interim testing at Day 5 will consist of vital signs, physician assessment, cognitive 
and behavioral testing as well as subject report of symptoms. 

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Post-Test 
Location: Clinical and Translational Science Institute (CTSI) 
Time: 2hours 
 
• Post-testing will occur 1 day following the 10-day intervention and, with the 
exception of an MRI, the same procedures will be followed as the pre-testing session, 
In addition the subject will be asked to complete a tDCS Feedback Survey 
Follow-Up 
Follow-Up will occur 6 months after the intervention, and participants and their 
families will be reimbursed for travel and housing for this return testing session. 
 
Location: Center for Magnetic Resonance Research (CMRR) 
Time: 1 hour 
• A pregnancy test for female subjects will be administered. 
• Subjects will be scanned on a Siemens 3T system. The scan protocol will include 
both a T1-weighted structural Magnetization Prepared Rapid Acquisition Gradient 
Echo (MPRAGE) scan and Diffusion Tensor Imaging (DTI). 
Location: Clinical and Translational Science Institute (CTSI) 
Time: 2 hours 
• Includes TMS testing, behavioral and cognitive measures defined in pre- and post- 
tests, vital signs measurements, and Subject Report of Symptoms, report of activities 
performed since post-test and a Family Feedback Survey. 
 
tDCS/Bimanual Therapy: 
ASSESSMENTSANDMEASUREMENTS 
PreTest 
#1 
Pre-tests 
# 2-4 
Pre-Test 
# 5-6 
Interim Test Post-Test Follow-up 
MRI/DTI 
 
 
x 
TMS 
X 
 
x 
x 
 
Vital Signs 
X 
 
x 
x 
 
Participant  Report of Symptoms 
X 
 
x 
x 
x 
x 
Behavioral to include: goal review, Box and 
Blocks 
X 
X 
x 
x 
x 
Behavioral Testing: Hand Dynamometer, AHA 
X 
X 
X 
X 
Classification Systems: MACS 
X 
X 
tDCS Survey 
x 
Study Feedback 
x 
 
 
Pre-Testing Session # 1:  
Location: Center for Translational Science Institute 
Time: 2-3 hours 
• Consent/Assent will be obtained and a pregnancy test for female subjects will be 
administered. 
• Cardiovascular Measurements: Subjects will be instrumented with a 3 or 12- 
Lead ECG for measurement of heart rate and a non-invasive blood pressure 

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measuring device that will be placed on a finger of their hand. (AD Instruments, 
Colorado Springs, CO). Subject Report of Symptoms survey will be completed. 
• The testing researcher will perform an assessment of cortical excitability using 
Transcranial Magnetic Stimulation. The subject will be comfortably seated in a 
reclining chair. Surface EMG electrodes will be attached over the first dorsal 
interosseous muscle serving the nonparetic hand, which will record the MEPs 
resulting from the magnetic stimulation to the contralesional M1. Next, the threshold 
for TMS activation of the target muscle will be determined. Subjects will wear a 
tracker made of light weight plastic to allow for co-registration of the MRI images to the 
child’s head dimensions with the use of stereotactic neuronavigation.  We will use a 70-
mm figure-eight TMS coil connected to a Magstim 200 machine. The coil will be 
handheld over the approximate hotspot area tangential to the scalp and oriented with 
the handle pointing posterolaterally at a 45° angle to the sagittal line. It will be 
moved systematically to find the true location of the hotspot. Single- pulse magnetic 
stimuli will be delivered manually at approximately 0.1 Hz starting at an intensity of 
60% of the stimulator maximum. This level will be adjusted systematically until the 
resting motor threshold is found, defined as the minimum intensity required to elicit 
MEPs >50 µV peak-to-peak in at least 5 of 10 trials with the target muscle at rest. 
• The testing researcher will perform an assessment of cognitive and behavioral 
function using: Assisting Hand Assessment, a measure of the child’s goals, 
Hand Dynamometry, the Manual Ability Classification System (MACS), and a 
measure of the child’s general activity level. 
 
Pre-Testing Sessions # 2-4:  
Location: Video phone calls 
Time: 30 minutes 
 
• The testing researcher will perform testing with the Box and Blocks test (wherein the child 
moves as many 1” wooden blocks within 1 minute) and child/caregiver questionnaires. For 
these pre-tests, we will mail you the supplies.  
 
Testing Session #5:  
Location: Center for Magnetic Resonance Research (CMRR) 
Time: 2 hours 
 
• Subjects will be scanned on a Siemens 3T system. The scan protocol will include 
both a T1-weighted structural Magnetization Prepared Rapid Acquisition Gradient 
Echo (MPRAGE) scan and Diffusion Tensor Imaging (DTI). 
• For children who have previously participated in our studies that included a MRI 
from the CMRR in the past 2.5 years, the MRI will not be repeated.  
 
Testing Session #6:  
Location: Clinical and Translational Science Institute (CTSI) 
Time: 2 hours 
• Cardiovascular Measurements: Subjects will be instrumented with a 3 or 12- 

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Lead ECG for measurement of heart rate and a non-invasive blood pressure 
measuring device that will be placed on a finger of their hand. (AD Instruments, 
Colorado Springs, CO). Subject Report of Symptoms survey will be completed. 
• 
The testing researcher will perform an assessment of cortical excitability using 
Transcranial Magnetic Stimulation. The subject will be comfortably seated in a 
reclining chair. Surface EMG electrodes will be attached over the first dorsal 
interosseous muscle serving the nonparetic hand, which will record the MEPs 
resulting from the magnetic stimulation to the contralesional M1. Next, the threshold 
for TMS activation of the target muscle will be determined. Subjects will wear a 
tracker made of light weight plastic to allow for co-registration of the MRI images to the 
child’s head dimensions with the use of stereotactic neuronavigation.  We will use a 70-
mm figure-eight TMS coil connected to a Magstim 200 machine. The coil will be 
handheld over the approximate hotspot area tangential to the scalp and oriented with 
the handle pointing  posterolaterally at a 45° angle to the sagittal line. It will be moved 
systematically to find the true location of the hotspot. Single- pulse magnetic stimuli 
will be delivered manually at approximately 0.1 Hz starting at an intensity of 60% of 
the stimulator maximum. This level will be adjusted systematically until the resting 
motor threshold is found, defined as the minimum intensity required to elicit MEPs 
>50 µV peak-to-peak in at least 5 of 10 trials with the target muscle at rest. 
• The testing researcher will perform an assessment of cognitive and behavioral 
function using: Assisting Hand Assessment, a measure of the child’s goals, 
Hand Dynamometry, the Manual Ability Classification System (MACS), and a 
measure of the child’s general activity level. 
 
Intervention 
Location: University of Minnesota—Center for Neurobehavioral Development (CNBD) 
Time: 2 hours/day for 10 (business) days with interim testing after Day 5 
 
• Before the tDCS session, skin under the electrode region will be assessed for lesions 
and evidence of skin disease or abnormalities which could cause potential irritation. 
tDCS is not administered if there is any skin damage, rash or other skin lesion under 
the electrode sites. 
• Skin is lightly cleaned with an alcohol swab, taking care NOT to abrade the skin in 
any manner.  Move hair away as best as possible from the site of stimulation in order 
to increase conductance. 
• Sanitized and disinfected rubber electrodes with clean, single-use sponges dampened 
with normal saline are placed over the stimulation sites and held against the head with 
wide rubber bands which cover the entire surface of the electrodes. Care is taken to 
ensure contact with the skin is firm and even over the entire surface of the electrode. 
• The static impedance measurement is checked- stimulation does not proceed unless 
levels are within limits recommended by the tDCS device manufacturer. 
• Active tDCS with bimanual therapy group (intervention): Stimulation is 
commenced and subjects are advised to report immediately if the stimulation feels 
painful, or anything other than low-level itchy or tingling sensations, common yet 
consistently reported at any time during the period of stimulation.  tDCS continues 
with a weak electrical current of up to 2.0 mA applied across the scalp for 20 
minutes in a single experimental session. 

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• After the first 2 minutes, the subject is questioned about pain at the electrode sites. If 
the stimulation is painful, a small amount of additional saline (approximately 4 mL) is 
added to the sponge, taking care to avoid wetting adjacent hair and thereby increasing 
the electrode area, and the tightness and placement of the band are checked.  If pain 
persists, the stimulation is stopped and the electrode sites are checked. This 
procedure is repeated twice (every 5 minutes during tDCS) with a small amount of 
saline solution being routinely applied at these times. 
• During this 20 minute tDCS session and then continuing for the next 1 hour and 40 
minutes, the child will be involved bimanual therapy.  The bimanual therapy will be 
administered to the child on an individual basis for these 2 hours each by an 
interventionist.  Individualized activities will be created by the supervising treatment 
therapist investigator for shaping and repetition activities. Additionally, children will 
continue to use their paretic limb during functional activities at home and during a 
daily parent-supervised and documented home program. 
• At the end of stimulation, the electrode site is checked for redness or skin damage. 
The rubber electrodes and headbands are cleaned with a disinfectant solution. 
• Vital signs measurements and Subject Report of Symptoms will be conducted before 
and after each daily session. 
• Interim testing at Day 5 will consist of vital signs, cognitive and behavioral 
testing as well as participant report of symptoms. 
Post-Test 
Location: Clinical and Translational Science Institute (CTSI) 
Time: 2hours 
 
• Post-testing will occur 1 day following the 10-day intervention and, with the 
exception of an MRI, the same procedures will be followed as the pre-testing session, 
In addition the participant will be asked to complete a tDCS Feedback Survey 
Follow-Up 
Location: Video conference call 
Time: 20 minutes 
• Follow-Up will occur 1 week after the intervention.  Includes a portion of the 
behavioral and cognitive measures defined in pre- and post- tests, and Subject 
Report of Symptoms, report of activities performed since post-test and a Family 
Feedback Survey. 
 
 
Study Protocol Compliance 
A home program will be issued by the treatment therapist investigator with journaling of 
activities performed.  This journal will be reviewed daily. 
 
If the subject or legal guardian displays an inability to complete the study due to non- 
compliance or incomplete involvement in the study, the subject will be withdrawn from 
the study and no further data will be obtained. 
 
Deviations from the Clinical Protocol 

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When a deviation from the protocol is necessary for an individual subject, the 
investigator must complete a description of the deviation from the protocol and 
justification on the Protocol Deviation Form and inform the IRB of the protocol deviation 
through formal documentation. 
 
Subject Withdrawal 
How to Withdraw Subjects: Subjects may discontinue participation at any time, for any 
reason. Any subject observed to have unacceptable responses to research procedures, or 
to be unable to safely or comfortably tolerate participation will be withdrawn. 
 
Subjects withdrawn from study will not be replaced, and the details surrounding the 
circumstances of the reason for withdrawing the subject from the study will be reported 
with no identifiers included. 
 
Data Collection and Follow Up for Withdrawn Subjects: If a subject and legal guardian 
are not compliant with establishing and meeting for the components of the study, the 
legal guardian will be contacted up to 2 times by phone in succession and by 1 letter 
thereafter. If no return contact is established, the subject will be withdrawn from the 
study and any data collected will be analyzed. 
 
6 
Data Analysis 
 
Subject Population(s) for Analysis 
Any subject who is observed in the study will have their data analyzed per the actual 
treatment received for evaluating safety. 
 
Statistical Methods 
Descriptive analyses of baseline characteristics and outcomes will include means and 
standard deviations for continuous variables with frequencies and percentages for 
categorical variables. Analysis Populations: There are 3 analysis populations planned. 
Intent-to-treat (ITT) will include any subject randomized according to their treatment 
assignment. Per-protocol (PP) will include randomized subjects without major protocol 
violations and who were compliant (at least 80% of planned sessions with their treatment 
assignment.  A detailed list of the major protocol violations warranting exclusion from 
the PP analysis will be determined prior to trial commencement. The Safety population 
will include all subjects who receive treatment, according to treatment received. We do 
not anticipate these groups to differ. 
 
Aim #1: Safety analyses will use the safety population and be primarily descriptive, 
reporting the number and percentage of adverse events, in particular, any instances of 
seizure or other serious adverse event. Instances of decline in paretic or nonparetic hand 
function as measured by the (Assisting Hand Assessment) AHA scaled score will also be 
evaluated. 
 
For tDCS/Bimanual Therapy: The same analyses will be conducted as the tDCS/CIMT 
study outlined in Aim #1. 
 
Aim #2: The primary analysis will use the ITT population to compare logit-based AHA 

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units between the intervention and control group adjusting for baseline values of AHA 
and presence of MEP for precision. Confidence intervals and P-values will be based on 
the t-distribution with corresponding degrees of freedom. P-values < 0.05 will be 
considered significant. Supportive analyses using the PP population will also be 
conducted. Secondary endpoints of Canadian Occupational Performance Measure 
(COPM), TOKEN test, Stereognosis and Finger force measurements will be analyzed in a 
similar fashion, adjusted for baseline values and presence of MEP with supportive 
analyses using the PP population.  The association of improved logit-based AHA units 
with DTI derived fractional anisotropy (FA) and MEP will be evaluated across all 
patients using generalized linear regression and the t-distribution with corresponding 
degrees of freedom for inference. Secondary analyses will evaluate these associations 
also adjusting for age and sex due to potential confounding influence though may be 
limited by sample size. Additional analyses for the comparisons mentioned above will 
consider non-parametric tests or transformations of variables in the event distributional 
assumptions do not hold. 
 
For tDCS/Bimanual Therapy:  The primary analysis will compare logit-based AHA 
units pre and post intervention.  Confidence intervals and P-values will be based on the 
t-distribution with corresponding degrees of freedom. P-values < 0.05 will be considered 
significant. Supportive analyses using the PP population will also be conducted. 
Secondary endpoints of Canadian Occupational Performance Measure (COPM), 
caregiver questionnaires will be analyzed in a similar fashion, adjusted for baseline 
values.  Secondary analyses will evaluate these associations also adjusting for age and 
sex due to potential confounding influence though may be limited by sample size. 
Additional analyses for the comparisons mentioned above will consider non-parametric 
tests or transformations of variables in the event distributional assumptions do not hold. 
 
Power and Sample Size: The sample size and power was primarily driven by the primary 
analysis of Hypothesis #1 of Aim #2. Power calculations for the primary outcome of 
logit-based AHA units were based on 10 patients in each group with variability estimates 
from the rTMS/CIMT study mentioned in the preliminary studies section suggesting a 
standard deviation of approximately 16. The correlation between pre- and post-treatment 
AHA scores in the rTMS/CIMT study was 0.97. Based on these estimates, we will have 
81% power to detect a difference of 5 logit-based AHA units. This study is intended to 
determine feasibility and explore preliminary efficacy results to inform the design of a 
future, larger RCT should promising results be found. 
 
Aim #3: Associations between changes in cortical excitability and the primary and 
secondary outcomes will be evaluated across all patients using generalized linear 
regression as in Aim #2. The change in contralesional M1 cortical excitability will be 
compared between intervention and control groups, adjusting for baseline values, using 
the ITT population. This comparison will be repeated within the subgroup of patients 
with an ipsilesional MEP. Similar to other aims, confidence intervals and P-values will 
be based on the t-distribution with corresponding degrees of freedom and supportive 
analyses using the PP population will also be conducted. Additional analyses for the 
comparisons mentioned above will consider non-parametric tests or transformations of 
variables in the event distributional assumptions do not hold. 
 

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7 
Safety and Adverse Events 
Definitions 
Adverse Event (AE): An adverse event (AE) is any symptom, sign, illness or experience 
that develops or worsens in severity during the course of the study. Intercurrent illnesses 
or injuries will be regarded as adverse events. Abnormal results of laboratory or 
diagnostic procedures are considered to be adverse events if the abnormality: 
• Results in study withdrawal 
• Is associated with a serious adverse event 
• Is associated with clinical signs or symptoms 
• Leads to additional treatment or to further diagnostic tests 
• Is considered by the Investigator to be of clinical significance. 
 
Serious Adverse Event (SAE): A serious adverse event (SAE) is any adverse event that is: 
• Fatal 
• Life-threatening 
• Requires or prolongs a hospital stay 
• Results in persistent or significant disability or incapacity 
• A congenital anomaly or birth defect 
 
Important medical events are events that may not be immediately life-threatening, but are 
clearly of major clinical significance and may be SAEs. They may jeopardize the 
subject, and may require intervention to prevent one or the other serious outcomes noted 
above. 
 
Hospitalization: Hospitalization shall include any initial admission (even if less than 24 
hours) to a healthcare facility as a result of a precipitating clinical adverse effect; to 
include transfer within the hospital to an intensive care unit. Hospitalization or 
prolongation of hospitalization in the absence of a precipitating, clinical adverse effect 
(e.g., for a preexisting condition not associated with a new adverse effect or with a 
worsening of the preexisting condition; admission for a protocol-specified procedure) is 
not, in itself, a serious adverse effect. 
 
Unanticipated Adverse Device Effect (UADE): An unanticipated adverse device effect is 
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 any other unanticipated serious problem associated with a device that relates to 
the rights, safety, or welfare of subjects. 
 
Unanticipated Problems Involving Risk To Subjects or Others (UPIRTSO): An adverse 
event that in the opinion of the Principal Investigator is unexpected, related to the device, 
and serious. 
 
Safety Monitoring Plan 
All research procedures will be performed by qualified personnel who have completed 
required training, including human subjects training. Dr. Bernadette Gillick has been 
investigating NIBS since 2007 with PhD training in TMS and Neuroimaging. 

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Additionally, she has been trained by the Harvard Berenson Center for Non-Invasive Brain 
Stimulation 2012 and NYC Neuromodulation Conference 2013 on the use and application of 
tDCS, and by Brainsight Stereotactic Neuronavigation President Roch Comeau in 2013. 
 
TMS cortical excitability testing will occur at the CTSI in the designated TMS room with 
the trained nursing/medical personnel on site, and the hospital emergency response team 
immediately available. 
 
tDCS/CIMT application will occur at Gillette Children’s Specialty Healthcare in St. Paul, 
Minnesota. Gillette specializes in diagnosing and treating neurological conditions as well 
as other complex medical conditions. Gillette encompasses a comprehensive team of 
specialists that provide medical, surgical rehabilitation and assistive technology services. 
They partner with Regions hospital in the operation of a pediatric intensive care unit. 
 
For tDCS/Bimanual Therapy: tDCS application and intervention will occur at UMN 
Center for Neurobehavioral Development in Minneapolis, Minnesota. We will have an 
on-call, physician during the intervention hours.    
 
All personnel will comply with all related regulations and laws, included, but not limited 
to 45CFR parts 60 and 64, and HIPAA Privacy Regulations. Study data and information 
will be kept confidential and managed in accordance with requirements of HIPAA.  All 
data will be stored in locked offices and not released without subject permission. 
 
Subjects will be rigorously screened against inclusion/exclusion criteria to ensure that 
their participation is safe.  This screening begins at the initial discussion in the phone 
screen, continues with review of the medical records by the physicians on the study and is 
again repeated in-person with an on-site screening tool. 
 
AEs and SAEs will be assessed and followed throughout the study.  Vital sign monitoring 
will occur before and after TMS and tDCS applications. Active adverse events collection 
through the Subject Report of Symptoms questionnaire will be employed before and after 
tDCS application 
 
Subjects will have contact information to enable them to contact study personnel easily 
and quickly. 
 
Anticipated Risks / Risk Mitigation- We anticipate minor adverse events as listed below 
in this table. For a serious adverse event such as seizure, please refer to the study 
stopping rules as listed in next section. 
 
Study Procedure 
Anticipated Risks 
Risk Mitigation 
tDCS 
Burn- Electrolysis 
Ensure proper electrode contact with skin 
tDCS 
Stimulation in subjects 
with reduced sensation 
Assess sensation, avoid placing electrodes 
over areas of decreased sensation 
tDCS 
Stimulation over 
broken skin, reduced 
resistance 
Assess skin integrity, avoid placement of 
electrodes over recent shaving, skin 
defects 

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tDCS 
Stimulation over 
conductive implants 
Screen appropriately for exclusion criteria 
of implants 
 
tDCS 
Stimulation over a 
tumor which may alter 
metabolic activity 
Screen appropriately for exclusion criteria 
of neoplasm. 
tDCS 
Threshold altering 
pharmacologic agent 
Screen appropriately for exclusion criteria 
of centrally acting agent. 
tDCS 
Itching, Tingling, 
Burning Sensation in 
the area of the 
electrodes 
Ensure proper contact of surface 
electrodes with skin. Maintain current 
dosage within low-range of researched 
dosages. Ensure that electrode sponges 
are properly sanitized and that saline 
solution is appropriately employed. 
tDCS 
Headache 
Ensure that headband securing electrodes 
is in proper placement, yet not to the level 
of impingement of scalp area. Maintain 
current dosage within low range of 
delivery. 
tDCS 
Pain- Neck, Scalp 
Ensure that electrodes are in proper 
contact with skin and adjust head position 
as needed for comfort. 
tDCS 
Skin Redness 
Ensure proper electrode position and 
proper level of moisture to even 
stimulation across the electrode 
tDCS 
Fatigue, Sleepiness 
Screen for continuous effect at follow-up 
visit. 
tDCS 
Concentration or Mood 
Changes 
Evaluate cognitive status through 
physician examination and psychometric 
testing at three timepoints. 
TMS 
Stimulation over a 
tumor which may alter 
metabolic activity 
Screen appropriately for exclusion criteria 
of neoplasm. 
TMS 
Threshold altering 
pharmacologic agent 
Physician review of each medical record 
for determination of appropriateness for 
study inclusion. 
TMS 
Headache 
Ensure that headband securing electrodes 
is in proper placement, yet not to the level 
of impingement of scalp area. Maintain 
current dosage within low range of 
delivery. 
TMS 
Fatigue, Sleepiness 
Screen for continuous effect throughout 
observation. 
TMS 
Temporary mild 
hearing loss due to 
noise level of 
equipment 
Ear plugs will be inserted before 
commencement of TMS testing. 
 

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CIMT 
Sling/Mitt Irritation 
Screen continuously during application 
and modify sling/mitt position to ensure 
comfortable fit. 
MRI 
Potential dislodging of 
indwelling metals and 
disruption of medical 
devices. 
Prior to participation screen for existence 
of indwelling metal/medical devices. 
Exclude, or, if metal/medical devices are 
compatible, obtain verification from 
appropriate physician. 
MRI 
Metal projectiles 
inadvertently presented 
during MRI 
Conduct on-site screen and removal of 
potential projectiles (coins, keys, etc) 
MRI 
Unknown effects of 
MRI on the unborn 
fetus 
Administer pregnancy test on all female 
subjects. Exclude if test is positive. 
MRI 
Temporary mild 
hearing loss due to 
noise level of 
equipment 
Subjects will wear earplugs and 
headphones during MRI to protect against 
excessive noise. 
MRI 
Strong claustrophobia 
Claustrophobia will be screened in 
advance of participation 
MRI 
Transient dizziness 
upon removal from the 
magnet 
Subject will be instructed to sit up slowly 
and remain seated for several minutes 
before standing. Subject will not be 
dismissed until dizziness subsides. 
 
Medical Monitoring for Participant Safety 
The Principal Investigator will oversee the safety of the study, including careful 
assessment and appropriate reporting of adverse events.  Medical monitoring will include 
a regular assessment of the number and type of serious adverse events. 
 
The Medical Monitor for the study is: 
Linda E. Krach, MD  
Vice President of Medical 
Operations 
Courage Kenny Rehabilitation Institute 
800 East 28th Street 
Mail Route 12101 
Minneapolis, MN 55407 
612-863-7150 
 
Study Stopping Rules 
Both Individual and Entire Study stopping rules are described below: 
 
Death. Study stopped for both individual and entire study. A full investigation of event 
will be explored by entire study team. The medical monitor will review all details. Report 
of event will be distributed to all governing and monitoring committees. 
Seizure: Individual- Immediate suspension of tDCS application for this particular child 
and initiation and follow-through of safe and effective seizure management. Refer to 

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comprehensive seizure management outline. Provide physician letter to subject which 
describes the research-related adverse event with physician interpretation. 
 
Study Medical Director Evaluation. Recommend further evaluation to the child and legal 
guardian by pediatric neurologist if not the pediatrician routinely involved in the child’s 
care. 
 
An identification of causality and re-evaluation of treatment design will occur by study 
researchers, including consultants, medical monitor and physicians in order to proceed. 
All procedures will be assessed for strict adherence to all intervention steps listed in the 
protocol.  If deviation is found, error will be corrected. Proceed with study. 
 
Entire Study- If another subject incurs a seizure proceed with steps for Individual 
Stopping Rules as noted above.  Study will be suspended at this point and a thorough 
review by research team, medical monitor and consultants will occur in order to assess 
the need for amendment of the protocol or full stop/termination of study for future safety 
concerns. 
 
Anticipated Adverse Events 
Subjects will be children who sustained a congenital stroke before, during or one-year 
after birth.  In addition to cited research procedure risk, they will be at risk for 
complications, morbidities and mortalities associated with pediatric strokes. 
 
Adverse Event Reporting 
All Adverse Events occurring during the study period must be recorded.  The clinical 
course of each event will be followed until resolution, stabilization, or until it has been 
determined that study treatment or participation is not the cause. 
 
The Sponsor-Investigator will promptly review documented adverse effects and abnormal 
test findings to determine 
1) if the abnormal test finding should be classified as an adverse effect; 
2) if there is a reasonable possibility that the adverse effect was caused by the 
investigational device or, if applicable, other study treatment or diagnostic 
product(s); and 
3) if the adverse effect meets the criteria for a serious adverse effect. 
 
If the Sponsor-Investigator’s final determination of causality is “unknown and of 
questionable relationship to the investigational device or, if applicable, other study 
treatment or diagnostic product(s)”, the adverse effect will be classified as associated with 
the use of the investigational device or study treatment or diagnostic drug product(s)    
for reporting purposes.  If the investigator-sponsor’s final determination of causality is 
“unknown but not related to the investigational device or, if applicable, other study 
treatment or diagnostic product(s)”, this determination and the rationale for the 
determination will be documented in the respective subject’s case history. 
Adverse Events 
All observed or volunteered adverse effects and abnormal test findings, if applicable, or 
suspected causal relationship to the investigational device or, if applicable, other study 

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treatment or diagnostic product(s) will be recorded in the subjects’ case histories.  For all 
adverse effects, sufficient information will be pursued and/or obtained so as to permit 
 
1) an adequate determination of the outcome of the effect (i.e., whether the effect should 
be classified as a serious adverse effect) and; 
2) an assessment of the casual relationship between the adverse effect and the 
investigational device or, if applicable, the other study treatment or diagnostic product(s). 
 
Adverse effects or abnormal test findings felt to be associated with the investigational 
device or, if applicable, other study treatment or diagnostic product(s) will be followed 
until the effect (or its sequelae) or the abnormal test finding resolves or stabilizes at a 
level acceptable to the Sponsor-Investigator. 
 
Adverse Events that do not qualify as Serious Adverse Events or as Unanticipated 
Adverse Device Effects will be reported the IRB with the continuing review progress 
report. 
 
Serious Adverse Events 
Unexpected serious adverse events that are at least possibly related will be reported to the 
IRB within 10 days of learning of the event. 
 
Unanticipated Adverse Device Effects (UADE) 
Investigators are required to submit a report of a UADE to the reviewing IRB as soon as 
possible, but in no event later than 10 working days after the Investigator first learns of 
the event. 
 
If the Adverse Event is Serious, Unanticipated, Device Related, and determined by the 
Sponsor-Investigator to present an unreasonable risk to subjects, the Sponsor must 
terminate the study within 5 working days of that determination. 
 
Unanticipated Problems Involving Risk To Subjects or Others (UPIRTSO) 
Investigators are required to submit a report of UPIRTSO events to the IRB within 10 
working days of first learning of the event. 
 
Data Safety Monitoring Board 
No DSMB will be incorporated in this study as a medical monitor is in place. 
 
8 
Data Handling and Record Keeping 
 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA). Those regulations require a signed subject authorization informing the subject 
of the following: 
• What protected health information (PHI) will be collected from subjects 
in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 

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• The rights of a research subject to revoke their authorization for use of 
their PHI. 
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization.  For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect at least vital status (i.e. that the 
subject is alive) at the end of their scheduled study period. 
 
Source Documents 
Source Data are the clinical findings and observations, laboratory and test data, and other 
information contained in Source Documents. Source Documents are the original records 
(and certified copies of original records); including, but not limited to, hospital medical 
records, physician or office charts, physician or nursing notes, subject diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, x-rays, etc. When applicable, information recorded on the CRF shall match 
the Source Data recorded on the Source Documents. 
 
Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study. 
All data requested on the CRF must be recorded. All missing data must be explained.  If 
a space on the CRF is left blank because the procedure was not done or the question was 
not asked, write “N/D”.  If the item is not applicable to the individual case, write “N/A”. 
All entries should be printed legibly in black ink.  If any entry error has been made, to 
correct such an error, draw a single straight line through the incorrect entry and enter the 
correct data above it.  All such changes must be initialed and dated. DO NOT ERASE 
OR WHITE OUT ERRORS.  For clarification of illegible or uncertain entries, print the 
clarification above the item, then initial and date it. 
 
A Case Report Form will be completed for each subject enrolled into the study. The 
investigator-sponsor will review, approve and sign/date each completed CRF; the 
investigator-sponsor’s signature serving as attestation of the investigator-sponsor’s 
responsibility for ensuring that all clinical and laboratory data entered on the CRF are 
complete, accurate and authentic. 
 
1) Eligibility Phone Screen 
2) HIPAA  Form 
3) Demographic Medical History Form including MRI Report 
4) Individual Data Collection Forms 
5) Exit Forms 
Data for this study will be entered by the research investigators and study coordinator 
immediately into the CRF. The data will then be entered within the next week into a 
REDCap database , which uses a MySQL database via a secure web interface with data 
checks used during data entry to ensure data quality. REDCap includes a complete suite 
of features to support HIPAA compliance, including a full audit trail, user-based 
privileges, and integration with the institutional LDAP server. The MySQL database and 
the web server will both be housed on secure servers operated by the University of 

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Minnesota Academic Health Center’s Information Systems group (AHC-IS). The servers 
are in a physically secure location on campus and are backed up nightly, with the 
backups stored in accordance with the AHC-IS retention schedule of daily, weekly, and 
monthly tapes retained for 1 month, 3 months, and 6 months, respectively. Weekly 
backup tapes are stored offsite. The AHC-IS servers provide a stable, secure, well-
maintained, and high-capacity data storage environment, and both REDCap and 
MySQL are widely-used, powerful, reliable, well-supported systems. Access to the 
study's data in REDCap will be restricted to the members of the study team by 
username and password. 
 
Records Retention 
All records will be kept in the study coordinator’s office in a locked file cabinet. The 
CRF’s will be kept with the study coordinator until the study is completed. Thereafter the 
PI will maintain all records for 6 years. 
 
9 
Study Monitoring, Auditing, and Inspecting 
 
This study will be monitored according to IRB/CTSI/GCP guidelines.  The Investigator 
will allocate adequate time for such monitoring activities. The Investigator will also 
ensure that the monitor or other compliance or quality assurance reviewer is given access 
to all study-related documents and study related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.), and has adequate space to conduct the monitoring visit. 
 
Study Monitoring Plan 
The study uses a non-significant risk device. Therefore, independent monitoring of the 
clinical study for clinical protocol and abbreviated IDE application compliance will be 
conducted periodically (i.e., at a minimum of annually) by qualified staff of the 
University of Minnesota’s Clinical and Translational Science Institute (CTSI). 
 
Quality Assurance Procedures 
Data will be reviewed for completeness and accuracy at the end of the trial by verifying 
missing data is indeed missing from the paper form and outliers are true values prior to 
beginning the study analysis. 
 
Auditing and Inspection 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, 
the sponsor, government regulatory bodies, and University compliance and quality 
assurance groups of all study related documents (e.g. source documents, regulatory 
documents, data collection instruments, study data etc.). The investigator will ensure the 
capability for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality 
assurance offices. 
 
10 
Ethical Considerations 
This study is to be conducted according to US and international standards of Good 

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Clinical Practice, applicable government regulations and Institutional research policies 
and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted 
independent Institutional Review Board (IRB), in agreement with local legal 
prescriptions, for formal approval of the study conduct.  The decision of the IRB 
concerning the conduct of the study will be made in writing to the investigator and a copy 
of this decision will be provided to the sponsor before commencement of this study. 
 
11 
Study Finances 
 
Funding Sources 
• This study is funded by a University of Minnesota Clinical and Translational 
Science Institute K01 Grant, with funds provided to the University by the National 
Institutes of Health (NIH).  Research reported is supported by the Eunice Kennedy 
Shriver National Institute of Child Health and Human Development of the 
National Institutes of Health under Award Number K01HD078484. The      
content is solely the responsibility of the authors and does not necessarily 
represent the official views of the National Institutes of Health. 
• Cerebral Palsy International Research Foundation (CPIRF) 
• Foundation for Physical Therapy Magistro Family Foundation Research Grant 
 
 
Conflicts of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, etc.) 
must refer to the Regents Policies on Individual Conflict of Interest Policy or Institutional 
Conflict of Interest Policy. These policies require University Faculty and staff to report 
external professional activities and business and significant financial interests related to 
his or her University activities by submitting a REPA (Report of External Professional 
Activities) at least once per year. Faculty and staff should also file a REPA when 
substantial changes in business or financial interests occur, when an activity that presents 
a potential conflict of interest is anticipated, or when submitting an application for 
research support or technology transfer, submitting research protocols to the IRB, or 
receiving financial contributions. All University of Minnesota investigators will follow 
the University conflict of interest policy. 
 
12 
Publications Plan 
Neither the complete nor any part of the results of the study carried out under this protocol, nor any 
of the information provided by the sponsor for the purposes of performing the study, will be 
published or passed on to any third party without the consent of the study sponsor.  Any 
investigator involved with this study is obligated to provide the sponsor with complete test results 
and all data derived from the study. 
 
13 
List of Reference Documents 
Below is a list of documents used in the conduct of this study. Copies of these 
documents can be found in the study’s regulatory binder: 
 

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1. Phone Screen 
2. Manual Ability Classification System form 
3. Physician Medical Records Screening Form 
4. On-Site Screening Form 
5. Consent Form 
6. Assent Form 
7. Addendum to Assent for Female Minors 
8. Subject Report of Symptoms Questionnaire 
9. Comprehensive seizure management outline 
10. Complete seizure observation documentation form 
11. Physician seizure note 
 
14 
References 
 
1. Gillick B, Krach L, Feyma T, Rich T, Moberg K,Thomas W, Cassidy J, Menk J, 
Carey J. Primed low-frequency repetitive transcranial magnetic stimulation and 
constraint-induced movement therapy in pediatric hemiparesis: A randomized 
controlled trial. Dev Med Child Neurol. 2014;56(1):44-52. doi: 10.1111/dmcn.12243. 
 
2. Kirton A, Deveber G, Gunraj C, Chen R. Neurocardiogenic syncope complicating 
pediatric transcranial magnetic stimulation. Pediatr Neurol. 2008;39(3):196-197. 
 
Bolognini N, Vallar G, Casati C, et al. Neurophysiological and behavioral effects of 
tDCS combined with constraint-induced movement therapy in poststroke patients. 
Neurorehabil Neural Repair. 2011;25(9):819-829. doi: 10.1177/1545968311411056 
3. Gillick B, Feyma T, Menk J, Usset M, Vaith A, Wood TJ, Worthington R, Krach 
LE.  Safety and feasibility of transcranial direct current stimulation in pediatric 
hemiparesis: randomized controlled preliminary study. Phys Ther. 2015; 95(3): 
337-49. 
4. de Brito Brandao M, Gordon AM, Mancini MC.  Functional impact of constraint 
therapy and bimanual training in children with cerebral palsy: A randomized 
controlled trial.  Am J Occup Ther.2012; 66(6): 672-81. 
5. Gelkop N, Burshtein DG, Lahav A, Brezner A, Al-Oraibi S, Ferre CL, Gordon 
AM. Efficacy of constraint-induced movement therapy and bimanual training in 
children with hemiplegic cerebral palsy in an educational setting.  Phys Occup 
Ther Pediatr.  2015; 35(1): 24-39. 
6. Bolognini N, Vallar G, Casati C, et al. Neurophysiological and behavioral effects of 
tDCS combined with constraint-induced movement therapy in poststroke patients. 
Neurorehabil Neural Repair. 2011;25(9):819-829. doi: 
10.1177/1545968311411056. 
 
7. Kirton A, Chen R, Friefeld S, Gunraj C, Pontigon AM, Deveber G. Contralesional 
repetitive transcranial magnetic stimulation for chronic hemiparesis in subcortical 
paediatric stroke: A randomised trial. Lancet Neurology. 2008;7(6):507-513. 
 
8. Ciechanski P, Kirton A.  Transcranial direct-current stimulation can enhance 
motor learning in children.  Cereb Cortex. 2016. pii: bhw114 [Epub ahead of 

IRB Code # 1408M53169 
Version Date: 5.9.2017 
37 of  37 
 
print]. 
 
9. Kirton A, Ciechanski P, Zewdie E, Andersen J, Nettel—Aguirre A, Carlson H, et 
al. Transcranial direct current stimulation for children with perinatal stroke and 
hemiparesis. Neurology. 2017; 88(3): 259-267. 
 
10. Bikson M, Grossman P, Thomas C, Zannou AL, Jiang J, Adnan T, et al. Safety of 
transcranial direct current stimulation: Evidence based updated 2016.  Brain 
Stimul. 2016; 9(5): 641-61.