Optimizing Current and Electrode Montage for Transcranial Direct Current Stimulation in Stroke Patients
Phase: NA
Conditions: Stroke
Sponsor: Medical University of South Carolina

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Optimizing Current and Electrode Montage for Transcranial Direct Current Stimulation 
in Stroke Patients 
 
Junior Investigator Proposal supporting 
MUSC Center of Biomedical Research Excellence (COBRE) Application 
 
Wayne Feng MD MS (PI); Michelle Woodbury PhD (Co-PI); Yusheng Zhu MD PhD (Co-I); Robert Adams MD  
 
MS (Co-Mentor); Mark George MD (Co-Mentor)  
NCT02763826   

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Specific Aims: 
Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique 1-4 that can 
modulate cortical excitability of targeted brain regions. One can measure tDCS induced changes in excitability 
using a different noninvasive brain stimulation method - transcranial magnetic stimulation (TMS). Various 
studies have investigated tDCS use in stroke patients with motor impairments (cumulatively about 200 cases) 
5-11. Although these studies are mostly “proof of concept” with small sample size, they do suggest that tDCS 
may improve motor function. Before a Phase II single-center clinical trial (a R01 application) to assess the 
efficacy of tDCS for stroke motor recovery is launched by the applicant, two critical scientific questions need to 
be answered FIRST in order to increase the likelihood of success of clinical trial in planning.  
What is the optimal current for stroke patients? No systematic investigation has been done to determine 
the most efficacious current that is both safe and tolerable for stroke patients. There is empirical evidence that 
tDCS with current up to 2 mA for 20-40 minutes for either single or multiple sessions can safely be 
administered to healthy subjects 1,3,12. It is probably safe for stroke patients, but there are no safety guidelines 
in this population12. Animal studies 13,14 have established a much higher safety limit (>50X) than the human 
protocols, but safety concerns have limited tDCS current to 2 mA for human subjects.  This is a critical issue to 
explore because it is likely that a higher current is more efficacious in increasing cortical excitability and hence 
motor recovery in stroke patients.  
Aim 1: To determine the optimal tDCS current in stroke subjects 
The optimal current balances cortical excitability and tolerability/safety in stroke patients. We will invesitigate 
the optimal curent in range of 1 mA to 4 mA. We hypothesize that 4 mA is tolerable, safe and can induce the 
highest level of cortical excitability in the lesional motor cortex. We will adapt the classic, gold-standard 3+3 
experimental design that is commonly used to find the maximal tolerable dose in drug trials. Tolerability/safety 
will be investigated by monitoring clinically detectable symptoms by monitoring vital signs and surveying 
subjects with a quesionnaire before and after stimulation, additionally by detecting subclinical neuronal injury 
using (1) Magnetic Resonance Imaging/Diffusion Weighted Imaging (MRI/DWI) to detect any focal ischemia; 
and 2) Molecular biomarkers: S100b and neuron-specific enolase (NSE) to detect neuronal injury. Cortical 
excitability is measured by the amplitude of motor evoked potentials (MEPs) induced by TMS from the 
abductor pollicis brevis muscle of the affected side. 
What is the optimal tDCS electrode montage for stimulation? According to the theoretical model 
underlying the use of tDCS for stroke motor recovery, stroke causes an “interhemispheric imbalance 15-17” with 
decreased motor excitability in the ipsilesional hemisphere and excessive excitability in the contralesional 
hemisphere. This has led to studies testing the effects of anodal (excitatory) stimulation to the lesional 
hemisphere 8,18, cathodal stimulation (inhibitory) to the non-lesional hemisphere 6,11 or combined bi-
hemispheric stimulation 19,20.  However, it has not been established which montage can induce the maximal 
cortical excitability, and eventually the maximal motor recovery.   
Aim 2: To determine the optimal tDCS electrode montage in stroke subjects 
We hypothesize that the bi-hemispheric stimulation with anodal stimulation on the lesional hemisphere and 
simultaneous cathodal stimulation on the non-lesional hemisphere induces more cortical excitability in the 
lesional hemisphere than either anodal stimulation on the affected hemisphere or cathodal stimulation on non-
lesional hemisphere alone. We will use a randomized, complete block design in which all stroke subjects 
undergo each of the three electrode montages (on different days) at the current determined in Aim1. As in Aim 
1, MEPs from the affected APB muscle will recorded pre- and post- stimulation to determine the optimal 
montage for the maximal cortical excitability from the lesional hemisphere. 

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This proposal lays the scientific foundation for systematic application of tDCS in stroke recovery research. It 
also serves as an important bridging step between the applicant’s prior training and his next milestone - a 
Phase II single-center clinical trial (a R01 application) to assess the efficacy of tDCS for stroke motor recovery 
with the optimal current and stimulation montage determined by this proposal.  
 
 
A: Significance: 
A1. Motor Deficits Associated with Stroke: There are 795,000 new strokes each year in the US and stroke 
is a leading cause of long term disability 21,22. Motor deficit is the most common deficit after stroke 23. Stroke 
recovery strategies, such as, innovative equipment (robotic24), cellular therapy25, and brain stimulation 
(invasively26 or noninvasively27) seek to enhance neural plasticity thereby improving function. tDCS is a 
portable, non-invasive brain stimulation technique 1-4 that can be applied simultaneously with rehabilitation 
therapy with potential to improve motor function in stroke survivors.  
A2. tDCS to Augment Motor Improvement: tDCS can modulate the excitability of targeted brain regions by 
altering neuronal membrane potentials resulting from low-voltage, direct current that is transmitted through the 
skull via surface electrodes 4. Behavioral effects after a single 10-40 minute stimulation session have been 
demonstrated to outlast the stimulation period by as long as 90 minutes 4,28,29. This is most likely due to the 
modulation of cellular NMDA-receptors 4,28 and through augmentation of synaptic plasticity that 
requires the presence of BDNF 30. To date, tDCS has been tested across the world in thousands of healthy 
subjects and patients with various disease conditions 12. In 12 published studies (summaried in applicant’s 
review31), mostly “proof of concept” studies with small sample size, subjects have included about 200 stroke 
patients with motor deficits with current ≤ 2 mA. This technique shows promise of emerging as an adjunctive 
therapeutic tool to promote motor recovery; however, two scientific questions must be answered before it can 
be further tested in large phase II/III clinical trial. For example, the optimal current (dose) is not clear, nor is the 
electrode montage for stroke patients.   
A3. Safety and Current (Dose) Issues: Theoretical knowledge regarding the safety and tolerability of 
electrical stimulation is based on physical aspect of this technique and data from both animal and healthy 
human studies. These data support the safety of the present tDCS protocols 1,3,4,13,14,32. Heatlhy subjects are 
exposed to “no significant risk” at currents ranging of 0.5 to 2 mA for up to 40 minutes either over a single 
session or multiple sessions. However, safety implications are not clear in stroke patients (i.e., subjects with a 
brain lesion) and there may be potential for increased risk. So far there has been no single, dedicated study to 
systematically evaluate the safey and tolerability of tDCS at various currents in the stroke population. 
Commonly reported side effects occured at the site where the electrodes are placed and are a minor issue 3,33: 
local scalp itching, tingling or burning sensations, transient headaches or stimulation-induced skin lesions 34,35 
or contact dermatitis 36. The size of the eletrode pad also matters in terms of safety and tolerability. Electrode 
size determines current density. It is defined as current/electrode contact area. Depending on the size of the 
electrode (typically 3 × 5 cm², 5 × 5 cm2 or 5 × 7 cm²), current density even at 4 mA – the highest current 
available for clinical research (Chattanooga Dual-Channel Iontophoresis Device), is approximately 0.11 
mA/cm2 to 0.27 mA/cm2. This current density is considerably below the safety threshold determined by 
invasive stimulation technique 32 or the safety limit (~2%) established in an animal study14. While underdosing 
is possible, safety concerns have led researchers to avoid higher tDCS current in stroke patients. Two studies 

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show that 2 mA is more effective than 1 mA in enhancing cognitive effects in healthy subjects 37 and working 
memory in patients with Parkinson disease38. It is not clear whether there is a linear current (dose) response 
relationship associated with current and cortical excitability, especially when the current exceeds 2 mA.  
Patient protocol evolution must balance safety and current (dose). For research with tDCS, it is critically 
important maximal current levels not be “frozen” at an arbitrary limit of 2 mA, especially if a higher dose is 
tolerated and produces more excitability changes and are thus likely more effective. Without performing an 
initial current (dose) finding and safety study, the field risks performing clinical trials that might be ineffective or 
less effective, but solely because of underdosing. Rather than wasting the time and money on potentially 
under-dosed studies, it is important to establish this knowledge of dose effects now.  
A4. Electrode Montage for Stimulation In Stroke Patients: The second scientific gap concerns the optimal 
electrode montage that is most favorable for cortical stimulation in stroke patients. The theoretical model 15-17 
that serves as the basis for tDCS for post-stroke motor recovery is that of “interhemispheric imbalance (Figure 
1A)”. After a stroke, there is decreased motor activity in the ipsi-lesional hemisphere and excessive activity in 
the contra-lesional hemisphere, and they are associated with poor motor recovery.  In efforts to correct such 
imbalance, tDCS was applied either by  
• 
Anodal stimulation (Figure 1B) on the affected hemisphere 8,18 to up-regulate the cortical excitability, or  
• 
Cathodal stimulation (Figure 1C) on the non-lesional hemisphere to down-regulate the cortical 
excitability 6,11, or 
• 
Bi-hemispheric stimulation (Figure 1D) with anodal stimulation on affected hemisphere and 
simultaneous cathodal stimulation on non-lesional hemisphere 19,20 to up regulate and down regulate 
cortical excitability simultaneously.  
All three electrode stimulation montages demonstrated various promising improvements in motor functions in 
stroke patients. Two studies 39,40 with healthy subjects suggest bi-hemispheric stimulation may have 
advantages over uni-hemispheric stimulation. One TMS study41 with bihemispheric rTMS suggested that the 
bi-hemispheric stimulation yielded stronger effects than uni-hemispheric stimulation. It remains unclear which 
approach is optimal for stroke patients.  
This proposal will address those two issues.  We aim to solve a much needed scientific issue and to close 
a scientific gap by establishing safety limits and identifying the optimal current and electrode montage for 
stroke patients.  This project defines the fundamental work needed before systematically investigating the 
application of the technique in promoting motor recovery in stroke patients, thereby improving the odds of 
success for the future clinical trial.  

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B.  Innovation:  
• 
Innovative trial design. We innovatively adapt a 3+3 trial design (Figure 4) that is commonly used in 
drug trials to assess safety and tolerability of tDCS current for Aim 1. Current associated with tDCS 
technique is like dosage to a drug that can be adjustable. Evaluating safety/tolerability of tDCS 
technique is similar to assessing drug safety and dosing finding. While innovative, the design is simple 
and easy to understand as well as to implement. 
• 
Use of MR imaging and biomarkers to test for subclinical neuronal injury. We will test for 
subclinical injuries with a combination of imaging and biomarker measurements to best ensure 
thesafety in stroke subjects, as opposed to only assessing safety and tolerability with clinically 
detectable symptoms as done in most of the previous tDCS safety studies. MRI Diffusion Weight 
Imaging, dependent on the motion of water molecules, provides information regarding tissue integrity. It 
is a gold standard for early detection of brain ischemia 42 with a high sensitivity as well as high 
specificity 43. An Apparent Diffusion Coefficient (ADC) value decrease represents diffusion restriction 
while an ADC value increase indicates an increase in water mobility in the stimulated cortex. Neuron-
specific enolase (NSE) and S-100b protein (S-100b) are two widely investigated molecular markers for 
brain injury 44-46. NSE originates from the cytoplasm of neurons and neuroendocrine cells. S-100 protein 
is a dimeric acidic calcium-binding protein found in the brain with high concentrations in astrocytes and 
Schwann cells. The serum levels of these proteins are elevated after different types of brain injury 
including focal and global ischemia 46-48, traumatic brain injury 49 and hypoxic brain injury 50. 
C:  Preliminary data:  
In the applicant’s lab, a pilot study “Bihemiespheric 
Stimulation and Constrainted-Induced ovement 
Therapy (CIMT) to Promote Post-Stroke Motor 
Recovery” is currently ongoing with 3 stroke subjects 
who have completed the protocol. While the main 
objective of the study is to determine whether tDCS 
can amplify the effects of CIMT, the study also provides 
a test of the safety and tolerability of stimulation current 
at 2 mA. To date, we have demonstrated that 
bihemispheric stimulation with 2 mA and electrode size 
of 15 cm² (current density is 0.133mA/cm²) for 30 
minutes is safe and tolerable in a single session as 
well as ten sessions over 2 weeks. One subject  
experienced transient mild headache and tingling 
during stimulation, and another subject  experienced 
transient scalp redness under the anodal stimulation 

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electrode.  Vital signs for all four patients were stable and no one discontinued the study due to side effects 
(Table 1). No new focal ischemic lesions were observed on MRI DWI sequence and no changes in Apparent 
Diffusion Coefficient (ADC) map was observed in any of 3 subjects (Figure 2) .  
We also observed an increased cortical excitability on the affected motor cortex in all three stroke subjects 
(Figure 3). The increased cortical excitability from lesional motor cortex is associated with postive changes 
with behavioral assessment using FM-UE scal and Wolf Motor Functional Test (data not shown). 
In summary, consisent with prior studies and consensus from experts in the field, 2 mA appears to be a safe 
current for stroke patients. Further, we have established the feasibility of recruiting stroke subjects and using 
tDCS as proposed and using TMS for cortical excitability assessment.  
D: Approach: 
This grant proposal is divided into two independent, but well-connected experiments – Aim 1 to determine the 
optimal current and Aim 2 to address the optimal stimulation montage.  
 
 
D1.1 Design:  
This aim is a phase I type study to determine the most efficacious current for tDCS, recognizing that this 
current level must be tolerable and safe. The trial 
design is adapted from the classical, gold-standard 3+3 
drug trial design 51,52, which is commonly used to find 
the maximal tolerable dose for a chemical drug. The 
main justification for this design is that the maximal 
tolerable current (dose) is usually and arbitrarily 
defined as the dose at which one-third of the patients 
experience current (dose)-limiting major side 
effects/response. The algorithm for current (dose) 
escalation is detailed in (Figure 4). The study starts 
with 1 mA : (a) if no major response occurs in any of 
the three subjects, a next current at 2 mA will be used 
next; (b) if major response occurs in 2-3 study subjects, 
then the trial will stop at this current level; (c) if major 
response occurs in one subject, then 3 additional study 
subjects will be entered to further test the safety of 
same current dose; if no major response occurs, then 
the current will be escalated next current level; if further major response occurs, then the trial will terminate. 
The previous current level will be defined as the maximal tolerable current (dose). The current tDCS device 
avaiable on the market (Chattanooga Dual-Channel Iontophoresis Device) for research use has a maximal 
current of 4.0 mA. The sequence for current escalation will be 1.0 mA  >> 2.0 mA  >> 2.5 mA >> 3.0 mA >> 3.5 
mA >> 4.0 mA. 
While we vary current in this protocol, other features of the stimulation will be controlled:   
• 
Duration of stimulation will be 30 minutes: Data show the increased excitability of tDCS can last as 
long as 90 minutes. Our rehabilitation intervention will take one hour. Thus, by using 30 minutes of 
Aim 1: To determine the optimal current in stroke patients 

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stimulation, as has been commonly used in stroke studies, we should ensure that the potentially 
beneficial effects of the stimulation will not wear off during the course of rehabilitation.  
• 
Size of electrode will be 3 × 5 cm²: The commonly used 3 × 5 cm² size pad is chosen because it is 
adequate to cover the the primary motor cortex – our area of interest for brain stimulation in stroke 
subjects to facilitate upper extremity motor function recovery.  
• 
Electrode montage will be bi-hemispheric stimulation : the bi-hemispheric stimulation montage is 
used for Aim 1 because safety profiles can be evaluted for both anodal stimulation and cathodal 
stimuation on the same study subject.  
 
Definition of Major Response and “Stopping Rule”:  
A major response is defined by any of the following serious adverse events occurring during the study period.  
It serves as the “stopping rule” as detailed in the Figure 4 above. 
• 
Second degree scalp burn at the site of electrode pad; or 
• 
Seizure; or 
• 
New lesion(s) on DWI sequence of MRI scan and the lesion(s) is not explained by any other cause(s) 
or decreased ADC under the electrode stimulating motor cortex area; or 
• 
Patient discontinues from the study due to any reasons above.  
Inclusion Criteria:  
Each subject must meet all of the following criteria to participate in this study. 
• 
18-80 years old with a first-ever ischemic stroke that occurred at least 6 months ago;  
• 
Finished rehabilitation therapy(including inpatient or outpatient PT/OT/SP) at least one month ago; 
• 
Unilateral limb weakness with Fugl Meyer-Upper Extremity Scale score less than or equal to 58 (out of 
66);  
• 
MEPs is inducible on abductor pollicis brevis (APB) muscle on the affected side by TMS.  
Exclusion Criteria:  
Subject who meets any of the following criteria will be excluded from the study. 
• 
Primary intracerebral hematoma, or subarachnoid hemorrhage,  
• 
Bihemispheric ischemic strokes;   
• 
History of prior stroke or old infarct demonstrated on the CT or MRI or documented in medical records;  
• 
Other concomitant neurological disorders affecting upper extremity motor function;  
• 
Documented history of dementia before or after stroke;  
• 
Documented history of uncontrolled depression or psychiatric disorder either before or after stroke 
which could affect their ability to participate in the experiment;  
• 
Uncontrolled hypertension despite treatment, specifically SBP/DBP>=180/100mmHg at baseline; 
• 
Presence of any MRI/tDCS/TMS risk factors: a) an electrically, magnetically or mechanically activated 
metal or nonmetal implant including cardiac pacemaker, intracerebral vascular clips or any other 
electrically sensitive support system; b) non-fixed metal in any part of the body, including a previous 
metallic injury to eye; c) pregnancy, since the effect of tDCS on the fetus is unknown; d) history of 
seizure disorder or post-stroke seizure; e) preexisting scalp lesion, bone defect or hemicraniectomy. 
D1. 2. Recruitment Process & Procedure: 
A schedule of assessments is presented in Table 2.  
Table 2 
Baseline* 
Stimulation Day (Day 0) 
Follow-up  

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(Day –7 ± 7) 
Pre-stim 
Post-stim 
(Day 14 ± 4) 
Eligibility Determination and Informed Consent 
X 
 
 
 
Demographics 
X 
 
 
 
Vital Signs and Safety Questionnaire  
X 
X 
X 
X 
TMS Evaluation 
X 
X 
X 
 
Laboratory 
 
X 
X 
X 
Brain MRI 
 
X 
X 
 
* Baseline can be same day as Stimulation Day to facilitate recruitment. 
 
• 
Baseline Day (Total Estimated Time:  ~ 2 hours) 
1. Subject reports to the College of Health Professions (CHP) building QBAR laboratory.  
2. Subject is consented first, then starts screening process.  
3. Vital signs are taken. Urine pregnancy test for subjects of childbearing age. Estimated time is 10 
minutes. 
4. Demographics collected, including age, ethnicity, gender, time from stroke (in months), side of 
infarct, handedness, medical history and medication list.  Estimated time is 20 minutes.  
5. A technician from the BSTIM Core will perform a Basic TMS Neurophysiological 
Assessment to determine if a MEP is inducible on abductor pollicis brevis (APB) 
muscle on the affected side by TMS (Details in BSTIM Core). Estimated time is 30 
minutes.  
6. Subject takes structured questionnaire. The questionnaire inquires whether the 
patient has experienced any of the following symptoms: headache, nausea, burning, tingling, 
itching, neck pain, electric shock, inattention and etc. It also has open questions inquiring about 
subject’s general impression about the stimulation. Estimated time is 10 minutes. 
7. A therapist from the QBAR Core will perform Clinical Assessments including 
upper-extremity Fugl-Meyer (UE-FM) scale.  Estimated time is 30 minutes.  
8. Subjects who meet the inclusion/exclusion criteria are eligible for the study and move 
to the next step.  
 
• 
Stimulation Day (7 days after baseline day; Estimated Time:  ~4 hours)  
9. Subject report to Center of Advance Imaging for Research (CAIR). The NI Core will 
perform structural 3T MRI (Details in NI Core and MRI protocol). Estimated time is 
30 minutes. 
10. Subject is transported to CHP research building QBAR laboratory (less than 100 
yards away). 
11. Blood draw is performed collecting 10 ml’s and specimen is sent to Dr. Yushing 
Zhu’s laboratory in the Children’s Hospital. . Urine pregnancy test for subjects of 
childbearing age. We have updated the protocol. Estimated time is 10 minutes. 
12. Subject takes structured questionnaire survey. Estimated time is 10 minutes. 
13. A technician from the BSTIM Core will perform a Basic TMS Neurophysiological 

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Assessment to determine cortical excitability (details in BSTIM Core and TMS protocol) in the 
BSTIM laboratory in the CHP research building (the room next door to the QBAR laboratory). 
Estimated time is 30 minutes. 
14. Vital signs are taken. Estimated time is 5 minutes.  
15. The BSTIM core oversees tDCS stimulation protocol. The PI will administer the tDCS under the 
supervision of the BSTIM core.  
16. Coincident with the beginning of stimulation, the therapist from the QBAR Core 
begins a one hour Upper Extremity Rehabilitation session of patient-targeted 
upper extremity function therapy (details in QBAR Core and Therapy Protocol). 
Estimated time is 60 minutes. 
17. At the end of the rehabilitation session, the technician from the BSTIM Core will 
again perform a Basic TMS Neurophysiological Assessment to determine cortical 
excitability. Estimated time is 30 minutes. 
18. The structured questionnaire survey is performed again. Estimated time is 10 
minutes. 
19. A second blood draw is performed and specimen is delivered to Dr. Yushing Zhu’s 
laboratory in the Children’s Hospital  l. Estimated time is 10 minutes. 
20. Subject is transported to CAIR. NI Core will again perform structural 3T MRI (Details in NI Core 
and MRI protocol). Estimated time is 30 minutes.  
21. Patients are advised to call the study team if they experience any untoward side effect before the 
follow up day. 
 
• 
Follow-up day (14 days after stimulation day; Estimated time: ~ 0.5 hour) 
22. Subject reports to CHP research building QBAR laboratory. 
23. A blood draw is performed collecting 10 ml’s and specimen is sent to Dr. Yushing Zhu’s laboratory  
in the Children’s Hospital. Estimated time is 10 minutes. 
24. The structured questionnaire survey is performed again. Estimated time is 10 minutes. 
 
• 
Final analyses:  
25. Note that these analyses must be completed for each set of 3 subjects in a group to determine 
whether one or more major responses occurred before enrollment continues. If no major response 
occurs, the next 3 subjects will be entered to go through procedure 9-23 according to Figure 4.  
D1. 3. Statistical Analysis: 
Due to the nature of 3+3 design (Figure 4), the theorectical sample size varies from 3 to 36 depends on when 
the trial stops under “stopping rule”. However, we hypotheize that no major responses will occur at any current 
(dose) level and the current will be escalate to 4 mA, thus we predict that 18 stroke subjects will be required for 
Aim 1. First, patients’ demographic and clinical characteristics will be summarized. Summary statistics for 
continuous variables includes number of subjects, means, median and standard deviations. Summary statistics 
for discrete variables includes counts and percentages for each category. Secondly, the safety measures will 
be summarized by current(dose) group with descriptive statistics. Thirdly, a current(dose) response curve will 
be plotted by MEPs amplitude versus current (dose) groups. Per DSMB recommendation, S-100 and NSE will 
not used as a stopping rule, however, they will be still collected and analysed separately and presented to 
DSMB meeting.The statistical analyses will be performed with SAS V9.2 (SAS Institute Inc., Cary NC).  
D1. 4. Anticipated Results:   

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We anticipate that 4.0 mA will be tolerable and safe both at clinical and subclinical levels, as evidenced by a 
lack of major responses in the study subjects. In addition we expect that 4.0 mA will produce the largest 
increase in MEPs amplitude compared with other current levels. 
 
 
 
D2.1. Design:  
This is a repeated measures design in which a group of stroke subjects will each receive one of three 
stimulation montages (anodal stimulation, cathodal stimulation and bihemispheric stimulation) on three 
different days (separated by at least two days in between). The order in which they receive the three montages 
will be randomized to account for order effects. The primary purpose here is to determine the stimulation 
montage that induces the largest cortical excitability on the lesional hemisphere. The rationale of the design is 
that each subject serves as his/her own control, thus eliminating between-subject variation and makes it easier 
to determine changes in cortical excitability between conditions. We will require at least two days between 
each stimulation session so that there is little risk of carry over as the after-effect from tDCS have been shown 
to last over one hour29.  
C2.2. Recruitment Process & Procedure: 
We will use the same study population as in Aim 1, defined by the same inclusion and exclusion criteria, for 
Aim 2. The same TMS, tDCS and Rehabilitation Protocols from Aim 1 will be applied to Aim 2. Those subjects 
who completed Aim 1 are still eligible to be enrolled in Aim 2. The subjects, therapist and assessor are all 
blinded to the condition.  
A schedule of assessments is detailed in the following Table 3. 
Table 3 
Baseline* 
(Day –7 ± 7) 
Session I 
(Day 0) 
Session II 
(Day 2) 
Session III 
(Day 4) 
Pre 
Post 
Pre 
Post 
Pre 
Post 
Eligibility Determination and Informed Consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Vital Signs and Safety Questionnaire 
X 
X 
X 
X 
X 
X 
X 
TMS Evaluation 
X 
X 
X 
X 
X 
X 
X 
* Baseline can be same day as Session I to facilitate recruitment. 
 
Baseline Day (Total Estimated Time:  ~ 1.5 hour) 
1. Subject reports to the CHP building QBAR laboratory.  
2. Subject gets consented first and starts screening process.  
3. Demographics collected, including age, ethnicity, gender, time from stroke, side of 
infarct, handedness, medical history and medication list.  Estimated time is 20 
minutes. 
Aim 2: To determine the optimal stimulation montage in stroke patients 

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4.  Subjects of childbearing age will have a urine pregnancy test. 
5. A technician from the BSTIM Core will perform a Basic TMS 
Neurophysiological Assessment to determine if a MEP is inducible on 
abductor pollicis brevis (APB) muscle on the affected side by TMS (Details in 
BSTIM Core). Estimated time is 30 minutes.  
6. A therapist from the QBAR Core will perform Clinical Assessments including 
upper-extremity Fugl-Meyer (UE-FM) scale. Estimated time is 30 minutes.  
7. Subjects who meet the inclusion/exclusion criteria are eligible for study and move 
to the next step.    
Stimulation Day (Total Estimated Time:  2.5 hours)  
8. Subject reports to the College of Health Professions (CHP) building QBAR 
laboratory. Subjects of childbearing age will have a urine pregnancy test prior to 
each stimulation session.  
9. The BSTIM core will perform cortical excitability assessment using TMS in the 
BSTIM laboratory in the CHP research building (the next room from the QBAR 
laboratory). Estimated time is 30 minutes.  
10. The BSTIM core oversees tDCS stimulation protocol. The PI will administer the 
tDCS under the supervision of the BSTIM core.  
11. Coincident with the beginning of stimulation, the QBAR core begins a one hour 
rehabilitation session of patient-targeted upper extremity function therapy.  
Estimated time is 60 minutes. 
12. At the end of the rehabilitation session, BSTIM core will again perform cortical 
excitability assessment using TMS. Estimated time is 30 minutes. 
13. Subject will go home and rest for 2 days, then come back to repeat the procedure 
7-11 twice to received other two stimulation sessions. 
 
D2.3 Statistical Analysis: 
The primary outcome measure will be the quotient of post/pre MEPs amplitude recorded from the affected APB 
muscle to represent the cortical excitability in the lesional motor cortex. Assuming power of 85% and type I 
error of 0.05, (Bonferroni adjusted for 3 comparisons), 18 subjects would be sufficient to detect an effect size of 
0.85 of the MEPs between two treatments groups using a paired t-test. We will summarize the demographic 
and clinical characteristics of the sample using means and proportions. Although the study is powered based 
on paired t-tests, we will analyze the data using a repeated measures ANOVA for the post/pre MEP quotient 
and include covariates in the secondary analyses to glean more information about the variability in the 
outcome. The statistical analyses will be performed with SAS V9.2 (SAS Institute Inc., Cary NC).  
D2.4 Anticipated Results:   
We anticipate that the bihemispheric stimulation ( anodal on the lesional hemisphere and cathodal stimulation 
on the non-lesional hemisphere) will induce the largest increase in the cortical excitability in the lesional 
hemisphere compared with the other two stimulation montages – anodal stimulation on the lesional 
hemisphere only or cathodal stimulation on non-lesional hemisphere only.  
D3.1 Limitation, Potential Pitfall and Alternative Approach: 

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• 
Why not perform these studies in healthy subjects first? We are pursuing a similar study in healthy 
subjects through other funding mechanisms. However, the information from healthy subjects can not be 
applied to stroke patients because they are completely different populations. In general, there is a 
concern for potential increased risk for stroke patients for tDCS stimulation.  
• 
We are testing for effects and safety with a single session, but the treatment studies would likely involve 
multiple tDCS sessions? Feasibility, unlikely to see cumulative safety issues over multiple sessions.  
• 
If the difference of induced cortical excitability between different electrode stimulation montage is 
smaller than expected, the alternative approach is to increase sample size or consider multiple 
sessions rather than single session. 
D4. 1 List of Protocols:  
MRI Protocol:   
Study subjects will be scanned at the Center of Advanced Imaging (NI core) by a Siemens 3T Trio MRI 
scanner using a standard radiofrequency head coil at before and within 2 hours after stimulation. During MRI, 
electrode positions will be marked by placing vitamin pills detectable in MRI scans at the center of the tDCS 
electrodes. Areas of 3* 5 cm, which were the size of the tDCS electrodes, will be determined as regions of 
interest (ROI) around this center for the stimulated primary motor cortex. Head motion will be minimized by 
foam padding and forehead-restraining straps if necessary. T1 contrast enhanced weighted anatomical image 
(IR/TR/TE = 1100/1900/3.37; resolution = 1 x 1 x 1 mm³; FOV = 256 x 256), Fluid attenuated inversion 
recovery (FLAIR, TR/TE = 9000/89; resolution = 0.43 x 0.43 x 5 mm³; FOV = 220 x 192.5) and DWI (TR/TE = 
5.5 s/99 ms; resolution = 3 x 3 x 3 mm³; FOV = 222 x 222). In T1- diffusion-weighted studies, and ADC maps 
will be visually inspected for signal changes by a blinded board certified neuro-radiologist or neurologist. 
Furthermore, pixel by-pixel subtraction of the post-stimulation ADC parametric images from the baseline ADC 
parametric images will be performed by means of an implemented scanner software algorithm for improved 
differentiation and highlighting of possible locally restricted ADC changes. Statistical difference between the 
ADC values before and after stimulation will be calculated and analyzed.  
Laboratory Protocol:  
The laboratory test will be processed and analyzed at  Dr. Yushing Zhu’s lan in the Children’s Hospital  The 
serum samples will be collected at baseline, before stimulation, after stimulation and one week after 
stimulation. The samples will be centrifuged at 3000 rpm for 10 min and stored at −20 °C prior to the analyses. 
The NSE assays will be performed using a radioimmunoassay technique (Cobas Core NSE EIA, Hoffmann-La 
Roche, Switzerland). The S-100b concentrations will be measured by an immunoluminometric assay for the 
quantification of protein (LIAmat® Sangtec®100, Sangtec Medical, Sweden). The sensitivity of the S-100b 
assay will be b0.02 μg/l.  
TMS protocol:  
The TMS evaluation will be conducted at the Brain Stimulation Laboratory (BSTIM Core) and performed by 
trained research staff members who are blinded to the study. Subjects will be seated comfortably in a chair 
specifically designed with a chin rest, head rest and molded armrest in which they could keep their arms in a 
constant relaxed position. Subjects have 9mm Ag/AgCl surface electrodes placed over the abductor pollicis 
brevis (APB) muscle. The TMS coil will be positioned using a neuronavigational guidance system (Brainsight 
™, Rogue Research Inc., Montreal Quebec) along with the participant’s MRI.  Given that neuroanatomy is 
often shifted post stroke, this system will allow us to maximize precision of the coil placement.  The stereotactic 
guidance system consisted of trackers attached to the TMS coil and to the subject’s head which could be 
detected by an optical position sensor. Following a calibration procedure, these trackers are monitored by the 

Version 03/02/2017 
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software which displayed the position and orientation of the coil on the subject's anatomical MRI scan. This 
technique facilitates repeated positioning of the TMS coil over the subject’s brain.  The location of the motor 
area governing the thumb is isolated for each individual by moving the TMS coil in 0.5 cm steps to find the site 
at which the maximum twitch could be elicited. EMG signals are recorded using a closed-loop system, in which 
feedback from the EMG is used to control the output of the TMS machine via specially written scripts (Spike2 
software, Cambridge Electronic Design, Cambridge, UK). The raw EMG signal is amplified and bandpass 
filtered (low-pass = 0.5 Hz, high-pass = 1 kHz) using the CED 1902 Quad-System (Cambridge Electronic 
Design Limited, Cambridge, U.K.). It is digitized (sampling rate = 5 kHz) and recorded onto a PC using Spike2 
software and a Micro 1401 data acquisition unit  (Cambridge Electronic Design Limited, Cambridge, U.K.). The 
resting motor threshold (rMT) is determined using a procedure known as the maximum-likelihood strategy in 
which the parameter estimation by sequential testing (PEST) algorithm is used 53,54. The PEST method uses 
the EMG response to the TMS pulse to determine if TMS intensity needs to be increased or decreased. In our 
closed-loop system, the TMS machine is automatically adjusted according to PEST output, resulting in an MEP 
of 50 µV in 50% of trials. Thus, the rMT is determined in a matter of minutes, is much less labor intensive 
compared with the Mills-Nithi IFCN method and less prone to human error. Cortical excitability was tested by 
delivering 10 TMS pulses to M1 of each hemisphere (TMS intensity of 20% above the individual rMT to induce 
MEPs of at least 1 mV, if MEPs size is smaller than 1mV, then TMS intensity will go up to 100% and kept at 
100%). The same intensity was kept constant pre and post-stimulation. Ten MEPs will be recorded for each 
hemisphere, and their peak-to-peak amplitude will be averaged to determine MEPs amplitude.   
tDCS Protocol:  
Direct current stimulation will be delivered to the study subjects through 2 saline-soaked EasyPad (3cm * 
5cm=15cm²) using a Chattanooga Dual-Channel Iontophoresis Device (Chattanooga Medical. Inc). For this 
protocol, the bihemispheric stimulation montage will be used because a safety profile can be evaluated for both 
anodal stimulation and cathodal stimuation on the same subject. The anodal stimulation will be placed over the 
ipsi-lesional and the cathodal over the contra-lesional motor cortex (C3 and C4 areas by using the international 
10 –20 EEG electrode systems). Electrode pads will be disposed after each stimulation session. During the 
middle of stimulation, an inspection of electrode pads will be conducted to make sure they have not dried out, 
and  the scalp temperature will be measured using a touchless thermometer. Stimulation will last for 30 
minutes. Thus, subjects will perform for thirty minutes with stimulation and 30 minutes after it has ended. The 
QBAR core therapist will be blinded to  dosage and montage of stimulation by the BSTIM core technician. The 
experiment will be conducted in the Upper Extremity Funciton Laboratory of the Center for Rehabilitional 
Research in Neurological Conditons (QBAR core).  
Customized Task-Oriented Training Protocol:   
Subjects will engage in one hour of concentrated task-practice directed at the paretic arm and hand. Task-
practice sessions will be structured and supervised by a trained and licensed therapist. Selection of functional 
motor tasks for a given subject will be derived from their baseline FM-UE score 55. Based upon assessment 
information obtained from the baseline FM-UE score, motor tasks will be selected that are optimally 
challenging and customized to personal abilities and goals.  This method also allows for systematic 
progression of task types and difficulty to maintain a “just-right” match between the subject’s abilities and task-
difficulty.  Tasks practices will address specific gross-motor, fine-motor, proximal, and/or distal movement 
components within the context of functional tasks. Repetition and feedback schedules and methods will follow 
the theoretical framework of the Task-Oriented Approach. 
D5. 1. Timeline: 

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About 600 patients per year with a primary diagnosis of acute ischemic stroke were admitted to MUSC Stroke 
Center. About 12-15% patients (6 - 8 patients per month) can meet the inclusion criteria. In addition, Center of 
rehabilitation Science in Neurological Conditions mains a database with 50 stroke subjects who were agreed to 
be contacted for future research studies, this study will also recruit from the Registry for Stroke Recovery 
(RESTORE-Pro#00037803), which is a registry with subjects consented for future contact. (please refer to 
details in D5.5). Thus, we should have no problem obtaining the required number of subjects from the CTTR 
Core. The protocol will be submitted to the MUSC IRB with expectation of final approval by June, 2013. 
Subject enrollment will begin immediately if the proposal is funded.  We expect to complete the Aim1 in year 1 
and aim 2 in year 2 (Table 1).  
D5. 2. Integration with COBRE:  
This proposal is well integrated into the COBRE application. It utilizes all of three scientific cores in the COBRE 
(Figure), and most importantly, the applicant has a clear plan for a next project to continuously utilize all of 
cores. Further, the proposed study will advance the BSTIM Core as it potentially leads to a new treatment for 
post-stroke motor recovery.  Specifically, much of the study will be performed in the QBAR Core laboratories 
and a QBAR therapist will conduct the therapy session for the experiments outlined in Aim 1 and Aim 2. The 
BSTIM Core will provide the tDCS device, TMS and necessary training. The research assistant from Brain 
stimulation laboratory, along with the applicant; will conduct TMS assessment of cortical excitability on stroke 
subjects.  The MR scan will be conducted at the Center of Advance Imaging Center (CAIR) where NI Core is 
located. The NI Core will also provide necessary training and 
staff for imaging process and analysis.  
The applicant already had multidisciplinary collaboration with 
other junior investigators in the COBRE application. For example, 
Dr. Feng has an established collaborative relationship with Dr. 
Hanlon whose expertise is neuro-imaging with functional MRI 
and cortical excitability assessment with TMS. They have 
collaborated on the ongoing pilot study “Bihemiespheric 
Stimulation and Constrainted-Induced Movement Therapy to 
Promote Post-Stroke Motor Recovery”. Part of data from this 
Table 1 
Pre-year 
Year 1 
Year 2 
Quarter 
1 
1 
2 
3 
4 
1 
2 
3 
4 
Research 
Plan 
Receive 
IRB 
Approval 
Start recruitment for Aim1, and plan to 
recruit 2-3 subjects per months, complete 
Aim1 by the end of year 1. 
Start recruitment for Aim2, and 
plan to recruit 2 subjects per 
months and complete it at the 
end of year 2  
Start R01 
proposal 
Training 
Classes 
 
Clinical Trial Methods Course in Neurology 
Imaging tool analysis in FSL and SPM 
Scientific 
Meetings 
 
Present data from Aim1 internally 
- Neuroscience Grand Rounds;  
- SCTR SOCRATES club 
- Monthly stroke team meetings; 
International stroke 
conference or 
American Society 
of Neuro-
rehabilitation 
Conference 
Present data from Aim2 internally 
- Neuroscience Grand Rounds;  
- SCTR SOCRATES club 
- Monthly stroke team meetings; 
Publications 
 
Manuscript#1: efficacy and safety of various 
current level of tDCS in stroke patients 
Manuscript # 2: Optimal tDCS stimulation 
montage for stroke patients   

Version 03/02/2017 
15 
 
study were used as preliminary data supporting two proposals for this COBRE application. Dr. Hanlon’s current 
project also provide a neurobiological basis for stroke recovery. The result from her project could be helpful for 
Dr. Feng to design the R01 project in planning to uncover the recovery mechanism associated with tDCS. Dr. 
Feng also has collaborated with Dr. Malcolm whose expertise is investigating rTMS as an adjunct tool for 
stroke recovery while Dr. Feng’s is studying how tDCS promote stroke recovery. tDCS and rTMS are two 
similar but different non-invasive brain stimulation techniques, they both have the capabilitlity to modulate 
cortical excitability and induce subsequent brain plasticity, currently they both hold promise for stroke motor 
recovery. They have been meeting regularly to trouble shoot technical aspects of the two techniques, and 
working together testing the new magstim® rTMS with brainsight.  
D5.3. Mentoring Plan: 
Dr. Robert Adams is the Primary Mentor.  He is a Professor, endowed chair and director of MUSC Stroke 
Center. His clinical research has involved selection of imaging methods, such as Transcranial Doppler (TCD) 
and MRI, to assess the intracranial arteries and help predict prognosis in patients with sickle cell vasculopathy.  
He is an expert in stroke trial design and execution of multicenter studies. He has continuous NIH funding 
since 1988, and his current portfolio includes a R01, one of three formal “Multiple PI’s” in a large U01 clinical 
trial, and he is the head of a stroke project funded by the Department of Defense.  Dr. Adams has substantial 
experience in nurturing junior faculty throughout his career, including one who has become Chair of Neurology 
in an academic institution. Since he has been at MUSC in 2007, he has trained two stroke fellows and 
mentored two junior faculty members who have K award in good standing. Thus, he is the ideal mentor for me 
as I aim to become a successful academic faculty member. Specifically he will supervise me on clinical trial 
design and execution and DSMB. 
Dr. Mark George is a Co-mentor. Dr. George is professor of Department of Behavioral Science and 
Psychiatry, director of brain stimulation laboratory, an internationally-recognized expert in Non-invasive brain 
stimulation techniques, including TMS and tDCS. He is one of the founders of therapeutic rTMS techniques, 
and Editor-in-Chief of the journal Brain Stimulation. He has extensive research experience with development 
and application tDCS in various disease conditions. He will specifically provide mentorship relating to tDCS 
application and trouble shoot during the experiments. 
In addition, I will also receive mentorship from the scientific cores through participation in all of their mentoring 
activities. By the end of the proposed project, my specific goals are to gain knowledge and be expert in training 
in trial design, Neuroimaging, and brain stimulation, in addition, I would like to transition into an independent, 
successful federally funded research scientist in stroke recovery and rehabilitation.  
D5.4. Applicant’s Future Project (Including R01):  
This proposal serves as a critic bridging step between the applicant’s prior training and his next milestone - an 
R01 application. The R01 is planned to submit in the end of year two when the proposed experiments are 
close to completion. The proposed R01 project is a Phase II single-center clinical trial to assess the efficacy of 
tDCS for post-stroke motor recovery with the current and stimulation montage determined from this proposal. If 
R01 project show promising result, Dr. Feng hope to launch a U01 project to further test the tDCS in post-
stroke motor recovery in a multi-center phase III clinical trial.  
D5.5 Additional information about recruiting patients from research database: 
Subjects with stroke will be recruited from the recruitment database maintained at the MUSC Center for 
Rehabilitation Research in Neurological Conditions (CRRND) which is housed in the CHP Department of 
Health Sciences and Research (secondary appointment of the PI and primary appointment of the research 
therapist). The research database (approved MUSC IRB #15991) currently contains ~200 persons with stroke 
who have signed informed consent and agreed to be contacted for research participation. The research 

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database is managed by a designated coordinator. This coordinator will be provided with the 
inclusion/exclusion criteria for the current study. This study will also recruit from the Registry for Stroke 
Recovery (RESTORE-Pro#00037803), which is a registry with subjects consented for future contact. 
RESTORE staff will query the registry for potential subjects and provide the Principal Investigator (PI) with the 
contact information of subjects who meet their criteria.  The PI or research staff will contact subject to further 
screen for potential enrollment. When a potential participant is identified that meet inclusion criteria the PI, 
project coordinator or research therapist will contact participants by phone to determine if they want to 
participate in the current study. If they wish to participate they will be scheduled for a time for the PI, project 
coordinator or research therapist to obtain informed consent for the study proposed. Consent will be obtained 
after reviewing the protocol and consent form with each potential subject. If a potential subject is deemed 
unable to participate in informed consent, consent will be obtained from a relative with the patient present. For 
patients consenting themselves, every attempt will be made to have a relative present during the informed 
consent. The MUSC IRB will approve the informed consent form. 
 
D5.6 Sharing Data:  
If the subject agrees, the data collected and generated from this study will be shared to the Registry for Stroke 
Recovery (RESTORE-Pro#00037803) by the subject’s registry ID. Sharing data from this study with the 
registry will allow for more targeted recruitment efforts in the future and allow researchers at MUSC to have a 
more complete registry with key stroke recovery elements including common data and physical function 
characteristics that are applicable to multiple studies. MUSC researchers and collaborating facilities will be 
able to query data sets to learn more about recovery of subjects after their stroke through institutionally 
managed secure servers that will assure HIPAA privacy and security compliance. 
 

Version 03/02/2017 
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Appendix: 
1. Total enrollment table 
Please refer to statistical analytic plan for sample size calculation, 36 subjects (18 subjects for part I and 
another 18 subjects for part II) are needed.  
TARGETED/PLANNED ENROLLMENT: Number of Subjects 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
2 
2 
4 
Not Hispanic or Latino 
16 
16 
32 
Ethnic Category: Total of All Subjects* 
36 
Racial Categories 
 
American Indian/Alaska Native 
1 
1 
2 
Asian 
1 
1 
2 
Native Hawaiian or Other Pacific Islander 
0 
0 
0 
Black or African American 
8 
8 
16 
White 
8 
8 
16 
Racial Categories: Total of All Subjects* 
18 
18 
36 
 
 
2) Protection to Human Subjects: 
Potential Risk to Human Subjects 
tDCS: Extensive animal and human evidence and theoretical knowledge indicate that the presently used tDCS 
protocols up to 2mA are safe1,3,4. It involves minimal risk to human subjects. Commonly reported side effects 
are as followed: skin irritation with itching,tingling, burning sensation, transient headache or nausea. For part 
one of the study where the level of current is being tested higher than 2mA, there maybe potential side effects.  
They include burns under the pads, seizure, changes on MRI, and changes in blood test results. If patient 
experience any of serious adverse event which meet the ‘stopping rule”, the trial will be evaluted by DSMB and 
make further decision. The risks associated with pregnancy and tDCS are unknown. Pregnant women are 
excluded. All female subjects that are of childbearing age that have not had a hysterectomy will be ask their 
method of birth control and will be questioned prior to each session if there is a possibility that they might be 
pregnant. Acceptable forms of include birth control condom use or hormonal contraceptives.  
 
MRI:  The test will be done using equipment similar to that used for clinical MRI. The current revision of the US 
Food and Drug Administration guidelines (U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Devices and Radiological Health, Guidance for the submission of premarket 

Version 03/02/2017 
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notifications for magnetic resonance diagnostic devices, Washington, DC. November 14, 1998) applies to this 
study. These guidelines state that magnetic resonance imaging systems with main static magnetic field 
strengths of 4.0T (a measure of magnetic strength) and less, such as the ones used for this study, can qualify 
as non-significant risk devices.  
Because the MRI machine acts like a large magnet, it could move iron-containing objects in the MRI room 
during your examination, which could in the process possibly harm you. Precautions have been taken to 
prevent such an event from happening; loose metal objects, like key chains, are not allowed in the MRI room. If 
you have a piece of metal in your body, such as a fragment in your eye, aneurysm clips, ear implants, spinal 
nerve stimulators, or a pacemaker, you will not be allowed into the MRI room and cannot have a MRI. Having a 
MRI may mean some added discomfort to you. In particular, you may be bothered by feelings of 
claustrophobia and by the loud banging noise during the study. Temporary hearing loss has been reported 
from the loud noise. This is why you will be asked to wear earplugs. At times during the test, you may be asked 
not to swallow for a while, which can be uncomfortable. 
 
Venipuncture: The risks of drawing blood include temporary discomfort from the needle stick, bruising and 
infection. Fainting could occur. There will be a total of 30 ml’s collected for the 3 blood draws (10 ml’s per 
draw). 
 
TMS: The TMS coil makes noise, much like a loud pop when it produces its magnetic energy.  You may or 
may not feel your thumb twitch depending on the strength of the TMS pulse, but you might also feel your facial 
muscles twitch slightly just around your eye.  This twitch is just as brief as the thumb twitch and is a result of 
the TMS directly stimulating the facial nerves and muscles that run directly under your scalp. It is not painful. 
TMS can cause heating or movement of metallic objects in or near the head.  In addition, the inactivation of 
pacemakers, medication pumps, cochlear prostheses and other implantable hardware may occur.  Magnetic 
media such as credit cards, etc. and watches near the coil may also be damaged.  To minimize this risk the 
researchers will have asked you about any metal implants which would exclude you from the study. There is a 
known risk of inducing a seizure during rTMS 56,57, however, it is not used in grant proposal.  
 
Motor assessments:  Motor assessments may occasionally cause fatigue; however you have the option to 
adjust your pace as needed to complete the test.  
 
Protection to Human Subjects: 
 
tDCS: 
1) Strictly follow the inclusion and exclusion criterias 
2) Study part 1 is a tolerabilty study. Adverse events are recorded carefully on every visit on every patients, if 
major response occurs, DSMB will be notified immediately. 
 
MRI: 
1)  MRI screening form will be done at the time of recruitment, and patient will be excluded from study if he/she 
has contraindication for MRI or can not tolerate the MRI scanner 
2)  Headphone or earplug is provided to the study patient to minimize the noise from magnetic field. 
 
TMS: 

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1) strictly follows the published guideline about TMS application. TMS is only applied by skilled and well 
trained staff in the center of brain stimulation. 
2) rTMS will not be used in our grant application which has a risk of seizure. 
3) Conduct a daily assessment after each study session to collect more information about side effect 
 
Potential Benefit of the study: 
There will be no other direct benefit to you from participating in this study except the one hour rehabilitation 
therapy; however, it is hoped that the information gained from the study will help in the treatment of future 
stroke patients with conditions like yours, and help the researchers to develop new rehabilitation treatment for 
stroke survivors in the future. 
 
Data Safety Monitor Board and Data safety monitoring plan: 
 
The DSMB will be composed of three of external members who are not involved with the study design or 
experiments: Dr. David Bachman(Chair of DSMB, MD, board certified neurologist, ex-IRB committee member), 
Christine Holmsted (DSMB member, DO and board certified Neurologist) and Andrea Boan (DSMB member, 
PhD biostatistician).  
 
The DSMB member will meet every 6 months.  If 2 or more major responses that occurs in the study part 1 at 
specfic current level, the study need to be stopped early. The DSMB will meet earlier than 6 months interval.  
 
The chair will lead the meeting with two members, Specifically they will 
1) protect the safety of the study participants; 
2) review the research protocol, informed consent documents, amendments, and plans for data safety and 
monitoring; 
3) evaluate the progress of the trial, including periodic assessments of data quality and timeliness, recruitment, 
accrual and retention, participant risk versus benefit, performance of the trial sites, and other factors that may 
potentially affect study outcome; 
4) review study performance, make recommendations and assist in the resolution of problems reported by the 
Principal Investigator; 
5) report to IRB on the safety and progress of the trial; 
6) ensure the confidentiality of the study data and the results of monitoring 
7) advise the IRB and the study investigators as to whether the protocol should continue as scheduled or 
undergo a modification due to a finding from the monitoring process 
 
 
 

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