Improving SCI Rehabilitation Interventions by Retraining the Brain
Phase: PHASE1
Conditions: Cervical Spinal Cord Injruy
Sponsor: The Cleveland Clinic

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 1 of 35 
 
CONTENTS 
1. INTRODUCTION…………………………………………………………………………………………..3 
1.1 
General overview…………………………………………………………………………………….3 
1.2 
Purpose……………………………………………………………………………………………….3 
1.3 
Duration of the Investigation………………………………………………………………………...3 
1.4 
Site Information……………………………………………………………………………………...3 
2. DEVICE DESCRIPTION…………………………………………………………………………………..5 
2.1  
Name of Device……………………………………………………………………………………....5 
2.2  
Soterix tDCS Principle of Operation………………………………………………………………....5 
2.3  
Soterix tDCS System and TMS system Regulatory Status…………………………………………...5 
2.4  
Proposed Indications for Use………………………………………………………………………....5 
2.5  
Manufacturing information…………………………………………………………………………...6 
2.6  
Labeling………………………………………………………………………………………….…...6 
3. BACKGROUND AND SIGNIFICANCE……………………………………………………………….….6 
3.1  
Overview of iSCI Epidemiology………………………………………………………………….….6 
3.2  
Unmet Clinical Needs…………………………………………………………………………….…..6 
3.3 
Current Standard of Care Approaches………………………………………………………….……6 
3.4 
Enhancing Clinical Outcomes……………………………………………………………….…….…7 
3.5  
Innovation…………………………………………………………………………………………….7 
3.6 
Significance……………………………………………………………………………………….…7 
4. REPORT OF PRIOR INVESTIGATIONS……………………………………………………………….8 
4.1 
Summary of Previous Studies…………………………………………………………………….…8 
4.2 
Conclusion…………………………………………………………………………………………...9 
5. STUDY DESIGN……………………………………………………………………………………………9 
5.1 
Study Objective……………………………………………………………………………………...9 
5.2 
Sample Size Estimation and Power Analysis……………………………………………………….9 
5.3 
Primary Endpoint…………………………………………………………………………………..10 
5.4  
Secondary Endpoints………………………………………………………………………………10 
6. SUBJECT SELECTION………………………………………………………………………………….11 
6.1 
Study Patient Population…………………………………………………………………………...11 
6.1a 
General Inclusion Criteria………………………………………………………………………….12 
6.1b 
General Exclusion Criteria…………………………………………………………………………12 
6.2 
Study Recruitment………………………………………………………………………………….12 
6.3 
Subject Screening…………………………………………………………………………………..13 
6.4 
Subject Enrollment…………………………………………………………………………………14 
7. STUDY VISITS…………………………………………………………………………………………….14 
7.1  
Study Schedule……………………………………………………………………………………..14 
7.1a 
Schedule of Study Visits……………………………………………………………………………14 
7.1b 
Schedule of Study Assessments…………………………………………………………………….15 
7.2  
Baseline TMS and Functional Testing……………………………………………………………...15 
7.3 
Rehabilitation with tDCS…………………………………………………………………………...15 
7.3a 
Rehabilitation……………………………………………………………………………………….15 
7.3b 
tDCS………………………………………………………………………………………………...16 
7.4 
Post TMS and Functional Testing…………………………………………………………………..16 
7.5 
Long term Follow-up………………………………………………………………………………..17 

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 2 of 35 
 
7.6 
Healthy Control Study Visit…………………………………………………………………………17 
8. SAFETY REPORTING…………………………………………………………………………………….17 
8.1 
Definitions and Classification………………………………………………………………………..17 
8.1a 
Adverse Event (AE)…………………………………………………………………………………..17 
8.1b 
Serious Adverse Event (SAE)………………………………………………………………………...17 
8.1c 
Relatedness to Study Procedures……………………………………………………………………...18 
 
9. DATA MANAGEMENT……………………………………………………………………………………..18 
9.1 
Identifiers and Code System…………………………………………………………………………..18 
9.2 
Completion and Storage of Case Report Forms……………………………………………………….18 
9.3 
Confidentiality…………………………………………………………………………………………19 
9.4 
Data Analysis Plan……………………………………………………………………………………..20 
9.5 
Sharing Study Results………………………………………………………………………………….21 
9.6 
Special Precautions…………………………………………………………………………………….21 
10. STUDY ADMINISTRATION………………………………………………………………………………...23 
10.1 
Data Safety Monitoring Board (DSMB)……………………………………………………………….23 
10.1a 
DSMB Responsibilities………………………………………………………………………………...24 
10.1b 
DSMB Meetings………………………………………………………………………………………..25 
10.1c 
Making recommendations……………………………………………………………………………...25 
10.1d 
DSMB Decision Guidelines for stopping the trial……………………………………………………..26 
10.1e 
Elements of DSMB Reports……………………………………………………………………………26 
11. RISKS/BENEFITS……………………………………………………………………………………………..27 
11.1         Risks associated with TMS……………………………………………………………………………….27 
11.2         Risks associated with tDCS………………………………………………………………………………28 
11.3         Risks associated in the SCI patient population…………………………………………………………...28 
11.4         Benefits……………………………………………………………………………………………………29 
12. INFORMED CONSENT MATERIALS……………………………………………………………………….29 
 
 
 

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 3 of 35 
 
1. INTRODUCTION 
1.1       General overview 
Spinal cord injury (SCI), a common cause of devastating paralysis, carries some sobering statistics: SCI affects 
nearly a million people in the U.S. alone. Of these, some 150,000 are U.S. veterans, according to the 
Christopher & Dana Reeve Foundation. Almost 12,000 new cases are added each year, following road-vehicle 
and military service-related injuries. SCI patients often lose feeling and movement in the upper body and all 
four limbs. They must then depend on family members and caregivers to meet every personal need, from 
feeding, bathing/toileting, and dressing to participating in family and community activities. SCIs mostly occur 
in adults between the ages of 28 and 43, in what would normally be their most productive years. The lifetime 
costs of managing such a disability are staggering: about $4.7 million per patient. In this project, three 
healthcare centers will test a new nonsurgical approach to help SCI patients (veterans and civilians) more 
quickly regain some of their lost functions. 
1.2        Purpose 
Primarily, the purpose of this phase I/II clinical trial for patients living with cervical spinal cord injury (SCI) is 
to promote recovery of the paretic upper limb and improve functional independence by using non-invasive brain 
stimulation (tDCS) in combination with upper limb rehabilitation to recruit any and all residual spared neural 
resources.  
 
Secondarily, the clinical trial will determine the safety and feasibility of pairing tDCS with rehabilitation in 
individuals with SCI. 
1.3 
Duration of the Investigation 
The estimated duration of this clinical trial is 5 years from the time of first subject enrollment to the last follow-
up visit for all patients enrolled. 
1.4 
Site Information 
Cleveland Clinic will serve as the lead site for the study. Dr. Ela Plow will be the lead PI and Mr. Kyle 
O’Laughlin will be the lead coordinator. Each of the four sites will have a clinical coordinator (Mr. O’ Laughlin 
at the Cleveland Clinic, Ms. McCabe at the Cleveland VA Medical Center, Ms. Friedl at MetroHealth Hospital 
and Ms. Martinez at Kessler Foundation/Kessler Institute for Rehabilitation). Mr. O’ Laughlin with supervision 
from Dr. Plow will help establish, maintain and monitor compliance with Good Clinical Practices (GCP) and 
Good Laboratory Practices (GLP).   
 
To ensure standardization of methodologies across all sites (Cleveland Clinic Foundation, Cleveland VA 
Medical Center, MetroHealth Hospital, and Kessler Foundation/Kessler Institute for Rehabilitation), and proper 
recording of data, we will adopt the following safeguards: 
o Functional Outcome Measures 
For this multi-site study two study staff from the Cleveland Clinic (Dr. Plow and Mr. Kyle O’Laughlin) will 
travel to the Cleveland VA Medical Center and Kessler Foundation/Kessler Institute for Rehabilitation to 
educate other site study staff in functional outcome methodology.  At this time, any alterations as suggested 
by Dr. Kirshblum and Dr. Richmond (SCI physicians from Kessler Rehab Institute and Cleveland VA 
respectively) and Anne Bryden (OTL/R from Metrohealth Hospital) will be implemented.  We anticipate 

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 4 of 35 
 
that this will occur by November-December 2018 (~3 months into the study).  Should any alterations in 
functional outcome measures occur while traveling to Cleveland VA Medical Center and Kessler 
Foundation/Kessler Institute for Rehabilitation, all Cleveland Clinic study staff will be re-trained to ensure 
standardization of methodology. By using this standardization plan, all study staff will be prepared to 
evaluate patients when we begin patient enrollment ~6 months after the clinical trial begins. MetroHealth 
Hospital team (Anne Bryden and Amy Friedl) will be trained on the standardized methodology during the 
first quarter of the fourth year (September 2021-November 2021). 
 
o Transcranial Magnetic Stimulation (TMS) 
Dr. Plow has over a decade of experience in delivering TMS and training others in the delivery of TMS. In 
this study we will collaborate with other experienced researchers in the field of TMS; Dr. Yue (Kessler 
Foundation), Dr. Cunningham (MetroHealth Hospital) and Drs. Pundik and Baker (Cleveland VA). Drs. 
Yue and Plow were previous colleagues and collaborators at the Cleveland Clinic Foundation prior to Dr. 
Yue’s transition to Kessler Foundation.  At the Cleveland Clinic, Drs. Yue and Plow led and developed 
multiple protocols for TMS as is evident by their co-published articles [8-15].  Therefore, both Drs. Yue and 
Plow are well trained in identical methodology in TMS protocols and possess the same equipment to deliver 
TMS. Drs. Pundik and Baker are experts in TMS as well and have performed TMS studies with Dr. Plow 
for a number of years [1-3, 8, 11, 12, 16-22]. Therefore, the prior success of collaborations between Drs. 
Plow, Yue, Pundik and Baker for TMS studies indicates that standardization of TMS methodology across 
sites would not be difficult. All study staff will be trained by Drs. Plow, Yue, Pundik and Baker at each site, 
and standard operating procedures for TMS will be developed and distributed by Dr. Plow and Mr. Kyle O’ 
Laughlin upon site visits within the first 4 months of the clinical trial in year 1. Dr. Cunningham was a 
previous student of Dr. Plow at the Cleveland Clinic, therefore the methodology of delivering TMS will be 
easily translated for this current trial. Dr. Cunningham and his team at MetroHealth Hospital will be trained 
during the first quarter of the fourth year (September 2021-November 2021). 
 
o Rehabilitation 
Dr. Plow has worked with SCI patients for upper limb rehabilitation for over 4 years through her recent 
DoD-funded study [1-3].  Sample rehabilitation tasks from the previous pilot study will be dispersed 
between sites to aide in customization of therapy tasks for each patient, between physical therapists (Dr. 
Plow at the Cleveland Clinic, Ms. Garbarini at Kessler Foundation/Kessler Institute for Rehabilitation, Terri 
Hisel at MetroHealth Hospital and Ms. McCabe at the Cleveland VA Medical Center).  In addition, study 
staff at each location involved in therapy will be trained by Dr. Plow on delivering rehabilitation based on 
massed-practice.      
 
o Transcranial Direct Current Stimulation 
Dr. Plow has had over a decade of experience in using transcranial direct current stimulation (tDCS) to 
promote restoration of functional outcomes in applications ranging from vision to motor ability.  With her 
experience, Dr. Plow has been able to optimize a dosage schedule for tDCS delivery for the proposed clinical 
trial using her previous pilot study.  Therefore, since all the same equipment exists at all locations, during the 
first fiscal year site visit in month 4, Dr. Plow will advise Dr. Forrest, Dr. Pundik and Dr. Baker along with 
their respective research personnel how to properly apply the tDCS stimulation during rehabilitation.  

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 5 of 35 
 
 
It would be important to ensure consistency of dosing or treatment fidelity in application of rehabilitation. 
Safeguards are planned to ensure that all patients participating at all study sites receive the same dose of 
massed-practice rehabilitation for same length of time, with a similar ratio between tasks practiced with the 
weaker upper limb and those practiced with the stronger upper limb. Therefore, therapists at all sites, including 
the PI Dr. Plow at the Cleveland Clinic, Ms. McCabe at the Cleveland VA medical center and Ms. Garbarini at 
the Kessler Foundation/Kessler Institute for Rehabilitation will participate in Skype phone/video calls before 
starting treatment for any patient in the first year of the study. These meetings will allow every therapist to 
become more comfortable with dosage and frequency required for the proposed protocol. Therapists will have 
one additional meeting in the middle of the training regimen (session 7 or 8 out of 15) to ensure continued 
treatment fidelity. In years 2-4, therapists will have similar meetings for every other patient to ensure that even 
over several years, consistency of fidelity of rehabilitation delivery is maintained.  Ms. Hisel at MetroHealth 
Hospital will be trained on administering tDCS by Dr. Plow and Mr. O’Laughlin during the first quarter of the 
fourth year (September 2021-November 2021). 
2. DEVICE DESCRIPTION 
2.1  
Name of Device 
This study will be conducted with the Soterix Medical 1x1 Low Intensity DC Stimulator. The Soterix Medical 
1x1 Low Intensity DC Stimulator is an Investigational Device developed by clinical researchers, scientists, and 
biomedical engineers for use in clinical standard tDCS protocols.    
2.2  
Soterix tDCS Principle of Operation 
For the specific steps on how to operate the Soterix Medical DC Stimulator, refer to the device manual. 
 
Transcranial Direct Current Stimulation is treatment that utilizes electrode pads placed at opposing points on the 
scalp and a direct current stimulator to deliver electrical energy which transfer from the anode, across the scalp 
and skull, to the targeted location in the brain and then to the cathode placed at a different location on the scalp.  
 
For the proposed indication, the aim is to deliver continuous bilateral transcranial direct current stimulation, 
directing the anode to the contralateral motor cortex of the more affected upper limb. The cathode will be 
placed on the ipsilateral orbit of the more affected upper limb. This will allow the current to flow from the 
motor hotspot (of the weaker muscle in the more affected upper limb) to its contralateral orbit. 
2.3  
Soterix tDCS System and TMS system Regulatory Status 
The Soterix Medical 1x1 Low Intensity DC Stimulator is an investigational device. Federal (or United States) 
law limits device to investigational use. The intended use of the tDCS system used in this protocol is 
investigational. 
 
The TMS System, Magstim Magnetic Stimulator and 70mm Double Coil is manufactured by Magstim Co. Ltd. 
These Devices have 510(k) Clearances for other intended uses. The intended use of the TMS system used in this 
protocol is investigational. 
2.4  
Proposed Indications for Use 

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 6 of 35 
 
The Soterix Medical 1x1 Low Intensity DC Stimulator will be used in this phase I/II clinical trial in 
combination with upper limb rehabilitation to improve functional outcomes and functional independence in 
individuals with chronic cervical spinal cord injury. 
 
The TMS system, Magstim Magnetic Stimulator, will be used in this phase I/II clinical trial to record the 
neurophysiology in the Spinal Cord Injury population. This device will be used before the start of the treatment 
phase and at the end of the treatment phase to capture the changes in neurophysiology of this population. 
 
2.5  
Manufacturing information 
Manufacturing information for the Soterix Medical 1x1 Low Intensity DC Stimulator is available on their 
website at soterixmedical.com 
Manufacturing information for the Magstim 2002 Magnetic Stimulator and Coil is available in Magstim Co. 
Ltd. Cleared 510k (K060847) 
2.6  
Labeling 
The Soterix Medical 1x1 Low Intensity DC Stimulator and the TMS System to be used this clinical trial will 
bear a label with the following statement: “CAUTION—Investigational device. Limited by Federal (or United 
States) law to investigational use.” 
 
3. BACKGROUND AND SIGNIFICANCE 
3.1        Overview of SCI Epidemiology 
Spinal Cord Injury remains a prominent cause of long-term disability. In the US alone, about 282,000 
individuals are affected with SCI; over half of them are between the ages of 28 and 43. SCI is especially 
common among veterans, who constitute ~15% (42,000) of the injured population [1-4]. Since SCI affects a 
younger demographic, lifelong costs of disability are staggering. Direct lifetime burden can be up to $4.7 
million per patient [2], while indirect costs can add another $701,000/year [5, 6]. This Clinical Trial seeks to 
offer cost-effective interventions that have the potential to reduce long-term disability in SCI. 
3.2  
Unmet Clinical Needs 
Restoring motor function of the paretic upper limbs would address significant 
unmet clinical needs of patients with tetraplegia. Capacity to use the paretic 
upper limbs predicts functional independence and patients’ subjective 
wellbeing. In a survey of 600 patients, up to 50% prioritized the return of 
upper-limb function over any other function lost after injury (fig. 1). 
Proportions were even higher among individuals with tetraplegia, of whom 
>75% reported the expectation for return of function of the upper limbs [8]. 
Our proposal seeks to offer interventions to restore motor function of the 
paretic upper limbs in tetraplegia to impact significant unmet clinical need. 
3.3 
Current Standard of Care Approaches 
Rehabilitation is the most common approach to restore motor function of the 
paretic upper limbs. According to the World Health Organization (WHO), 
“rehabilitation can [substantially] decrease the consequences of injury, improve health and quality of life and 

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 7 of 35 
 
decrease the use of health services…[over the long term]” [9]. Rehabilitation typically involves engaging the 
paretic upper limbs in exercise and practicing tasks simulating activities of daily living (ADLs) [10-16]. 
Benefits of rehabilitation, however, come slowly and are often insufficient. A minimum of 8 weeks of 
rehabilitation is required to elicit even modest improvement; >9 months are required to elicit clinically 
meaningful benefit [16, 17]. This Clinical Trial offers a simple, practical and inexpensive approach to enhance 
the outcomes of rehabilitation. 
 
 
3.4 
Enhancing Clinical Outcomes 
Outcomes of rehabilitation remain limited because neural resources that survive SCI cannot effectively 
contribute to recovery [18-22]. Motor cortices and the emergent descending pathways (that survive in >65% of 
injuries, called “incomplete” SCI [23, 24]) demonstrate injury-induced imbalances in excitability. These 
substrates come to represent muscles spared above the level of injury and lose control of weak muscles affected 
below that level. Therefore, surviving neural resources are “taken over” by muscles spared above the level of 
injury, which leaves little opportunity for representation of weak muscles affected below that level [22, 38]. 
Weak muscles as such continue to weaken in the absence of rehabilitation/re-training [20, 27, 33, 35-37,39]. 
Although rehabilitation can help restore excitability of surviving neural resources devoted to weak muscles, 
these plastic changes are insufficient to dramatically affect their contribution towards recovery [40-44]. 
Therefore, here, we test the scientific premise that delivering electrical stimulation to motor cortices and 
residual descending pathways during rehabilitation would generate greater restoration of excitability and 
enhance their contribution towards recovery.  
Evidence generated from hundreds of studies, including our own work, has especially highlighted the promise 
of tDCS. Findings from our work have revealed that tDCS delivered to the motor cortices and the residual 
corticospinal pathways can elicit promising improvements in rehabilitative outcomes of the paretic upper limb 
in patients with neurologic diseases like stroke. A four-fold greater improvement in motor function can be 
generated by adding positive (anodal) tDCS during rehabilitation. Mechanisms entail increase in excitability of 
motor cortical maps and residual corticospinal pathways devoted to the weak muscles [46-58]. 
3.5  
Innovation 
This clinical trial will be the first study to test the effectiveness of multiple sessions of tDCS in individuals with 
SCI. Study of the use of tDCS in SCI is in the elementary stages compared to the evidence available in the field 
of stroke or other neurologic injuries [45, 52]. Only a handful of studies have explored the effects of tDCS upon 
restoration of upper-limb motor function, and even then only short-term effects, based on the application of 
single sessions, have been studied [69-72]. Our recently published DoD-funded pilot study was the first study in 
which tDCS was given for multiple sessions in rehabilitation of SCI individuals [61]. Though another group had 
adopted a similar design, they had paired tDCS with an investigational treatment (robotic therapy) not clinical 
rehabilitation [73, 74]. Therefore, our proposed study will be the first efficacy trial to report upon the functional 
benefits of combining tDCS with clinical rehabilitation for multiple sessions in SCI. As such, our design carries 
more clinical relevance and has the potential to generate longer-lasting functional benefits than contemporary 
studies. 
3.6 
Significance 

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 8 of 35 
 
The approach of noninvasive brain stimulation is, we believe, a simple, safe, and affordable technique to restore 
upper-body function after SCI. This method can be delivered during standard rehabilitation, with no need for 
additional time or resources; it has the potential to become an easily applied, cost-effective, practical tool that 
can easily be offered at a number of sites. Also, since our evidence indicates that this technique can help 
generate promising gains in rehabilitation within a short time, it also has the potential to substantially reduce the 
costs of managing disability in SCI.   
 
 
4. REPORT OF PRIOR INVESTIGATIONS 
4.1 
Summary of Previous Studies 
Our recent published and preliminary work funded by the DoD and the Conquer Paralysis Now foundation 
indicates that tDCS can be effective for enhancing rehabilitative outcomes in SCI [59-62]. In a pilot, 
randomized, double-blinded, placebo-controlled clinical trial, we allocated 14 patients with C2-C6 incomplete 
SCI (≥1year post injury; having sparing to muscles in the upper extremities below the level of injury) to either 
receive tDCS (n= 8) or sham tDCS (n= 6) during rehabilitation. Interventions were given for 2 hours/day, 5 
days/week for 2 weeks. Before receiving these interventions, patients completed a baseline control phase lasting 
2 weeks, during which they continued with the typical routine. After receiving the interventions, patients 
completed a 3-month follow-up phase, during which they engaged in a home exercises prescribed by the 
physical therapist (PI, Plow).  
Outcomes included metrics specified in the Common Data Elements (CDEs), developed through the 
collaboration of the International Spinal Cord Society, the AIS, and the National Institute of Neurological 
Disorders and Stroke (NINDS). The primary outcome was the Upper Extremity Motor Score (UEMS), which 
rates power/strength of 10 muscles of the arm and hand, each on a 0-5 scale of the UK’s Medical Research 
Council (MRC; 0, no voluntary twitch; 5, maximum contraction against resistance). The sum total ranges 
between 0 and 50. The secondary outcome was fine-motor control or dexterity tested using the Nine-Hole Peg 
Test (NHPT), which requires patients to place tiny pegs into holes on a board, then remove and replace them as 
quickly as possible. Neurophysiologic metrics were also collected, with the use of TMS. Excitability of motor 
cortical maps and residual corticospinal pathways was quantitated for strong muscles above the level of injury 
(C3-C6) and weak muscles below that level (C6-T1).  
Our results, published in Spinal Cord and Journal of Spinal Cord Medicine, have revealed several noteworthy 
findings in line with the aims of the proposed study [60-62]. Regarding Aim 1, results of our pilot study have 
revealed that patients receiving tDCS during rehabilitation show twice as much gain in strength of the muscles 
of the weaker upper limb than patients receiving rehabilitation alone (4- vs. 2-point gain on UEMS) (t7, 0.05 = 
7.3, p < 0.0001). Gains are maintained even 3 months after the completion of tDCS (t4, 0.05 = 3.1, p < 0.018). 
Gains are particularly evident for muscles innervated below the level of injury (C6-T1). Greater number of 
muscles innervated below the level of injury shows clinically detectable improvements in strength after tDCS 
(≥1 full muscle grade increase on MRC [63, 64]) (t10, 0.05 = 1.55, p = 0.07). Triceps muscle (C7), one of the 
most functionally important muscles for performing transfers, for instance, improves by 1-full muscle grade on 
average after two-weeks of tDCS (clinically detectable gain) (t6, 0.05 = 3.33, p < 0.008). Improvements 
witnessed for strength translate to improvements in dexterity (t12, 0.05 = 1.84, p = 0.045). Improvements 

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 9 of 35 
 
witnessed with rehabilitation alone, however, remain less remarkable (<0.5 muscle grade increase on MRC) (t4, 
0.05 = 2.14, p = 0.05). 
In accord with the proposed Aim 2, patients receiving tDCS during rehabilitation show greater gains in 
excitability of the brain and the residual descending pathways devoted to weak muscles. Although at baseline, 
patients show a greater number of excitable brain sites devoted to the stronger than the weaker muscles, in line 
with findings of injury-induced imbalances in excitability reported in earlier preclinical and clinical studies (t7, 
0.05 = 1.82, p = 0.05) [20, 26-31], after tDCS, balance tends to become restored. The number of brain sites 
devoted to the stronger muscles tends to decrease (t6, 0.05 = 1.07, p = 0.16), whereas that devoted to the weaker 
muscles tends to increase after tDCS (t6, 0.05 = 1.43, p = 0.1) (fig. 4A, D). What is equally compelling is that 
such re-balancing is not witnessed after rehabilitation (without tDCS); instead, patients show further increase in 
the number of brain sites devoted to the strong muscles (t4, 0.05 = 1.84, p = 0.07). Therefore, the ratio of weak vs. 
strong muscle map in the motor cortices shows larger gains after tDCS than after rehabilitation, i.e., the ratio or 
the balance shifts in favor of the weak muscles (t10, 0.05 = 1.92, p = 0.08). Restoration of balance is associated 
positively with gains in strength of the weak muscles. Patients who show the greatest gain in the number of 
brain sites devoted to weak muscles also experience the greatest gains in strength of those muscles. Thus, tDCS 
helps re-balance or restore the excitability of surviving neural resources, plasticity that is functionally adaptive. 
Regarding Aim 3 of the proposed study, patients receiving tDCS during rehabilitation experienced no serious 
adverse events. Further, these patients were not any more likely to guess which group they were in compared to 
patients who received sham tDCS (Χ2= 0.69; p= N. S.). Thus, overall, the application of tDCS during 
rehabilitation is safe for individuals with SCI based on the findings of our pilot study. Our study also shows that 
it is feasible to test tDCS against a placebo condition in the proposed randomized, sham-controlled, double 
blind, phase I/II safety-efficacy clinical trial.  
4.2 
Conclusion 
In general, results of our pilot study indicate that tDCS is a promising technique to enhance rehabilitative 
outcomes of the paretic upper limbs in patients with incomplete cervical SCI [60, 61, 65]. Effects of tDCS are 
related to mechanisms of restoration of balance in excitability– re-mergence of the brain representation of weak 
muscles and reduction of the brain representation devoted to spared, strong muscles within residual neural 
resources. What speaks to the scientific rigor of our findings is the evidence that effects of tDCS observed here 
cannot be explained based on spontaneous shifts in function or excitability, or test-retest effects. Metrics of 
strength and dexterity and those indexing neurophysiology remained stable in the absence of any intervention. 
Values of UEMS and TMS metrics showed excellent and moderate-to-excellent reliability during the baseline 
control phase (concordance correlation coefficient [CCC] = 0.964, and CCC= 0.644 to 0.935, respectively) [60]. 
Therefore, greater confidence can be placed upon the findings demonstrating promise of tDCS during the 
intervention phase. Here, our objective is to investigate whether the promise of tDCS, and the mechanisms 
underlying its effect, observed in our recently published single-center pilot study can be replicated by 
performing the study at other multiple centers [60, 61, 65]. A multi-center investigation is a natural, logical 
progression to establish the generalizability of the effect of tDCS across different types of patients and confirm 
the validity of our findings.  
5. STUDY DESIGN 

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 10 of 35 
 
5.1 
Study Objective 
The objective of the proposed trial is to extend the scope of our pilot study and conduct a phase I/II multi-site 
randomized controlled, double-blinded clinical trial to test the safety, feasibility, efficacy, and mechanisms of 
delivering tDCS with rehabilitation in SCI. At least forty-nine (up to 54) patients with chronic, incomplete (having 
sparing to muscles in the upper extremities below the level of injury) C1-C8 SCI will be enrolled across 4 sites: 
Cleveland Clinic (at least 21[up to 25] subjects), Kessler Foundation/Kessler Institute for Rehabilitation (14 
subjects), Cleveland VA Medical Center (6 patients), and MetroHealth Hospital (8 patients). Patients will first 
complete a baseline control phase lasting 3 weeks, during which they will continue with their typical routine and 
activities (fig. 4). After the baseline control phase, they will be randomly assigned to either receive tDCS (n = 22) 
or sham tDCS (n = 22) during rehabilitation. Rehabilitation will be given for 2 hours/day, 5 days/week for 3 
weeks. Rehabilitation will especially involve exercises for weak muscles innervated below the level of injury, 
such as triceps (C7). After the completion of the rehabilitation/intervention phase, patients will participate in a 3-
month follow-up phase, during which they will be asked to continue with exercises prescribed as part of the home-
exercise routine. Up to 42 age matched healthy control participants will also be enrolled to record ‘normal’ neural 
indices (15 at the Cleveland Clinic, 6 at Kessler Foundation, 6 at Cleveland VA, and up to 15 at MetroHealth 
Hospital). 
 
Assessments will be completed before and after the baseline control phase (pretests 1/2), the intervention phase 
(posttest) and the 3-month follow-up phase (follow-up) (fig. 4). Assessments will include metrics of strength and 
dexterity (Graded Redefined Assessment of Strength, Sensation and Prehension [GRASSP]); functional abilities 
(Wolf Motor Function Test [WMFT]); activity limitations (self-care subscale of the Spinal Cord Independence 
Measure [SCIM]); and participation restrictions (Canadian Occupational Performance Measure [COPM]). TMS 
will be used to study excitability of neural resources devoted to a weaker muscle and a spared muscle. The 
Hoffmann reflex (H-reflex) involving peripheral electrical stimulation will be used to study spinal excitability. 
Up to 42 age-matched (5 years), healthy control subjects will also undergo testing of TMS/H-reflex at a cross-
sectional time-point. The goal will be to establish age-based norms for neurophysiologic metrics related to non-
dominant biceps and triceps muscles. In accordance with feedback provided by DoD reviewers, adverse effects, 
SCI-specific symptoms (e.g., pain, autonomic dysreflexia) and attrition and integrity of blinding will also be 
recorded. The following aims and hypotheses will be tested in the proposed study. 

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 11 of 35 
 
 
 
5.2 
Sample Size Estimation and Power Analysis 
Sample size was calculated 
based on PI Dr. Plow’s 
recent DoD-funded pilot 
study [60, 61]. Differences 
in effect size between 
tDCS-+-rehab and sham-+-
rehab groups were used to 
estimate sample sizes, based on two sample t statistics compiled at α = 0.05 for 80% power (Table 2). For Aim 
1, data concerning strength/power of muscles and dexterity (NHPT) was used since both of these metrics are 
components of the primary outcome for Aim 1 (GRASSP). Based on between-group comparison of the numbers 
of weak (C6-T1) muscles that achieved clinically detectable improvements on MRC (≥1 full grade gain [63, 
64]), we would require a total of 40 patients, and based on between-group comparison of % improvement on the 
NHPT (pegs per second), we would require 32 patients for achieving 80% power. This estimate would be 
sufficient for Aim 2 as well. For Aim 2, data concerning motor cortical map excitability was used, as this is the 
primary outcome for Aim 2. Based on between-group comparison of % change in map ratio (weak map/strong 
map), we would require 26 patients for achieving 80% power. Considering that there could be attrition of 10%, 
we expect to enroll 44 patients. A sample of 44 patients with 22 patients included in each SCI group would also 
be sufficient for study of Aim 3, which is designed to show that tDCS-+-rehab is at least as safe and feasible (no 
greater attrition or probability of guessing the group) as rehabilitation given alone (sham-+-rehab). 
5.3 
Primary Endpoint 
EFFECTIVENESS OF PAIRING TDCS WITH REHABILITATION. Hyp. 1: Patients receiving tDCS with 
rehabilitation will achieve greater gains in strength and dexterity, with reduction in activity limitations and 
participation restrictions, than those getting rehabilitation alone. Responders/non-responders will be identified 
Fig. 4: Study Design and follow-up procedures. TMS= Transcranial Magnetic Stimulation; H-reflex= Hoffman Reflex; tDCS= transcranial direct 
current stimulation (tDCS) 
Outcomes/Metrics
Effect size (tDCS vs. Sham)
α
80% 85% 90% 95%
UEMS (# Weak muscles
showing clinically detectable 
improvement)
0.938
0.05
40
44
52
62
Δ% Nine Hole Peg Test
1.033
0.05
32
36
42
52
Aim 2
Δ% Map Ratio (Weak 
map/Strong map)
1.192
0.05
26
30
34
40
Aim 1
Table 2: Sample Size Estimation based on Power Analysis

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 12 of 35 
 
based on baseline clinico-demographic characteristics, such as the level of injury, degree of incompleteness and 
time post-injury, etc. 
5.4  
Secondary Endpoints 
MECHANISMS OF PAIRING TDCS WITH REHABILITATION. Hyp. 2: Patients receiving tDCS with rehabilitation 
will exhibit larger gains in excitability of neural resources devoted to the weak triceps muscle (C7) and greater 
reductions in excitability of neural resources devoted to the spared biceps muscle (C5) compared with patients 
receiving rehabilitation alone. Patients receiving tDCS in rehabilitation will also exhibit larger gains in spinal 
excitability. Relationship between neural mechanisms and gains in strength and dexterity and functional 
abilities will be explored. 
SAFETY AND FEASIBILITY OF PAIRING TDCS WITH REHABILITATION. Hyp. 3: Patients receiving tDCS with 
rehabilitation will show no greater adverse effects or attrition or ability to correctly guess the group allocation 
than those receiving rehabilitation alone. 
6. SUBJECT SELECTION 
6.1 
Study Patient Population 
Subjects participating in the study will be medically stable individuals who have been diagnosed with 
incomplete cervical spinal cord injury over 1 year ago and continue to have difficulties using one or both of 
their upper limbs. Subjects will be selected to participate in the study based on the inclusion/exclusion criteria 
listed below. Subjects will not participate in any study-specific tests or procedures before their written informed 
consent. 
 
 
6.1a 
General Inclusion Criteria 
Patients with incomplete (having sparing to muscles in the upper extremities below the level of injury) C1-C8 
SCI; age ≥18 years; 1 year time post injury (to avoid confounding effect of cervical root recovery [77]) will be 
enrolled. On the more affected side, patients will be required to have sparing of either the biceps or the triceps 
muscle, defined as 3-muscle power grade on the MRC scale. They will also be required to show weakness of 
the muscle antagonist to the spared muscle i.e. triceps in case of spared biceps, or biceps in case of spared 
triceps on the affected side. Weakness will be defined as a MRC grade of 1-3, and a clinically detectable 
difference in power compared to the power of the spared muscle, i.e., 1 muscle grade lower on the MRC scale 
[63, 64]. Criteria requiring sparing of one muscle and the weakness of the antagonist muscle are meant to create 
a homogeneous sample for the study of neurophysiology using TMS in Aim 2. These criteria will not be 
limiting for subject recruitment, as evident from the successful completion of our recent pilot work, because 
patients with cervical SCI either commonly show sparing of biceps (C5) and weakness of triceps muscles (C7), 
or this order of weakness is reversed in patients with central cord syndrome [60, 61]. On the contrary, these 
criteria will allow inclusion of even more-impaired individuals, who may not have “active hand function” as 
required by typical SCI studies [66, 68] and an ongoing study (NCT02611375). 
6.1b 
General Exclusion Criteria 

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 13 of 35 
 
Patients with contraindications to tDCS and TMS, including pacemaker, metal in the skull, seizure history, or 
pregnancy will be excluded [75, 77]. Patients with spine stabilization will be included because the site of 
TMS/tDCS application to the head is distant from the site of the metal implant in the neck. Patients on an anti-
spasticity or pain medication regimen will also be included, as long as the same dose and regimen are 
maintained. Patients with active pressure ulcers, however, will be excluded to avoid disruption of ongoing 
medical treatment. Patients with traumatic brain injury (TBI), diagnosed based upon acute injury Rancho scale 
<5 or positive MRI/CT findings at the time of injury will also be excluded to prevent confounding of TMS 
metrics. Patients with excessive tone/spasticity (Modified Ashworth Scale [MAS] >3) and severe contractures 
or soft tissue shortening at elbow/wrist will be excluded. Finally, patients participating in ongoing upper-limb 
therapies will be excluded to minimize the possibility of confounding effects. For healthy control participants, 
the exclusionary criteria will be the same as mentioned above. Healthy control inclusion criteria is age between 
18-70 years old, without any diagnosis of neurological disease.  
 
 
 
 
 
6.2 Subject Recruitment 
Patients will be recruited via methods found successful in the PI’s recent pilot trial (NCT01539109), funded by 
the Department of Defense. Patients will be recruited from 9 area hospitals within the Cleveland Clinic, from 
outpatient and community-based programs, support groups, and referrals. We will also enroll directly from 
Cleveland Clinic Physician Dr. Greg Nemunaitis. Dr. Nemunaitis is new to the Cleveland Clinic, however he 
has held the largest practice for SCI in NE Ohio for decades. Therefore, his patients who visit him at CCF will 
serve as the ideal candidate population. Dr. Nemunaitis and the Research Personnel will tell his patients about 
research studies when they arrive for their exam visit.  Enrolling past trial participants will also prevent delays 
in enrollment. Those on the Pilot study’s waiting list could be contacted for the proposed study. Subject 
recruitment will be significantly enhanced through the use of Cleveland Clinic’s KP, which logs each 
neurological outpatient visit within Cleveland Clinic and therefore provides valuable long-term and follow-up 
information, aiding in study recruitment. KP will be used to request a list of potential participants. KP generates 
a list of patients seen at a particular center at the Cleveland Clinic that can be filtered by certain center metrics. 
We will send KP request to centers at the Cleveland Clinic that have been known or are suggested to us by site 
physicians at location on campus that SCI patients are seen. KP then will send us the password protected list 
and we will save on our private server with a password protection only know to lab personnel. Patients of the 
KP query that seem to be a potential fit will have a letter sent to their physician to see if we can contact their 
subject in regards to our study and potentially screen. Another recruitment method we will adopt is the use of 
eResearch and an EPIC heat request. eResearch Requests allows us to request patient MRN’s from the 
Cleveland Clinic medical records system that fit a certain criteria that we provide. From this request we will be 
receiving monthly excels from the eResearch team with the names of individuals which fit the request filters we 
initially provided to them. Epic Heat requests will allow us the ability to request a report of patient MRNs from 
the EPIC team based on a set criteria for participants to fit are inclusion criteria. We will save these Excel sheets 
sent to us by the respective teams as password protected documents and review the MRNs through our usual 

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 14 of 35 
 
chart review method. After subjects are identified we will following our usual route of contacting subjects 
which involves sending physician letters via email or EPIC Messaging, then send the patient letters via physical 
postal mail or EPIC Messaging/MYCHART to those patients that physicians do not say no to sending a letter, 
and then calling the potential participants after 1-2 weeks to gauge their interest in participating if they do not 
call us first.  
In addition, we will be working with our partners at Select Medical to identify potential candidates 
housed in their acute rehab hospitals (Edwin Shaw, Avon, and Beachwood) and provide study fliers/brochures 
to them via intake binders or advertisements placed at the facilities. It is anticipated that these patients in Select 
Medical CCF acute rehabilitation hospitals will not meet the 1 year post-cervical spinal cord injury inclusion 
criteria for the study, however, providing these potential participants with our study information may help give 
the patients an idea of what avenues they can pursue upon completion of their clinical care. As a preparatory 
step in research, if an interested candidate reaches out to us, we will perform phone screening even though they 
will not meet our time post injury criteria. This will allow us to identify any immediate exclusionary criteria 
related to the study protocol and provide input to the interested candidate on their potential for participation 
after their clinical care. 
 
Dr. Plow has also created links with the many agencies and support group for SCI survivors across Ohio, on 
which she has relied or help with patient recruitment. 
We also will potentially use the following for posting advertisements in the region and nationwide: National 
Spinal Cord Injury Association Newsletter, Publications of the Paralyzed Veterans of America, Local 
Newspapers, Posting the clinical trial on SCOPE (www.scope-sci.org), nationally on clinicaltrials.gov.  
A Brochure and flyer will also be used to advertise for the study.  
  
6.3 Subject Screening 
SCI physicians at each site (Dr. Bethoux at Cleveland Clinic; Dr. Richmond at Cleveland VA Medical Center; 
Dr. Kirshblum at Kessler; Dr. James Wilson at MetroHealth Hospital) will screen patients at the beginning of 
the study to determine eligibility, either on-site or through a video screen for subjects who cannot reasonably 
make it to one of the sites. International Standards for Neurological Classification of SCI (ISNCSCI) will be 
used to confirm the diagnosis, the degree of completeness of injury (AIS A, B, C, or D), and zones of partial 
preservation below the level of injury. Strength or muscle power will be recorded using UEMS to identify the 
weaker upper limb. Physicians will quantify spasticity using the MAS and note any tightness and contractures. 
Complaints of neuropathic pain and autonomic dysreflexia will be noted. Medication usage will be screened and 
documented. Physicians will examine patients and exclude those with active pressure ulcers. Physicians will 
also determine whether patients had suffered an associated TBI at the time of SCI. A diagnosis of TBI will be 
made based on original radiographs and clinical records, as well as history and physical examination. Patients 
who are found to have had a Rancho Los Amigos Scale score of level V or below, and/or any MRI- or CT- 
evidence of focal cerebral cortex involvement or hydrocephalus from the time of injury, and/or history of (non-
sedated) post traumatic amnesia lasting >48 hours, will be excluded. ISNCSCI, medical history and physical 

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 15 of 35 
 
examination are considered part of the NINDS CDEs for SCI. Therapists will also conduct a screening to assess 
upper limb functionality before subjects are enrolled. This is done on-site before or after the physician 
screening, unless subjects are not within a reasonable distance to the Cleveland Clinic and a virtual visit is more 
appropriate. 
 
6.3 
Subject Enrollment 
A subject is enrolled in the study after they have provided informed consent. The subject also has to meet all of 
the inclusion and none of the exclusion criteria determined by the site PI. 
 
7. STUDY VISITS 
7.1  
Study Schedule 
Figure 2 below provides a study flow diagram from the point of subject screening and consent through the final 
follow-up visit. 
 
Fig.2 
 
7.1a 
Schedule of Study Visits 
Study Phase 
Visit 
Schedule 
Screening/ Informed Consent 
The screening/informed consent visit will occur with 
a single on-site visit or if necessary, an additional 
video screening before the on-site screening. After 
informed consent, screening functional tests will be 
performed. 
1 on-site visit and a potential 
video screen 
Baseline Rehab Functional 
and Neurophysiology Testing 
Pre-Test #1 will involve functional tests and 
Neurophysiology (TMS, H-Reflex)  tests. The visits 
will occur over 2 days and last 8-11 hours. 
2 on-site visits (any day after 
informed consent/screening visit)
Pre-Test #2 will involve functional tests and 
Neurophysiology (TMS, H-Reflex)  tests. The visits 
will occur over 2 days and last 8-11 hours. 
2 on-site visits (at least 3 weeks 
after Pre-test #1) 
Rehab Phase 
15 visits of rehab. During rehab visits subject will 
have SHAM or REAL tDCS administered. Each 
rehab session will last for 2 hours. 
15 on-site visits. (5 times per 
week for 3 weeks) 
Post-Rehab Functional and 
Neurophysiology Testing 
Post-Test will involve functional tests and 
Neurophysiology (TMS, H-Reflex) tests. The visits 
will occur over 2 days and last 8-11 hours 
2 on-site visits (within 1 week 
after the final rehab visit) 

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 16 of 35 
 
3 Month Follow-up Testing 
Follow-up will involve functional tests. This visit 
will last between 1-3 hours. 
Optional Neurophysiology testing (TMS, H-Reflex)
1 on-site visit, (OPTIONAL: +1 
on-site visit) (3 months after the 
final rehab visit)
6 Month Follow-up testing  
(OPTIONAL) 
Optional Follow-up will involve functional tests and 
Neurophysiology (TMS, H-Reflex) 
2 on-site visits (6 months after 
the final rehab visit) 
12 Month Follow-up testing  
(OPTIONAL) 
Optional Follow-up will involve functional tests and 
Neurophysiology (TMS, H-Reflex) 
2 on-site visits (12 months after 
the final rehab visit) 
 
7.1b 
Schedule of Study Assessments 
 
Fig.3 
7.2  
Baseline TMS and Functional Testing 
Patients found to be eligible after screening will be tested on pre-test 1 and pre-test 2 (fig. 2). Both pre-test 1 
and pre-test 2 will be conducted over 2 days lasting 8-11 hours (1 day functional testing, 1 day neurophysiology 
testing). They will be asked to continue with their typical routine and activities during what will be called the 
baseline control phase, lasting for 3 weeks. Patients will be asked specifically to refrain from participating in 
new training regimens involving the paretic upper limbs. During the Baseline Control Phase subject will 
participate in 2 Pre-testing visits. During each pre-test visit subject will undergo functional tests and 
Neurophysiology tests as seen in figure 3. There will be a 3 week break period between each pre-test visit (pre-
test visits 2 should be at least 14 days after pre-test visits 1). 
7.3 
Rehabilitation with tDCS 
Each subject with SCI will perform rehabilitation while receiving tDCS (randomly assigned active or sham 
stimulation) for 15 total visits.  
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15
phone screening document
X
Inclusion/Exclusion
X
ASIA Classification
X
Upper Extremity Motor Score(UEMS)
X
MRC Muscle Strength Scale
X
Spinal Cord Independence Measure(SCIM)
X
X
X
X
X
X
Canadian Occupational Performance Measure (COPM)
X
X
X
X
X
X
GRASSP
X
X
X
X
X
X
Neurogenic Bladder Symptom Score (NBSS)
X
X
X
X
X
X
Modified Ashworth Scale (MAS)
X
X
X
X
X
X
Capabilities of Upper Extremity Test (CUE-T)
X
X
X
X
X
X
Transcranial Magnetic Stimulation (TMS) Neurophysiology Tests
X
X
X
X
X
X
H-Reflex
X
X
X
X
X
X
TMS Adverse Effects Questionnaire
X
X
X
X
X
X
vital signs(blood pressure, heart rate, respirations, blood 
oxygen saturdation) 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
tDCS Adverse Effects' Questionnaire 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
6-month Follow-Up 
(OPTIONAL)
12-month Follow-Up 
(OPTIONAL)
Schedule of Study Assessments
Preliminary Screening
Pre-Test #1
Pre-Test #2
Rehabilitation 
Post-Test
3-month Follow-Up
Informed consent/ 
Formal Evaluation
3-month Follow-Up 
(OPTIONAL)

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 17 of 35 
 
7.3a 
Rehabilitation 
Patients in both groups will receive 15 sessions of rehabilitation delivered for 2 hours a day, 5 days a week, for 
3 weeks. Rehabilitation will be prescribed by site physical therapists: the PI Dr. Plow at Cleveland Clinic; Ms. 
Garbarini at Kessler; Ms. Jessica McCabe at Cleveland VA Medical Center; and Ms. Hisel at MetroHealth 
Hospital. Rehabilitation will be based on the principle of massed practice [17, 66, 67]. Massed practice involves 
intensively engaging the paretic upper limbs in 10-15 tasks. Massed practice has shown promise at reducing the 
weakness of the upper limbs in our recent study and studies by other groups [17, 61, 66, 67].  
Training of the weaker upper limb will be emphasized with massed practice. Training of the weaker upper limb 
is more functionally relevant than training of the stronger one. In addition, training of the weaker upper limb 
will also maximize the potential of restoring function with tDCS. tDCS will be delivered using the typical uni-
hemispheric montage, i.e., targeting the hemisphere contralateral to the weaker limb. The weaker upper limb 
will be identified based on patient report and UEMS collected at screening. About 80% of the tasks will engage 
the weaker upper limb, while remaining tasks will engage both limbs.  
Tasks will be chosen based on the patient’s preference and priority for achieving functional independence and 
will be designed so as to maximize the transfer to performance of real-world activities. Similar to practices 
commonly used in rehabilitation clinics, tasks will primarily engage muscles innervated below the level of 
injury (C6-T1). Engagement of the weak triceps (C7) will be especially emphasized, for instance, through 
activities like rising from a chair while pushing on armrests, or reaching for different targets positioned on a 
tabletop. Return of triceps strength is functionally relevant because triceps is critical for performing transfers to 
and from the wheelchair/surfaces and reducing caregiver assistance.  
Each task will be performed 10 times and will be repeated if deemed necessary. Performance metrics like speed, 
accuracy, number of trials completed, etc., will be recorded and tracked. Feedback will be provided. Tasks will 
be made more (or less) challenging as patients recover movement abilities [76, 79]. Patients will also be asked 
to practice the tasks at home for 30 min a day, 5 days a week, for 3 weeks. Adherence to home exercises will be 
monitored using a home-exercise log that will be shared with investigators at every training session. 
 
 
7.3b 
tDCS 
Transcranial Direct Current Stimulation (tDCS) will be delivered using a 9-V battery-operated device (Soterix 
Medical, New York, NY). Surface electrodes will be placed inside saline-soaked sponge inserts (5x7 cm2) and 
applied to different regions on the scalp. The anodal electrode will be applied over the primary motor cortex, 
contralateral to the weaker upper limb. The center of the electrode will be positioned at a site evoking the 
largest muscle potentials in weak triceps using TMS (details follow). Location of the rectangular electrode (four 
corners and center) will be marked using stereotactic navigation. An overlap of the electrode locations will be 
generated for the 15 sessions to establish reproducibility. The cathodal electrode will be applied over the 
opposite supra-orbital area. 
 
Current will be delivered at a dose of 2mA. Currents will be delivered for the first 30 minutes of the first hour 
of rehabilitation and the first 30 minutes of the second hour of rehabilitation for each rehab session. Sham tDCS 

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 18 of 35 
 
will be delivered using the same application, but currents will be ramped up slowly at the beginning and ramped 
down slowly at the end. This sham technique facilitates blinding of the subject. 
 
 
 
7.4 
Post TMS and Functional Testing 
 
Post rehabilitation TMS and Functional testing will happen within the week of finishing rehab visit 15. During 
the Post TMS and Functional testing visit, subject will undergo the same testing that occurred during pre-testing 
visits 1 and 2. The functional tests and neurophysiology (TMS) testing that the subject will undergo can be seen 
in figure 3. 
 
7.5 
Long term Follow-up 
After the posttest, patients will continue to engage in a home-exercise program prescribed by the site physical 
therapist. Patients will be expected to perform exercises for 30 min/day, 5 days/week, for 3 months. Adherence 
will be monitored using exercise logs, similar to those used during the intervention phase. Patients will  receive 
monthly phone calls from study coordinators from respective sites (Mr. O’ Laughlin from Cleveland Clinic, Ms. 
McCabe from Cleveland VA Medical Center, Ms. Martinez from the Kessler, and Ms. Amy Friedl from 
MetroHealth Hospital sites). During these calls, exercise logs will be reviewed, questions/concerns will be 
addressed, feedback about performance will be provided, and tasks will be made more (or less) challenging if 
necessary, based on direction from the site physical therapists [76, 79]. After follow-up, patients will return to 
their respective study site for testing of function (fig 3). 
 
 
7.5A    OPTIONAL Long term Follow-Up 
 
Optional long term follow-up visits at 3(Optional Neurophysiology) and/or 6 and/or 12 months will be 
performed on select patients to monitor longer term changes in chosen patients who have opted into the 
extended long term follow-up. During the long term follow-up patients will not be expected to perform the 
exercises given after the completion of the intervention. Also Phone calls will not be made during this time. We 
will ask patients to continue to work on exercises for the more affected limb and allow them to call us with any 
questions or input to their home exercise routine. Subjects will not be limited from participating in any clinical 
procedures during this time as well. At 3(Optional Neurophysiology) and/or 6 and/or 12 months the chosen 
subjects who opted in at the time of consent will come back into the clinic to perform 1 day of functional testing 
and 1 day of neurophysiology testing as was done at post-testing.  
 
7.6 
Healthy Control Study Visit. 
Healthy controls that are enrolled in the study will come in for one site visit. The site visit will involve TMS 
neurophysiology testing, identical to Pre-test 1 that patients perform (fig 3). The time involved in study 
procedures for healthy controls is approximately 4-6 hours. 
8. SAFETY REPORTING 
8.1 
Definitions and Classification 

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 19 of 35 
 
The following definitions are from Good Clinical Practice (ISO 14155:2011) and FDA Code of Federal 
Regulations for Medical Devices (21 CFR 812.3(s)). 
 
8.1a 
Adverse Event (AE) 
An AE is any untoward medical occurrence, unintended disease or injury or any untoward clinical signs 
(including an abnormal laboratory finding) in subjects, users or other persons whether or not related to the 
investigational medical device.  
 
AE includes all hospitalizations and events related to the investigational device or the comparator. This Includes 
events related to the procedures involved (any procedure in the clinical investigation plan). For users or other 
persons this is restricted to events related to the investigational medical device. 
 
AE does not include conditions pre-existing to the subject’s enrollment. Pre-existing conditions will not be 
reported as AEs unless the condition has an increased occurrence or intensity. 
8.1b 
Serious Adverse Event (SAE) 
An SAE is any AE that: 
a. led to a death 
b. led to a serious deterioration in health that either: 
i. resulted in a life-threatening illness or injury, 
ii. resulted in a permanent impairment of a body structure or a body function, 
iii. required in-patient hospitalization or prolongation of existing hospitalization, 
iv. resulted in medical or surgical intervention to prevent life threatening illness or injury or 
permanent impairment to a body structure or a body function, 
v. resulted in a substantial disruption in ability to conduct normal life functions. 
SAE does not include in-patient hospitalization for a planned study procedure. Planned study-related in-patient 
hospitalization is not an SAE. 
SAE includes device deficiencies that might have led to a serious adverse event if (a) suitable action had not 
been taken or (b) intervention had not been made or (c) if circumstances had been less fortunate. These are 
handled under the SAE reporting system. A planned hospitalization for pre-existing condition, or a procedure 
required by the Clinical Investigation Plan, without a serious deterioration in health or to prevent life 
threatening illness or injury or permanent impairment to a body structure or a body function, is not considered 
to be a serious adverse event. 
8.1c 
Relatedness to Study Procedures 
The probability that a particular AE is related to any of the study procedures shall be coded on the AE case 
report form as unrelated, possibly related, or related. Probability ratings are based on the temporal relationship 
to the intervention, the likelihood that the symptom could have been produced by the participant’s clinical state, 
the environment or other interventions, whether the participant’s symptom course follows a known pattern of 
response to the intervention, and the experience and judgement of the lead investigators at each site. 
 

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 20 of 35 
 
9. DATA MANAGEMENT 
9.1         Identifiers and Code System 
All patients will be given an identification code at first contact with the study. This identifier will be unrelated 
to any aspect of subject’s protected health information (PHI). Each site will have a unique identifier system 
consisting of a letter related to the specific study and a random 3-digit number. All study data will be de-
identified and only the study identification code system will be followed. 
 
 
9.2  
Completion and Storage of Case Report Forms 
To ensure data quality and completeness, all required study data shall be recorded on case report forms (CRFs). 
Hard-copy version of study-related data will be kept separate from identifiable information in a locked cabinet. 
All electronic data will be backed up on a separate secure server to ensure data protection. As stated earlier, 
Cleveland Clinic, Cleveland VA Medical Center, Kessler foundation/Kessler Institute for Rehabilitation, and 
MetroHealth Hospital provide secure servers to each laboratory to help save and back-up de-identified 
electronic study data. On these secure servers and on laboratory’s authorized computers, electronic data will be 
kept in a folder available only to the researchers named and authorized at each site. Authorized individuals 
would access this data on their respective laboratory-based computers for which their use is authorized and 
monitored. Each site will be responsible for the storage of its own data and identifiable information. Hard-copy 
data will be verified by two independent evaluators before it is entered electronically. At each site, study-related 
data will be kept for seven years from the date of application to the IRB and the Human Subject Research 
Protection Office (HRPO) (GLP), based on Good laboratory practices (GLP) (21CFR 58). Data will be stored 
on laboratory’s authorized computers and any hard-copy data would be converted to electronic data with 
REDCap capture. The Cleveland Clinic, Kessler Foundation/Kessler Institute for Rehabilitation, Cleveland VA, 
and MetroHealth Hospital will all be adding data to the Cleveland Clinic REDCap system. Study Personnel 
from each site will be granted access to REDCap to enter the data and CRF’s into the Cleveland Clinic 
REDCap. During this time, only the principal investigator, study coordinator and authorized study staff will 
have access to the Cleveland Clinic computer that would be password-protected and locked for access. The 
database will be password-protected and backed-up to ensure that data integrity is maintained. 
9.3        Confidentiality 
At the beginning of the study, a physician-confirmed diagnosis of spinal cord injury (SCI) is important. For this, 
medical records, MRI, and radiology reports will be requested from patient’s physician/hospital through written 
approval. Following the process of informed consent, the SCI physician for each site, Dr. Bethoux (Cleveland 
Clinic), Dr. Kirshblum (Kessler Foundation/Kessler Institute for Rehabilitation), Dr. Richmond (Cleveland VA 
Medical Center), and Dr. James Wilson (MetroHealth Hospital) will screen patients. Rehabilitation evaluation 
will be completed by SCI physical therapists: Dr. Plow at the Cleveland Clinic, Ms. McCabe at the Cleveland 
VA Medical Center, MS. Garbrini at Kessler Foundation/Kessler Institute for Rehabilitation, and Ms. Friedl at 
MetroHealth Hospital. For determining eligibility, the site physicians and site PIs (Drs. Plow, Forrest, 
Kirshblum, Pundik, Bryden and Cunningham) will review past medical history, history of present illness, family 
history when relevant, and review physical therapy and medical evaluation to make a final determination bout 
subject’s eligibility.  

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 21 of 35 
 
All of patient’s medical information, and PHI such as age, date of SCI, name, and address collected at the 
beginning of the study will be saved in a confidential manner at respective study sites. This private information 
will be protected and available only to the PI and authorized team members at each site. All identifiable 
information and health information will be stored separately from study data in a locked cabinet within a locked 
room. Only the study coordinator and the principal investigator at each site (Mr. O’ Laughlin and Dr. Plow at 
the Cleveland Clinic, Ms. Martinez and Drs. Forrest and Kirshblum at Kessler Foundation/ Kessler Institute for 
Rehabilitation, Drs. Baker and Pundik at Cleveland VA Medical Center, and Ms. Friedl and Drs. Cunningham 
and Bryden at MetroHealth Hospital) will have access and will have the keys for the room and cabinet separate 
at each site. Keys will be stored away from plain sight in authorized individual’s locked office cabinet. Any 
electronic files that contain identifiable information will be password-protected and only stored on computers 
with limited access as described below. The Cleveland Clinic, Cleveland VA Medical Center, the Kessler 
Foundation/ Kessler Institute for Rehabilitation, and MetroHealth Hospital provide networks that are secured 
for use by the authorized user only. All PHI will be stored on computers that are accessible only to the 
authorized team members on the study.  
All identifiable information will remain at the parent study site (Cleveland Clinic, Kessler Foundation/ Kessler 
Institute for Rehabilitation, Cleveland VA Medical Center, and MetroHealth Hospital) and only de-identified 
information will be shared between sites (see special precautions later). Per guidelines of the Congressionally 
Directed Medical Research Programs (CDMRP), CDMRP-funded studies should make their ‘final research 
data’ as freely and widely available as possible. To meet this specification yet safeguard the privacy of our 
patients, and protect confidential and proprietary data, and any intellectual property, we would share de-
identified data (see Precautions later). Since subaward sites, MetroHealth and Kessler Foundation/ Kessler 
Institute for Rehabilitation, are both SCI Model System centers, we would request co-investigators at these 
institutions (Drs. Kilgore, Bryden, Forrest, Kirshblum, Yue) to enter the de-identified data describing the 
clinico-demographic characteristics, function, and level of independence in self-care etc., in the national 
database. This process will be facilitated because we use common data elements (CDEs). Sharing of de-
identified data based on CDEs would allow all SCI Model Systems across the U.S. to have access to our raw 
(de-identified) values and the change to compare values from our patients with the values from their patients 
and participants. In the informed consent process, patients will be made aware of the sharing of de-identified 
data via the SCI Model Systems database.  
Accurate and complete study records from both sites will be maintained and made available only to 
representatives of the respective institutional review boards (IRBs), the U. S. Food and Drug Administration 
(FDA), the Department of Health and Human Services and representatives of the U.S. Army Medical Research 
and Materiel Command (USAMRMC). In unusual situations, all study sites will comply with legal requirements 
that mandate disclosure of identifiable information. The IRB-approved research consent document includes 
Health Information Portability and Accountability Act (HIPAA) authorization elements in the privacy and 
confidentiality section, where it will be explained that data from patients can be shared with federal authorities 
(listed above) and representatives of USAMRMC as stated above and that de-identified data can be shared with 
researchers at the Cleveland Clinic, Kessler Foundation/Kessler Institute for Rehabilitation, and Cleveland VA 
Medical Center, and SCI Model Systems database via Metrohealth and Kessler Foundation/Kessler Institute for 
Rehabilitation. Informed consent process will also explain that subjects have the right to withdraw their 

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 22 of 35 
 
authorization at any time and if they choose not to sign the consent form, they are choosing not to participate in 
the research study. 
Dr. Kilgore and Dr. Bryden from MetroHealth Rehabilitation institute in Cleveland will be informing their 
patients with SCI of our study at the Cleveland Clinic. To maintain confidentiality of patients from 
MetroHealth, Dr. Kilgore and Ms. Bryden will not release any PHI about their patients. They will simply 
inform their patients of the study at the Cleveland Clinic site (see letters from Kilgore and Bryden). It would be 
at the patient’s discretion as to whether or not they want to follow up with study staff at lead site or local site in 
Cleveland (Cleveland Clinic or Cleveland VA Medical Center). In the event that interested participants contact 
the study staff, it would be their discretion to release information to participate in the study. Therefore, even 
though co-investigators at other institutions would initiate referrals, privacy and confidentiality will be ensured.   
Each site will comply with the same management plan for PHI. Whether a participant was enrolled or could not 
screen in into the study, we would ensure that their PHI is stored and accessed securely. Identifiable and 
protected health data of enrollees will be saved for 6 additional years after expiration of study authorization 
based on Code of Federal Regulations (45 CFR 164.530(j)(2). 
9.4 
Data Analysis Plan 
For aim 1, measures of function, strength/muscle power, dexterity, sensation, prehension, perception of 
independence in self-care, and quality of life will be collected, while for aim 2, metrics characterizing 
neurophysiology will be acquired and for aim 3, vital measurements will be noted daily. 
Functional metrics adopted here are part of the National Institute of Neurological Disorders and Stroke 
(NINDS) Common Data Elements (CDEs), developed through the collaboration of the International Spinal 
Cord Society, the AIS, and the NINDS. The functional metrics span across all domains of the World Health 
Organization’s (WHO’s) International Classification of Function (ICF) model, including body function and 
structure, activity limitations, and participation restrictions. Metrics include Graded Redefined Assessment of 
Strength, Sensibility and Prehension (GRASSP), comprising the Upper Extremity Motor Score (UEMS) for 
strength, Nine-hole peg test (NHPT) for dexterity and sensation and prehension; Wolf Motor Function Test 
(WMFT) for measurement of functional abilities; Spinal Cord Independence Measure (SCIM) for evaluation of 
patient’s ability to perform self-care; Canadian Occupational Performance Measure (COPM) to identify the 
patient’s perceived level of daily participation in functional activities (e.g. cooking, cleaning, and hobbies). 
Each set of tests gives a different perspective of disability and testing all will allow us to get a full picture of 
patient function and quality of life before and after therapy. All measurements for aim 1 will take 120-150 min 
to complete. We will determine whether patients receiving tDCS in conjunction with rehabilitation experience 
greater recovery of function and independence than patients who receive rehabilitation alone (aim 1). 
In aim 2, we will study the patient’s neurophysiology, which will include the study of excitability of output 
pathways to a weaker muscle and a stronger muscle, and the cortical representations of these muscles. These 
measures of neurophysiology will be acquired using TMS and Hoffman or H-reflex. Neurophysiological tests 
will take 150-180 min to complete, which includes time allotted for breaks. We will test whether patients 
receiving tDCS in conjunction with rehabilitation experience greater gains in excitability of substrates devoted 

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 23 of 35 
 
to the weak muscle and larger decreases in the excitability of the substrates devoted to the stronger muscle than 
patients receiving rehabilitation alone (aim 2).  
For aim 3, we will compare effects of interventions on patient’s vital measurements, attrition, experience of 
adverse events (AEs) like tingling, itching, burning underneath the electrodes and likelihood of correctly 
guessing the group allocation. We anticipate that patients receiving tDCS in conjunction with rehabilitation will 
show no greater adverse effects or attrition than those receiving rehabilitation alone. 
9.5         Sharing Study Results 
Since neurophysiology tests are not diagnostic, no clinical report will be generated. But data from screening and 
functional outcomes, such as that collected by SCI physicians (Dr. Bethoux at the Cleveland Clinic; Dr. 
Richmond at the Cleveland VA Medical Center; Dr. Kirshblum at Kessler Foundation; Dr. Wilson at 
MetroHealth Hospital) and physical therapists to determine eligibility is used in clinical diagnosis as well. This 
includes the International Standards for Neurological Classification of SCI (ISNCSCI) for confirmation of 
diagnosis and American Spinal Injury Association (AIS) for rating the completeness of injury (A, B, C, and D) 
and zones of partial preservation below the level of injury. Physicians and therapists also record strength or 
muscle power using UEMS, and spasticity using MAS. Complaints of neuropathic pain and evidence of 
autonomic symptoms are noted as well. Diagnosis of associated TBI is made based on original radiographs and 
clinical records, and history and physical examination. Further, in line with aim 3, vitals and symptoms such as 
fatigue, restlessness, trouble concentrating, pain, etc. will be recorded. If an incidental finding is observed 
during the screening, i.e., a result that was not evident from original medical record review, or if a patient 
consistently demonstrates abnormal values during safety testing, then the study physicians, Dr. Bethoux at the 
Cleveland Clinic, Dr. Richmond at the Cleveland VA Medical Center, Dr. Kirshblum at Kessler 
Foundation/Kessler Institute, and Dr. Wilson at MetroHealth Hospital will notify the patient’s primary care 
provider, referring physician or SCI physician to share findings. Regarding healthy controls as well, a similar 
protocol will be followed.  
 
       9.6         Special Precautions 
Special precautions taken during laboratory evaluations to ensure patient safety: TMS carries a rare risk of 
seizures. Plus, patients with cervical SCI could experience autonomic dysfunction. To manage any AE therefore 
we will perform all procedures under the supervision of the Clinical Research Unit (CRU). CRU resources will 
be indispensable for patient safety and comfort in the current study. CRU comprises of a core group of clinical 
research administrators who help assure the most efficient and effective ways for researchers and clinical trials 
participants to interact. CRU coordinates and provides a culturally sensitive and welcoming clinical 
environment for volunteer research participants, inpatient and outpatient facilities such as examination rooms, 
specialized procedure rooms, core laboratories, services such as metabolic meal preparation, research dietician 
consultation, human exercise performance measurement and highly trained personnel to carry out research 
protocols in the hospital and in outpatient medical centers. Experienced research nurses staff both inpatient and 
outpatient areas. The research nursing staff is highly trained in initiating and maintaining time-sensitive 
procedures. Resources also include on-site crash code cart for immediate medical attention and drugs specific to 
potential risks associated with different protocols. The arrangement of CRU support will be similar to that used 
in Dr. Plow’s current clinical trials where any TMS-based studies are conducted with CRU supervision by 
trained research nurses and on-call physicians to manage risks of seizures, and headaches. In consultation with 

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 24 of 35 
 
SCI physicians and CRU, a seizure protocol is put in place to ensure that in case of an AE, medical attention is 
prompt, such as crash cart availability and on-site medications and patient is stabilized without difficulty.  
 
Safeguards and procedures are in place to ensure GCP are followed.  Specifically, on-call CRU nursing staff 
and trained study staff will continually monitor patient safety and health during each site visit. Every 1 hour or 
whenever it becomes necessary, vital monitoring will be performed by CRU nursing staff, where values 
including blood pressure, heart rate, oxygen saturation and respiratory rate will be collected.  In case vital 
measurements are significantly abnormal or a serious AE occurs, hospital-wide medical emergency response 
team will be paged; on-call physician (Dr. Bethoux at the Cleveland Clinic; Dr. Richmond at the Cleveland VA 
Medical Center; Dr. Kirshblum at Kessler Foundation and Kessler Institute for Rehabilitation; Dr. Wilson at 
MetroHealth Hospital) will be contacted and on-call CRU nurses will be reached as well. Depending on the type 
of emergency, SCI physicians and emergency response team will determine the next course of action. In 
addition, study staff will always record minor but noticeable changes in patient’s state and vitals.  All staff will 
be required to have completed the basic life support training before conducting procedures on the study.  
 
To date, no AEs have occurred during the duration of our current SCI pilot study.  This is likely since we use 
fairly strict inclusion and exclusion criteria. However, should an AE occur that could have been prevented, 
clinical coordinators, under the direction of PI/Co-I’s, will update the patient screening process to identify what 
makes a patient susceptible to such an event.  In addition, all patients currently participating in the clinical trial 
would be informed of the event and any subsequent changes to the consent form through a re-consenting 
process. 
 
Special precautions taken to ensure confidentiality during data compilation and data sharing across sites: Raw 
data of neurophysiology and functional metrics shared between Cleveland Clinic, Cleveland VA Medical 
Center Kessler Foundation/Kessler Institute for Rehabilitation and MetroHealth Hospital will be de-identified 
and placed on locked drives and will not affect patient confidentiality. Since only a copy of de-identified data 
will be transported between sites, original data will still be available at each site in case the copy is damaged or 
destroyed in transport. Still, to ensure that data is completely de-identified and that privacy rules are being 
followed, we will take additional precautions. 
 
Data will be collected without the use of the any of the 18 protected health identifiers, which could be used to 
identify the individual or the individual's relatives, employers, or household members. De-identified data will 
not have names, geographic divisions smaller than a State, including street address, city, county, precinct, zip 
code, and their equivalent geocodes; elements of dates (except year) for dates directly related to an Individual, 
including birth date, admission date, discharge date, date of death, and all ages over 89 and all elements of dates 
(including year) indicative of such age; telephone numbers; fax numbers; electronic mail addresses; social 
security numbers; medical record numbers; health plan beneficiary numbers; account numbers; 
certificate/license numbers; vehicle identifiers and serial numbers, including license plate numbers; device 
identifiers and serial numbers; web universal resource locators (URLs); internet protocol (IP) address numbers; 
biometric identifiers, including finger and voice prints; full face photographic images and any comparable 
images; and any other unique identifying number, characteristic, or code, except as otherwise permitted. 
 

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 25 of 35 
 
Informed consent process will seek approval from patient for sharing of de-identified study-related data with 
researchers at the other sites- Cleveland Clinic, Kessler Foundation/Kessler Institute for Rehabilitation, 
Cleveland VA Medical Center, and MetroHealth Hospital. Since per guidelines of CDMRP, CDMRP-funded 
studies should make their ‘final research data’ as freely and widely available as possible, while safeguarding 
privacy of patients, and protecting confidential and proprietary data, and any intellectual property, we would 
share raw data that is completely de-identified. Raw data of neurophysiology and functional metrics, which are 
completely de-identified, and ascribed dummy study identification codes will be uploaded to the SCI Model 
Systems database through two of our collaborating sites that are also leading model systems centers, including 
Kessler Foundation/Kessler Institute for Rehabilitation and Metrohealth Rehabilitation Institute Cleveland. 
 
10. STUDY ADMINISTRATION 
10.1 
Data Safety Monitoring Board (DSMB) 
This study will be performed in accordance with the Charter of the Data and Safety Monitoring Board (DSMB) 
provided below. The members of the Board are  
• 
Paul T. Scheatzle, DO, MS, Fellow of the American Academy of Physical Medicine and 
Rehabilitation (FAAPMR) (Medical Monitor), Chair 
 
Bailey Rehabilitation Services 
• 
Steven W. Brose, DO 
 
Syracuse VA Medical Center; Spinal Cord Injury and Disorders Center 
• 
Doug Gunzler PhD (Biostatistician) 
 
Case Western Reserve University; Center for Health Care Research and Policy 
• 
Denise Peters, PT, PhD (Research Monitor) 
 
University of Vermont  
• 
Mr. Christopher Wynn (Consumer Advocate) 
 
Buckeye Wellness Center 
Dr. Steven Brose is Chief of Spinal Cord Injury at the Syracuse VA Medical Center in New York State. He has 
extensive experience in spinal cord injury in both clinical and research settings. Dr. Paul Scheatzle is a 
Physiatrist at the Edwin Shaw Rehabilitation Institute (Cuyahoga Falls, Ohio). He has over 21 years 
specializing in physical medicine and rehabilitation. Dr. Denise Peters of the University of Vermont’s College 
of Nursing and Health Sciences is a physical therapist and rehabilitation scientists with  research expertise in 
translating mechanistic research to evidence-based clinical application in the field of neurologic rehabilitation 
specifically spinal cord injury. Mr. Wynn is a military veteran, and owner of Buckeye Wellness Center (Valley 
View, Ohio), which specializes in training those with spinal cord injury in exercise programs. As part of the 
DSMB, Mr. Wynn will serve as the consumer advocate. 

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 26 of 35 
 
The DSMB will be responsible for reviewing the draft DSMB charter, safety and efficacy of the phase I/II 
clinical trial, and reviewing any adverse events occurring during this study. The Board will have the authority to 
make a final ruling on contested site-reported events as necessary and appropriate.  
The Charter of the Data and Safety Monitoring Board is attached (with names of the committee members 
redacted, per instructions). 
10.1a 
DSMB Responsibilities 
The DSMB will review the draft DSMB charter and make recommendations for any changes. 
The DSMB will monitor the safety of the trial via a report provided by Douglas D. Gunzler, PhD, Case Western 
Reserve University (Cleveland, Ohio). 
The initial review of the data by the full DSMB will take place after the first 13 patients have completed the 
study. Thereafter, the DSMB will meet after every 13th patient has completed the study, or at least once a year, 
to examine the safety of the trial in accordance with Aim 3 of the study and integrity of data collecting in terms 
of efficacy in Aim 1. These assessments will include, at a minimum, a review of all adverse events, deaths, or 
deviations from the study protocol and results of functional outcomes and metrics. 
The DSMB will make recommendations to the Trial Operations Committee regarding the modification or 
continuation/discontinuation of the trial. 
DSMB member Dr. Denise Peters is the Research Monitor of this Project. As described in the Department of 
Defense Instruction 3216.02, Dr. Peters is responsible in overseeing the safety of the research subjects and 
report observations/findings to the IRB. She will review all unanticipated problems involving risks to subjects 
or others associated with the protocol and provide an independent report of the event to the IRB. She may 
discuss the research protocol with investigators; shall have authority to stop a research protocol in progress, 
remove individual human subjects from a research protocol, and take whatever steps necessary to protect the 
safety and well-being of human subjects until the IRB can assess the monitor’s report; and shall have the 
responsibility to promptly report their observations and findings to the IRB or other designated official, other 
DSMB members, and the HRPO. 
10.1b 
DSMB Meetings 
The first meeting of the DSMB will be an organizational meeting. This meeting is intended to formally establish 
the DSMB and to thoroughly acquaint the DSMB with the protocol and the interim analysis plan. It also affords 
the DSMB an opportunity to recommend final revisions of the interim analysis plan, the DSMB protocol, mock 
tables, and the plan for communication between the DSMB and the Sponsor/Investigator. 
1. The initial review of the data by the full DSMB will take place after the first 13 patients have completed 
the study. Thereafter, the DSMB will meet after every 13th patient has completed the study, or at least 
once a year. 
2. The DSMB will determine if additional reviews of the data are needed. If necessary, the DSMB can 
request more frequent reports. 
3. The confidential DSMB reports will be hand delivered to the members 5 days before the scheduled 
meeting. 

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 27 of 35 
 
4. Statisticians will send the DSMB quarterly summaries of adverse events, endpoints, and device data. 
Whenever the DSMB thinks it is necessary, a full DSMB conference call will be held. 
The DSMB meeting will consist of three parts: 
1. Open Discussion: The first part of the meeting will be attended by the DSMB members, the statistician 
(Dr. Xiaofeng Wang), and the Trial Operations Committee. Its purpose is to discuss the conduct of the 
trial, study status, and issues related to data quality and interpretation. 
2. Presentation of the Results: The DSMB members and the statistician will attend the second part of the 
meeting only. During this part of the meeting, the statistician will present the results of the statistical 
analysis of the study to the DSMB members.  
3. Closed Discussion: The third part of the meeting will be attended by DSMB members only. During this 
part, the board will discuss the results and make any decisions regarding the conduct of the trial. Based 
on its review, the DSMB may, if warranted, recommend one of the following actions to the sponsors. 
a. Continue the study according to the protocol and any existing amendments. 
b. Continue the study, but modify the study protocol. Modifications may include, but are not limited 
to, changes in the inclusion/exclusion criteria, frequency of safety monitoring, and alterations in 
study procedures and follow-up period for purposes of safety as defined in the protocol. 
c. Discontinue the study, with provisions for orderly discontinuation in accordance with good 
clinical practice. 
4. Confidential minutes will be recorded. They will be stored in a secured location by the statistician.  
5. As soon as possible, but within 3 days following each of its meetings, the DSMB will prepare a written 
report for the Trial Operations Committee outlining any serious safety concerns and explaining their 
recommendations. 
 
10.1c 
Making Recommendations 
The DSMB may recommend one of the following actions to the Trial Operations Committee (fig 4): 
1. Stop the Study 
2. Continue the Study without changes 
3. Change the Protocol 

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 28 of 35 
 
 
Fig. 4 
 
 
10.1d 
DSMB Decision Guidelines for stopping the trial 
Upon review of the data while the trial is in progress, the DSMB will make decisions regarding the continuation 
of the trial. The final decision to stop the trial is left to the recommendation of the DSMB. 
 
 
 
10.1e 
Elements of the DSMB Reports 
Dichotomous and categorical data will be reported as total numbers and percentages. Continuous data will be 
reported as means, medians, and standard deviations. 
Reports should have page numbers and sections need to have explanatory tabs. 
If objectives are different for subsequent DSMB meetings, the meeting minutes should reflect the report(s) 
needed for each meeting. 
Elements of the DSMB Report: 
1. Patients enrolled 
2. Protocol deviations 
3. Selected clinical risk factors 
4. Demographic/baseline factors to include gender, race, and age 
5. Deaths (patient listing of the event to indicate study-related vs. not study-related) 
6. Serious and/or severe adverse events and unanticipated adverse device effects on subjects 

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 29 of 35 
 
7. Narrative reports of serious adverse events 
8. Narrative reports of subject outcomes 
The DSMB report will include the total number of patients whose data were derived from final Case Report 
Forms (CRFs). 
11. RISKS/BENEFITS 
Foreseeable Risks: There are several risks involved with the proposed study procedures that are either related to 
techniques/devices proposed for the present study or are unrelated to study procedures but represent risks 
intrinsic to the nature of the study population – those with tetraplegia. 
 
11.1 
Risks associated with TMS 
Transcranial magnetic stimulation (TMS) has been used in a growing number of laboratories worldwide since 
1984, and safety guidelines have been developed. In the present study, the investigators will use all 
recommended safety precautions for TMS. Although unlikely, given the low levels of stimulation applied in the 
present study, the following side effects are still possible: 
 Headache: Subjects may have a headache following TMS. This is believed to be due to muscle tension. 
In the case of headache, subjects will be offered acetaminophen or aspirin, which in all prior cases of 
headaches induced by TMS have promptly resolved the discomfort. The risk of headache is estimated to 
be approximately 10%-25%. 
 Hearing: TMS produces a loud clicking sound when a current is passed through the stimulation coil. 
This loud clicking can result in ringing in the ear and temporary shifts in the subject’s ability to 
determine the pitch and loudness of sounds, if no protection is used. To prevent this possible side-effect, 
we will ask subjects to wear earplugs that block the noise of the TMS. Hearing damage is possible; one 
person is known to have suffered permanent hearing damage when the hearing protection fell out of the 
ear. Animal and human studies have shown that earplugs or headphones can effectively prevent the risk 
of hearing disturbance due to TMS.  
There are also several rare side effects of TMS: 
 Seizure: Subjects may have a seizure induced by TMS. If a seizure were to occur, it would occur during 
the TMS application itself, not after. If the subjects are currently taking a prescription medication that 
has the potential to lower the seizure threshold, they may be at increased risk for seizure from the 
procedures in this study. It will be made clear to them that they must maintain their current medications 
at the prescribed dose for the entirety of their involvement in this study. Seizures are a very rare 
complication. First, the TMS levels that we propose to use have never been reported to induce a seizure. 
Second, during the TMS session, subjects will undergo continuous monitoring of EMG activity to allow 
investigators to detect the earliest warning signs of a seizure and be able to prevent it. Nevertheless, a 
seizure could occur. For this reason, TMS will be applied by investigators properly trained in the prompt 
recognition and treatment of a seizure and certified in basic life support. Clinical Research Unit nursing 
support, physicians, and resources, such as “crash cart” medications related to seizure protocol, will be 
available. Should a seizure occur, subjects will receive prompt treatment by a physician. Experiencing a 
seizure induced by TMS does not mean that subjects will have another seizure again; it does not make 
the subject an epileptic person and will not mean that subjects will have to take medications to prevent 
seizures in the future. A letter approved by the FDA documenting these facts will be offered to any 
subject who experiences a seizure induced by TMS. Nevertheless, seizure occurrence with single-pulse 

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 30 of 35 
 
TMS is rare. Only two persons have had seizures induced by the approach of TMS we are using (single-
stimulus/-pulse TMS) among the many thousands of subjects who have undergone TMS worldwide. 
Furthermore, the investigators will use precautions to further reduce the risk.  
 Memory or attention may be affected for a short period of time (a few minutes) after receiving TMS. 
The low TMS levels used in this study have never been shown to cause such problems.  
 There may be unforeseen risks to an unborn child associated with undergoing TMS. To address this risk, 
women subjects will be excluded from the study if they are found to be pregnant during our prior testing 
procedures.  
 Finally, even though TMS has been used in many laboratories worldwide since 1984, there could be 
some unforeseen complications. There may be unforeseen risks to an unborn child associated with 
undergoing TMS. To address this risk, subjects will be excluded from the study if they are found 
pregnant during our testing procedures. 
 
11.2 
Risks associated with tDCS 
Although many researchers have studied the safety of transcranial direct current stimulation (tDCS) and 
determined that it is a painless stimulating technique with almost no harmful effects, there are several minor 
adverse effects that need to be reported. These effects include: 
 Temporary itchiness and/or redness of the skin in the area of stimulation. The reddening is transient for 
levels of stimulation proposed in this protocol. However, skin will be inspected regularly at the site of 
stimulation to ensure redness is relieved.  
 Transient and mild headache, tingling, and a burning sensation in the area of stimulation. However, 
these effects have been reported while delivering higher doses than what will be used in the proposed 
study. 
 Application of tDCS might result in temporary cognitive and motor side effects such as dizziness, 
disorientation, or confusion. These effects are transient, and the subject will be constantly supervised by 
study staff.  
 
11.3 
Risks associated in the SCI patient population 
The patient population we propose to study, those with tetraplegia, is typically more functionally limited, since 
the injury affects all limbs and the trunk. Further, in comparison to those with paraplegia, many patients with 
tetraplegia have reported severe difficulties with neuropathic pain, sensation, walking, bladder and bowel 
function, trunk stability, sexual function, and arm/hand function. They also typically present with more serious 
co-morbidities, especially autonomic emergencies, spasticity, and depression. Therefore, even though their co-
morbidities may be unrelated to study procedures, patients can still experience the following: 
 Autonomic dysreflexia: This syndrome occurs in individuals with spinal cord lesions above the T6 level. 
Since the proposed study plans to enroll patients with levels of injury between C1 and C8, patients may be 
at risk for autonomic dysreflexia. The syndrome is caused by overstimulation of the involuntary nervous 
system, which is usually a result of improper emptying of the bowels or bladder or a urinary tract infection. 
Study staff is aware of the symptoms of autonomic dysreflexia (severe hypertension, headaches, sweating, 
flushing of skin, and slow heart rate). If a patient develops the syndrome during a study session, the patient 
will immediately inform the responsible treating physician. Clinical Research Unit nurses will be on-site 

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 31 of 35 
 
during all sessions and will help identify signs early on. They will help initiate preventive measures, such as 
ensuring catheter bags are not full or there is no obstruction to catheter tubing. If an event occurs, study staff 
will initiate the emergency code for paging the emergency response team; the on-call physician will be 
paged, and nursing staff will implement the medical orders. With such precautionary measures, no 
autonomic emergencies have occurred in Dr. Plow’s pilot clinical trial in patients with tetraplegia.  
 Exacerbated spasticity: Some SCI patients experience spasticity, which is described as involuntary stiffness 
of the muscles. Depending on the severity, spasticity could affect the patient’s comfort level as well as 
ability to perform tasks during the rehabilitation phase of the study. During the intervention, breaks will be 
provided to minimize fatigue and allow passive movements and stretching. Patients will be asked to 
maintain their dose of anti-spasticity medications.  
 Neuropathic pain: Patients with SCI could have damaged nerve fibers, which transmit incorrect signals and 
cause pain. This neuropathic pain could affect the patient’s comfort level as well as ability to perform tasks 
during the intervention phase of the study. The level of neuropathic pain will be taken into consideration 
when designing the specific intervention for a patient to minimize any exacerbation of the pain.  
 
11.4         Benefits 
Subjects will be receiving rehabilitation in the study, however, this will not guarantee benefit from their 
participation in the study.  
 
12. INFORMED CONSENT MATERIALS 
Informed Consent will be obtained from each study participant. The investigator and/or study coordinator at 
each respective site will approach the potential subject, verbally explain the study, and provide an IRB and 
HRPO approved written informed consent document for his/her review and signature. The site lead PI and 
coordinator will be available to answer all questions the subject may have pertaining to the nature of the study 
or any of the study procedures. Subjects will not be allowed to participate in any study procedures until 
informed consent is provided.  
 
REFERENCES CITED 
 
1. 
Spinal Cord Injury Facts and Figures at a Glance. 2013; Available from: http://www.uab.edu/nscisc. 
2. 
Center, N.S.C.I.S., Facts and Figures at a Glance. 2015, University of Alabama at Birmingham: 
Birmingham, AL. 
3. 
Schoenfeld, A.J., et al., Spinal injuries in United States military personnel deployed to Iraq and 
Afghanistan: an epidemiological investigation involving 7877 combat casualties from 2005 to 2009. Spine 
(Phila Pa 1976), 2013. 38(20): p. 1770-8. 
4. 
Blair, J.A., et al., Spinal column injuries among Americans in the global war on terrorism. J Bone Joint 
Surg Am, 2012. 94(18): p. e135(1-9). 
5. 
Devivo, M.J., Epidemiology of traumatic spinal cord injury: trends and future implications. Spinal Cord, 
2012. 50(5): p. 365-72. 
6. 
Jackson, A.B., et al., A demographic profile of new traumatic spinal cord injuries: change and stability 
over 30 years. Arch Phys Med Rehabil, 2004. 85(11): p. 1740-8. 

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 32 of 35 
 
8. 
Anderson, K.D., Targeting Recovery: Priorities of the Spinal Cord-Injured Population. Journal of 
Neurotrauma, 2004. 21(10): p. 1371-1383. 
9. 
Organization, T.W.H.; Available from: http://www.who.int/mediacentre/factsheets/fs384/en/. 
10. 
Duran, F.S., et al., Effects of an Exercise Program on the Rehabilitation of Patients With Spinal Cord 
Injury. Arch Phys Med Rehabil, 2001. 82: p. 1349-1354. 
11. 
Taylor, A.W., E. McDonell, and L. Brassard, The effects of an arm ergometer training programme on 
wheelchair subjects. Paraplegia, 1986. 24(2): p. 105-14. 
12. 
Seeger, B.R., et al., Functional Electrical Stimulation for Upper Limb Strengthening in Traumatic 
Quadriplegia. Arch Phys Med Rehabil, 1989. 70: p. 663-667. 
13. 
Kohlmeyer, K.M., et al., Electrical Stimulation and Biofeedback Effect on Recovery of Tenodesis Grasp: 
A Controlled Study. Arch Phys Med Rehabil, 1996. 77: p. 702-706. 
14. 
McLean, K.P. and J.S. Skinner, Effect of Body Training Position on Outcomes of an Aerobic Training 
Study on Individuals With Quadriplegia. Arch Phys Med Rehabil, 1995. 76: p. 139-150. 
15. 
Vanden Berghe, A., et al., Reconstruction of the upper extremity in tetraplegia: functional assessment, 
surgical procedures and rehabilitation. Paraplegia, 1991. 29(2): p. 103-12. 
16. 
Hicks, A.L., et al., Long-term exercise training in persons with spinal cord injury: effects on strength, arm 
ergometry performance and psychological well-being. Spinal Cord, 2003. 41(1): p. 34-43. 
17. 
Kloosterman, M.G., G.J. Snoek, and M.J. Jannink, Systematic review of the effects of exercise therapy on 
the upper extremity of patients with spinal-cord injury. Spinal Cord, 2009. 47(3): p. 196-203. 
18. 
Raineteau, O. and M.E. Schwab, Plasticity of motor systems after incomplete spinal cord injury. Nat Rev 
Neurosci, 2001. 2(4): p. 263-73. 
19. 
Saturno, E., et al., Motor cortex changes in spinal cord injury: a TMS study. Neurol Res, 2008. 30(10): p. 
1084-5. 
20. 
Brouwer, B. and D.H. Hopkins-Rosseel, Motor cortical mapping of proximal upper extremity muscles 
following spinal cord injury. Spinal Cord, 1997. 35(4): p. 205-12. 
21. 
Streletz, L.J., et al., Transcranial magnetic stimulation: cortical motor maps in acute spinal cord injury. 
Brain Topogr, 1995. 7(3): p. 245-50. 
22. 
Tandon, S., et al., Complete reorganization of the motor cortex of adult rats following long-term spinal 
cord injuries. Eur J Neurosci, 2013. 38(2): p. 2271-9. 
23. 
Raineteau, O. and M.E. Schwab, Plasticity of Motor Systems after Incomplete Spinal Cord Injury. Nature 
Reviews Neuroscience, 2001. 2: p. 263-276. 
24. 
McKinley, W., et al., Incidence and outcomes of spinal cord injury clinical syndromes. J Spinal Cord 
Med, 2007. 30(3): p. 215-24. 
25. 
Darian-Smith, C., Synaptic plasticity, neurogenesis, and functional recovery after spinal cord injury. 
Neuroscientist, 2009. 15(2): p. 149-65. 
26. 
Streletz, L.J., et al., Transcranial Magnetic Stimulation: Cortical Motor Maps in Acute Spinal Cord Injury. 
Brain Topography, 1995. 7(3): p. 245-250. 
27. 
Freund, P., et al., Corticomotor representation to a human forearm muscle changes following cervical 
spinal cord injury. Eur J Neurosci, 2011. 34(11): p. 1839-46. 
28. 
Thomas, S.L. and M.A. Gorassini, Increases in corticospinal tract function by treadmill training after 
incomplete spinal cord injury. J Neurophysiol, 2005. 94(4): p. 2844-55. 
29. 
Saturno, E., et al., Motor cortex changes in spinal cord injury: a TMS study. Neurological Research, 2008: 
p. 1-2. 
30. 
Topka, H., et al., Reorganization of corticospinal pathways following spinal cord injury. Neurology, 1991. 
41(1276-1283). 

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 33 of 35 
 
31. 
Mikulis, D.J., et al., Adaptation in the motor cortex following cervical spinal cord injury. Neurology, 
2002. 58(5): p. 794-801. 
32. 
Qi, H.X., et al., Functional organization of motor cortex of adult macaque monkeys is altered by sensory 
loss in infancy. Proc Natl Acad Sci U S A, 2010. 107(7): p. 3192-7. 
33. 
Jiang, Y.Q., P.T. Williams, and J.H. Martin, Rapid and persistent impairments of the forelimb motor 
representations following cervical deafferentation in rats. Eur J Neurosci, 2013. 38(12): p. 3702-11. 
34. 
Martinez, M., et al., Differential tactile and motor recovery and cortical map alteration after C4-C5 spinal 
hemisection. Exp Neurol, 2010. 221(1): p. 186-97. 
35. 
McKay, W.B., et al., Neurophysiological examination of the corticospinal system and voluntary motor 
control in motor-incomplete human spinal cord injury. Exp Brain Res, 2005. 163(3): p. 379-87. 
36. 
Lewko, J.P., I.M. Tarkka, and M.R. Dimitrijevic, Neurophysiological assessment of the motor and sensory 
spinal pathways in chronic spinal cord injury. Restor Neurol Neurosci, 1995. 7(4): p. 225-34. 
37. 
Nakanishi, K., et al., Corticospinal tract conduction block results in the prolongation of central motor 
conduction time in compressive cervical myelopathy. Clin Neurophysiol, 2006. 117(3): p. 623-7. 
38. 
Davey, N.J., et al., Comparison of input-output patterns in the corticospinal system of normal subjects 
and incomplete spinal cord injured patients. Exp Brain Res, 1999. 127(4): p. 382-90. 
39. 
Simpson, R.K. and D.S. Baskin, Corticomotor evoked potentials in acute and chronic blunt spinal cord 
injury in the rat: correlation with neurological outcome and histological damage. Neurosurgery, 1987. 
20(1): p. 131-7. 
40. 
Song, W., et al., Transspinal direct current stimulation immediately modifies motor cortex sensorimotor 
maps. J Neurophysiol, 2015. 113(7): p. 2801-11. 
41. 
Peterson, C.L., et al., Posture-dependent changes in corticomotor excitability of the biceps after spinal 
cord injury and tendon transfer. Conf Proc IEEE Eng Med Biol Soc, 2014. 2014: p. 4302-5. 
42. 
Hoffman, L. and E. Field-Fote, Effects of practice combined with somatosensory or motor stimulation on 
hand function in persons with spinal cord injury. Top Spinal Cord Inj Rehabil, 2013. 19(4): p. 288-99. 
43. 
Martinez, M., et al., Sensorimotor training promotes functional recovery and somatosensory cortical map 
reactivation following cervical spinal cord injury. Eur J Neurosci, 2009. 30(12): p. 2356-67. 
44. 
Galea, M.P. and I. Darian-Smith, Manual Dexterity and Corticospinal Connectivity Following Unilateral 
Section of the Cervical Spinal Cord in the Macaque Monkey. The Journal of Comparative Neruology, 
1997. 381: p. 307-319. 
45. 
Fregni, F. and A. Pascual-Leone, Technology insight: noninvasive brain stimulation in neurology-
perspectives on the therapeutic potential of rTMS and tDCS. Nat Clin Pract Neurol, 2007. 3(7): p. 383-
93. 
46. 
Carey, J.R., et al., Comparison of finger tracking versus simple movement training via telerehabilitation 
to alter hand function and cortical reorganization after stroke. Neurorehabil Neural Repair, 2007. 21(3): 
p. 216-32. 
47. 
Carey, J.R., E. Plow [nee (Bhatt)], and A. Nagpal, Neuroplasticity promoted by task complexity. Exerc 
Sport Sci Rev, 2005. 33(1): p. 24-31. 
48. 
Cunningham, D.A., et al., Tailoring brain stimulation to the nature of rehabilitative therapies in stroke- 
a conceptual framework based on their unique mechanisms of recovery. Physical Medicine and 
Rehabilitation Clinics of North America, 2015. In Press. 
49. 
Cunningham, D.A., et al., Stimulation targeting higher motor areas in stroke rehabilitation: A proof-of-
concept, randomized, double-blinded placebo-controlled study of effectiveness and underlying 
mechanisms. Restorative Neurology and Neuroscience, 2015. In press. 

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 34 of 35 
 
50. 
Halko, M.A., et al., Neuroplastic changes following rehabilitative training correlate with regional 
electrical field induced with tDCS. Neuroimage, 2011. 57(3): p. 885-91. 
51. 
Plow [nee (Bhatt)] , E., et al., Effect of finger tracking combined with electrical stimulation on brain 
reorganization and hand function in subjects with stroke. Exp Brain Res, 2007. 182(4): p. 435-47. 
52. 
Plow, E.B., et al., Invasive cortical stimulation to promote recovery of function after stroke. Stroke, 2009. 
40(5): p. 1926-31. 
53. 
Plow, E.B., et al., Effectiveness and neural mechanisms associated with tDCS delivered to premotor cortex 
in stroke rehabilitation: study protocol for a randomized controlled trial. Trials, 2013. 14: p. 331. 
54. 
Plow, E.B., et al., Rethinking stimulation of the brain in stroke rehabilitation: why higher motor areas 
might be better alternatives for patients with greater impairments. Neuroscientist, 2015. 21(3): p. 225-40. 
55. 
Plow, E.B. and A. Machado, Invasive Neurostimulation in Stroke Rehabilitation. Neurotherapeutics, 2013. 
56. 
Plow, E.B., et al., Comparison of Visual Field Training for Hemianopia With Active Versus Sham 
Transcranial Direct Cortical Stimulation. Neurorehabil Neural Repair, 2012. 
57. 
Plow, E.B., et al., Combining visual rehabilitative training and noninvasive brain stimulation to enhance 
visual function in patients with hemianopia: a comparative case study. PM R, 2011. 3(9): p. 825-35. 
58. 
Plow, E.B., et al., Temporal Profile of Functional Visual Rehabilitative Outcomes Modulated by 
Transcranial Direct Current Stimulation. Neuromodulation, 2012. 
59. 
Plow, E.B. and M.G. Fehlings, Hypoxic locomotor rehabilitation for incomplete spinal cord injury: not 
an oxymoron. Neurology, 2014. 82(2): p. 98-9. 
60. 
Potter-Baker, K.A., et al., Reliability of TMS metrics in patients with chronic incomplete spinal cord 
injury. Spinal Cord, 2016. 
61. 
Potter-Baker, K.A., et al., Transcranial direct current stimulation (tDCS) Paired with massed practice 
training to promote adaptive plasticity and motor recovery in chronic incomplete tetraplegia: a pilot 
study. J Spinal Cord Med, 2017: p. 1-15. 
62. 
Potter-Baker, K.A., Y.L. Lin, and E.B. Plow, Understanding cortical topographical changes in liminally 
contractable muscles in SCI: importance of all mechanisms of neural dysfunction. Spinal Cord, 2017. 
55(9): p. 882-884. 
63. 
Mahony, K., et al., Inter-tester reliability and precision of manual muscle testing and hand-held 
dynamometry in lower limb muscles of children with spina bifida. Phys Occup Ther Pediatr, 2009. 29(1): 
p. 44-59. 
64. 
Cuthbert, S.C. and G.J. Goodheart, Jr., On the reliability and validity of manual muscle testing: a literature 
review. Chiropr Osteopat, 2007. 15: p. 4. 
65. 
Potter-Baker, K.A., Y.L. Lin, and E.B. Plow, Understanding cortical topographical changes in liminally 
contractable muscles in SCI: importance of all mechanisms of neural dysfunction. Spinal Cord, 2017. 
66. 
Beekhuizen, K.S. and E.C. Field-Fote, Massed practice versus massed practice with stimulation: effects 
on upper extremity function and cortical plasticity in individuals with incomplete cervical spinal cord 
injury. Neurorehabil Neural Repair, 2005. 19(1): p. 33-45. 
67. 
Harvey, L.A., et al., The effectiveness of physical interventions for people with spinal cord injuries: a 
systematic review. Spinal Cord, 2009. 47(3): p. 184-95. 
68. 
Popovic, M.R., et al., Functional electrical therapy: retraining grasping in spinal cord injury. Spinal 
Cord, 2006. 44(3): p. 143-51. 
69. 
Cortes, M., et al., Improved grasp function with transcranial direct current stimulation in chronic spinal 
cord injury. NeuroRehabilitation, 2017. 41(1): p. 51-59. 
70. 
Murray, L.M., et al., Intensity dependent effects of transcranial direct current stimulation on corticospinal 
excitability in chronic spinal cord injury. Arch Phys Med Rehabil, 2015. 96(4 Suppl): p. S114-21. 

Title: Improving Spinal Cord Injury Rehabilitation Interventions by Retraining the Brain 
PI: Ela B Plow 
Sub-site PI’s: Gail Forrest, Svetlana Pundik, Kevin Kilgore, Anne Bryden, David Cunningham 
Protocol V 5.1 —2/3/2023 
 
Page 35 of 35 
 
71. 
Estes, S.P., J.A. Iddings, and E.C. Field-Fote, Priming Neural Circuits to Modulate Spinal Reflex 
Excitability. Front Neurol, 2017. 8: p. 17. 
72. 
Gomes-Osman, J. and E.C. Field-Fote, Cortical vs. afferent stimulation as an adjunct to functional task 
practice training: a randomized, comparative pilot study in people with cervical spinal cord injury. Clin 
Rehabil, 2015. 29(8): p. 771-82. 
73. 
Yozbatiran, N., et al., Transcranial direct current stimulation (tDCS) of the primary motor cortex and 
robot-assisted arm training in chronic incomplete cervical spinal cord injury: A proof of concept sham-
randomized clinical study. NeuroRehabilitation, 2016. 39(3): p. 401-11. 
74. 
Yozbatiran, N., et al., White matter changes in corticospinal tract associated with improvement in arm 
and hand functions in incomplete cervical spinal cord injury: pilot case series. Spinal Cord Ser Cases, 
2017. 3: p. 17028. 
75. 
Nitsche, M.A., et al., Safety criteria for transcranial direct current stimulation (tDCS) in humans. Clinical 
Neurophysiology, 2003. 114(11): p. 2220-2222. 
76. 
Plow, E.B., et al., Effectiveness and neural mechanisms associated with tDCS delivered to premotor cortex 
in stroke rehabilitation: study protocol for a randomized controlled trial. Trials, 2013. 14: p. 331. 
77. 
Steeves, J.D., et al., Extent of spontaneous motor recovery after traumatic cervical sensorimotor complete 
spinal cord injury. Spinal Cord, 2011. 49(2): p. 257-65. 
78. 
Rossi, S., et al., Safety, ethical considerations, and application guidelines for the use of transcranial 
magnetic stimulation in clinical practice and research. Clin Neurophysiol, 2009. 120(12): p. 2008-39. 
79. 
Wolf, S.L., et al., Effect of constraint-induced movement therapy on upper extremity function 3 to 9 months 
after stroke: the EXCITE randomized clinical trial. JAMA, 2006. 296(17): p. 2095-104.