Enhancement of Hand Motor Function After Cervical Spinal Cord Injury
Phase: NA
Conditions: Spinal Cord Injury
Sponsor: VA Office of Research and Development

Internal Reference Number: 6961.01 
Date: 03/01/19 
 
1 
Study Title: Enhancement of motor function after spinal cord injury.  
Principal Investigator:  Monica Perez P.T., Ph.D. 
Co- Investigator: Dr. Alberto Martinez- Arizala, M.D. 
Brief Description  
Motor function is largely disrupted in veterans with spinal cord injury (SCI). This has tremendous impact 
in daily-life activities. This study will examine physiological changes in pathways controlling motor 
function after SCI and novel methods to enhance the recovery of upper and lower extremity motor 
function by combining non-invasive repetitive brain stimulation with motor training. The repetitive brain 
stimulation will occur using a wire coil placed over the participants' head. When activated, this coil will 
generate a magnetic pulse over a specified area of the head. During training, we will monitor muscle 
activity through the use of surface electrodes. Subjects will perform precision grip and wrist movements. 
Impairment in hand function is a major problem after stroke, amyotrophic lateral sclerosis, multiple 
sclerosis, and other motor disorders, therefore, our work may also be relevant for individuals with other 
lesions of the nervous system.  
Objectives: The goals of this study are to examine the physiology of Central Nervous System pathways 
contributing to the control of upper and lower extremity movements after SCI, and to promote the 
recovery of extremity movements by using non-invasive brain stimulation and motor training. 
A. Specific Aims and Hypothesis: 
Aim 1. Neural Control of Movements in SCI and Control Subjects 
 Investigate physiological mechanisms contributing to the control of hand movements. 
Aim 2. Enhance recovery of motor function by using non-invasive repetitive transcranial magnetic 
stimulation (rTMS) 
To accomplish this aim we propose to complete two main experiments. First we will use rTMS to test the 
hypothesis that rTMS induced cortical plasticity during movement will enhance voluntary output in hand 
muscles (as measures by electromyography and Jebsen Taylor Test) after spinal cord injury (Aim 2a). 
Second, we will combine precision grip and wrist training with rTMS to test the hypothesis that precision 
grip training outcomes will be enhanced by rTMS induced cortical plasticity (aim 2b). 
 
B. Background and Significance to the VA Mission 
 
Deficits in motor function are one of the most devastating functional impairments affecting individuals 
with SCI because of the tremendous impact in daily-life functions such as eating, grasping, writing, and 
many others (Snoek et al., 2004; Herrmann et al., 2010). This has important socio-economic implications 
that are a significant drive towards the development of treatments for the recovery of motor function. 
Although a number of studies have reported the beneficial effects of hand motor training after cervical 
SCI the overall improvements remain limited (for review see Spooren et al., 2009). Therefore, there is a 
need to develop novel mechanistic-driven therapeutic interventions to enhance hand motor function of 
individuals with chronic SCI. 
 

Internal Reference Number: 6961.01 
Date: 03/01/19 
 
2 
Neural Control of Movements in SCI and Control Subjects (Aim 1): Animal  studies have demonstrated 
that the motor cortex is involved in the control of hand actions including a precision grip and wrist 
movements through a selective activation of the corticospinal tract (Lemon, 2008). In agreement, human 
studies using functional magnetic resonance imaging have shown activity-dependent changes in BOLD 
signal activity in both motor cortices during a precision grip involving fingers and a wrist task (Ehrsson 
et al., 2000; Sehm et al., 2010). Studies using TMS have shown an increase in corticospinal drive 
targeting finger and wrist muscles during a similar motor task (Perez and Cohen, 2008, 2009a). The sizes 
of motor evoked potentials (MEPs) elicited by TMS in a finger muscle were larger during a precision 
compared to a power grip force (Schieppati et al., 1996; Tinazzi et al., 2003). It has been proposed that 
the increase in corticospinal excitability is, at least in part, related to a cortical mechanism since 
intracortical and interhemispheric inhibition were decreased and H-reflexes remained unchanged during 
this motor task (Schieppati et al., 1996; Tinazzi et al., 2003). Together, these data highlight the 
contribution of the motor cortex and corticospinal drive to the control of hand movements in humans. 
After cervical SCI, the number of corticospinal projections and voluntary drive to affected muscles is 
reduced. At rest, there have been multiple demonstrations of corticospinal reorganization after SCI (Levy 
et al., 1990; Bruehlmeier et al., 1998; Ellaway et al., 2007) but little is known about motor cortical and 
corticospinal reorganization during the remaining hand voluntary activity. This is a critical issue for 
elucidating the role of the corticospinal tract in motor recovery and rehabilitation strategies after SCI. 
 
Effects of rTMS on motor function and corticospinal plasticity (Aim 2a): Previous evidence has 
demonstrated that neurorehabilitation programs can improve motor outcomes by enhancing 
reorganization in the corticospinal pathway (Nudo, 2003). 
 
Impact of combining rTMS with motor training (Aim 2b): Motor training strategies used in individuals 
with cervical SCI often focus on increasing volitional arm muscle activation through strength training, 
electrical stimulation, and general exercises (see Spooren et al., 2009). While these studies reported that 
motor training enhances hand motor function, behavioral improvements remain limited. Over the last 
decades, high frequency rTMS applied over the motor cortex has been shown to induce changes in motor 
cortical excitability (see section above). Since the mechanisms underlying these effects are related to 
CNS plasticity, rTMS has been combined with motor training as a tool for enhancing motor function in 
individuals with movement disorders. 
Impairment in motor function is a major deficit in veterans with spinal cord injury (SCI). While 
rehabilitative interventions have shown success in improving aspects of hand motor function their 
overall effects remain limited. The goals of this study are to examine the physiology of nervous system 
pathways contributing to the control of movements after cervical SCI, and to promote the recovery of 
upper and lower extremity movements by using non-invasive brain stimulation and motor training. We 
focus on both hand and arm function, which are necessary for most of our daily-life activities, as well as 
lower extremity movement; therefore, our results may directly impact the quality of life for veterans and 
their caregivers by enhancing their independence and level of care. 
C. Study Design 
This study will focus on two basic aspects involved in upper and lower extremity motor function, and 
how these are affected after chronic SCI using a randomized sham control design with single blind. 
 
 

Internal Reference Number: 6961.01 
Date: 03/01/19 
 
3 
Methodology: 
This study will consist of electromyography (surface and intramuscular), peripheral nerve stimulation, 
and transcranial magnetic stimulation, electrical stimulation, of the hand, arm, leg, and foot representation 
of the primary motor cortex, as well as MRI scans of the brain. We will examine the physiological 
measurements of upper and lower extremity muscles (such as in the first dorsal interosseous (FDI), biceps 
brachii (BIC), anterior deltoid (AD), tibialis anterior (TA), hamstring (HAMS) and quadriceps (QUAD)). 
This study may occur at the Miami Project to cure Paralysis at the University of Miami. We will include 
subjects between the ages of 18 and 85, both healthy controls and individuals with chronic spinal cord 
injuries that occurred at least 6 months prior to recruitment. Both healthy controls and those with spinal 
cord injuries will be able to perform small hand and arm movements and small leg and foot movements. 
The primary outcome measures of this study are muscle responses to stimulation with magnetic pulses 
using TMS and electrical stimulation of a peripheral nerve in the arm or leg. We propose to enhance the 
recovery of motor function by using new protocols of high frequency non-invasive repetitive TMS 
(rTMS) and motor training. Repetitive TMS will be used during hand, arm, leg and foot movements in a 
task-dependent manner to induce cortical plasticity and enhance voluntary output of the muscles 
associated with those movements. Second, rTMS will be applied in a task-dependent manner during a 
visuo-motor training task that also involves movements of the hands, arms, legs or feet. 
Phase 1 
Aim 1. Neural Control of Movements in SCI and Control Subjects  
We will use TMS, CMEPS, and peripheral nerve stimulation to test the hypotheses that ‘precision grip 
and wrist movements will be associated with reduced motor cortical (as measured by intracortical 
inhibition) and spinal inputs (as measured by F-wave persistence and amplitude) to hand and wrist 
motoneurons after cervical SCI compared to controls’. Subjects will be instructed to perform a precision 
grip (between index and thumb) and simultaneously wrist flexion or extension movements. Measurements 
of cortical and motoneuronal excitability will be acquired during movement. 
Each testing session will be separated by at least two days. Subjects will be instructed to perform a 
precision grip (between index and thumb) and simultaneously wrist flexion or extension movements. 
Measurements of cortical and motoneuronal excitability will be acquired during movement. Tasks 
involving lower-limb movement will also be tested as control tasks. In each session, we will use the 
following experimental setup and motor tasks: 
 
Experimental setup – During testing, individuals will be seated in an armchair with both elbows flexed at 
90°. Each arm will be supported by a custom device attached to a potentiometer to measure wrist flexion 
and extension angles and a load cell to measure grip forces. Index fingers and thumbs will be positioned 
in a customized gripping tube attached to a two-axis load cell. Subjects who cannot be transferred will be 
tested in their wheelchair by using customized platforms that we previously used in individuals with SCI. 
Surface electrodes will be positioned bilaterally on the skin overlying upper and lower-limb muscles in a 
bipolar montage (inter-electrode distance approximately 2 cm). The amplified EMG signals will be 
filtered, sampled, and stored for analysis. Forces will be measured by load cells and angles by 
potentiometers and stored for analysis. 
 
Motor task – In a first test, subjects will be instructed to perform full wrist flexion and simultaneously 
perform a precision grip (between index and thumb) with one hand. In a second test, subjects will be 
instructed to perform full wrist extension and a precision grip with one hand. At the start of testing, 

Internal Reference Number: 6961.01 
Date: 03/01/19 
 
4 
individuals will perform 3 brief precision grip maximum voluntary contractions (MVCs) (3–5 s) and wrist 
flexion and extension MVC with 30 seconds of rest. Custom software will be used to acquire signals from 
potentiometers and load cells to display visual feedback corresponding to wrist flexion and extension 
angles and 10% of MVC grip force. Subjects will be instructed to move a cursor at a comfortable speed 
and to hold the cursor in the target force and position for 2-4 seconds. During lower-limb tasks subjects 
will be instructed to move as cursor by performing ankle dorsiflexion and plantar flexion movements. 
Approximately thirty repetitions of each task will be randomly tested. 
 
During these motor tasks we will examine: (A) TMS measurements and (B) motoneuronal excitability in 
the first dorsal interosseous, and flexor and extensor carpis radialis muscles. TMS and peripheral nerve 
stimulation pulses will be delivered when subjects reach a certain degree of wrist flexion or extension and 
a certain percentage of MVC in the precision grip. Stimulation will be triggered if both goals are reached. 
This window in both directions will be modified for individuals who showed more difficulties in 
performing the movement in either direction. 
 
 (A) TMS measurements- Transcranial magnetic stimuli will be delivered from a stimulator through a 
figure-eight coil. TMS will be delivered to the optimal scalp position for activation of the left or right first 
dorsal interosseous, and flexor and extensor carpis radialis muscles. The TMS coil will be held to the 
head of the subject with a custom coil holder while the head is firmly secured to a headrest by straps to 
limit head movements. TMS measurements during precision grip and wrist movements will include the 
following: 
 
MEPs – Resting and active motor thresholds (RMT and AMT) will be tested in each of the muscles. For 
this testing, TMS intensity will be adjusted to produce an MEP of 50% of the maximal MEP on each 
muscle tested. 30 MEPs will be average in each condition. Cervicomedullary Motor Evoked Potentials 
(CMEPs): Supramaximal electrical stimulation will be administered posterior to the mastoid process to 
ellicit motor evoked potentials to upper and lower limb muscles. 
 
Short-interval intracortical inhibition (SICI) – A conditioning stimulus (CS) will be set at an intensity of 
70% of AMT. The test stimulus (TS) will be adjusted to produce an MEP of 50% of MEP-max. Test 
stimuli will be delivered 2.5 ms after CS. 25 TS and CS will be averaged in each condition. 
 
Interhemispheric inhibition (IHI) – A supra-threshold CS will be set at an intensity above the RMT and 
given 10-50 ms before a TS delivered to the contralateral motor cortex. The coils will be positioned at the 
optimal location for activating the muscle tested and attached to coil holders. 
 
(B). Motoneuronal excitability (reflected by F-wave persistence and amplitude): F-waves will  
be tested by using supra-maximum stimulus intensity (120% of the maximal motor response)to the ulnar 
nerve at the wrist and the median nerve at the elbow. The anode and cathode will be approximately 3 cm 
apart and 1 cm in diameter. We will examine F-waves in first dorsal interosseous, flexor and extensor 
carpis radialis muscles. 
 
 
Phase 2 
Aim 2a. Enhance recovery of motor function by using non-invasive repetitive transcranial magnetic 
stimulation (rTMS) 

Internal Reference Number: 6961.01 
Date: 03/01/19 
 
5 
To accomplish this aim we propose to complete two main experiments. First we will use rTMS to test the 
hypothesis that rTMS induced cortical plasticity during movement will enhance voluntary output in hand 
muscles (as measures by electromyography and Jebsen Taylor Test) after spinal cord injury (Aim 2a). 
Second, we will combine precision grip and wrist training with rTMS to test the hypothesis that precision 
grip training outcomes will be enhanced by rTMS induced cortical plasticity (aim 2b). 
 
Experiment 1 (Aim 2a)  
Participants will be randomly assigned to three groups: (1) rTMS, (2) Sham rTMS and (3) sham rTMS 
over control brain area. Randomization will be performed by lottery (i.e. Drawing from an envelope a 
piece of paper indicating the intervention). In the first two groups, rTMS stimulation will be targeting 
finger and wrist muscles during precision grip and write voluntary contractions. In the last group, rTMS 
will be applies over the dorsolateral prefrontal cortex (DLPFC) or at the leg presentation of the primary 
motor cortex, or at other related control area as needed. Each subject will be asked to participate in all 
sessions separated by a washout period of approximately one week. During testing, subjects will be seated 
in an armchair with both arms flexed at the elbow by 90 degrees. In each group we will used the same 
apparatus described in Aim1. At the start of the experiment subjects will perform 3 brief MVCs (3-5s) 
into index finer abduction and writs flexion and extension, separated by 30 seconds. The maximal forces 
will be sued to set targets for subsequent submaximal contractions. 
rTMS protocol- rTMS will be applied by a magnetic stimulator through a figure of eight coil with the 
same coil position as in Aim1. rTMS will consist of a total of 1200 pulses at an intensity of 80% of the 
AMT applied during a precision grip. At each time three targets will be presented on a computer screen. 
Each target will indicate a GO signal to compete a precision grip. During each precision grip 5 pulses at 
5Hz will be applies. In total, 8 blocks of 10 trains of 15 pulses at 5Hz separated by inter train interval of 
10s will be applied (1200 pulses). Each block will be separated by 30s of rest. The periods of stimulation 
will last approximately 24 minutes.  
Measurements before and after rTMS protocol- We will examine: (a) MEPs, SICI, and F-waves (see 
procedures in AIM1), and (b) EMG and force output. Before rTMS, to examine EMG and force output 
individuals will receive visual feedback on a computer screen corresponding to 10% of MVC during a 
precision grip. The target will be presented for 1 second and then it will disappear at intervals of 5-6 
seconds. Subjects will be instructed to reach the target as accurately as possible without making any 
corrections. Three sets of 20 repetitions will be tested. Signals will be acquired and the mean of force 
displacement plus 1 standard deviation (SD) will be calculated. After rTMS, subjects will not be told 
whether the visual feedback is derived from their actual or from their previous performance. Then, the 
visual feedback presented in the computer screen will correspond to mean forces +1SD values exerted 
prior rTMS. 
The Jebsen Taylor Hand Function Test 
The JHFT was developed to provide a standardized and objective evaluation of several major 
aspects of hand function using simulated activities of daily living.  
(Jebsen et al. 1969) 
The Jebsen Taylor Hand Function Test is a standardized test with high intra-tester (r = 0.85; p > 0.05) and 
inter-tester reliability (intraclass correlation coefficient ranging from 0.82 to 1.00). It is designed for 
adults with neurological or musculo-skeletal conditions involving hand disabilities. The test items include 
a range of fine motor, weighted and non-weighted hand function activities: (i) writing (copying) a 

Internal Reference Number: 6961.01 
Date: 03/01/19 
 
6 
sentence, (ii) turning over 3 × 5 cards, (iii) picking up small common objects such as a paper clip, bottle 
cap and coin, (iv) simulated feeding using a teaspoon and 5 kidney beans, (v) stacking checkers, (vi) 
picking up large light objects (empty tin cans), and (vii) picking up large heavy objects (0.5 kg tin cans). 
The time to complete each task was recorded in seconds. The affected hand was tested first. Subjects were 
allowed a maximum of 180 s to complete each sub-test. If the subject could not complete the task within 
the time allowed, 180 s was taken as the completion time to avoid fatigue (109). 
ASIA examination  
 ASIA 2002; Marino et al., 2003 
•Pin prick with a safety pin and light touch with a cotton ball are tested. For pinprick the result is graded 
as 2- normal; 1- impaired where difference between sharp and dull is appreciated but less; 0- difference 
could not be appreciated between sharp and dull. For light touch 2- reports when touched and feels the 
same as face 1- reports touched but less than in face 0-does not reliably report being touched  
•The dermatomes tested are  C2 - occipital protruberance behind the ear C3 - supraclavicular fossa C4 - 
AC joint apex (C4 may extend down the chest almost to the nipple line) C5 - lateral antecubital fossa C6 - 
dorsal surface of proximal phalanx of thumb C7 - dorsal surface of proximal phalanx of middle finger C8 
- dorsal surface of proximal phalanx of little finger T1- medial antecubital fossa T2- axilla apex T4- 
nipple liine T6 - xiphisternum T10 - umbilicus T12 - inguinal ligament midline L1,23 - thigh L4- medial 
malleolus L5 - dorsum of foot at 3rd MTP joint S1- lateral heel S2- popliteal fossa S3- ischial tuberosity 
S4,5 - perianal region  
•Optional sensations that can be tested are joint movement (reported as absent, impaired - correct in 8/10 
of large joint movements only or normal-correct 8/10 of large and small movements both) , deep pressure 
sensation (reported as present or absent) 
Electrical Perceptual Threshold 
The EPT method uses incrementing electrical stimulation and the method of limits to determine sensory 
threshold. (Ellaway and Catley 2013; Macklin and Perez et al, 2015).   
Chedoke Arm and Hand Activity Inventory 
The purpose of this is to evaluate the functional ability of the hemiplegic arm and hand to perform tasks. 
The performance of the affected limb is scored using a 7 point activity scale ranging from  total assistance 
to complete independence.  
Lower Extremity Physiological Examination Components: 
Range of Motion (ROM): active ankle and hip ROM will be measured by a motion capture system (Opti 
Track, V120: Tri camera, NaturalPoint, Inc) in sitting and standing position. In sitting, subjects will be 
instructed to complete maximal voluntary dorsiflexion for 10 times separated for period of 10 sec of rest. 
In standing, subjects will be instructed to complete maximal voluntary hip flexion for 10 times separated 
for period of 10 sec of rest. Trunk movements will be avoided during testing. The motion capture system 
will also be utilized to measure foot drop and hip flexion. Markers will be positioned on the external line 
of the mid trunk, hip, knee, external malleolus, and the lateral side of the 5th metatarsophalangeal joint. 
The elevation of the toe above ground level will be taken as a measure of foot drop. The amplitude of toe 
elevation will be calculated from the distance between the marker placed on the 5th metatarsophalangeal 
joint and the ground (Barthélemy et al., 2010). The largest distance between these two points will be 
determined and will be referred to as the highest toe elevation. The presence or absence of the second toe 
elevation prior to heel strike will measured by subtracting the excursion of the malleolus marker from the 
elevation of the toe. Hip angle will be constructed by using the trunk, hip and knee markers. 
 

Internal Reference Number: 6961.01 
Date: 03/01/19 
 
7 
Pinch Grip Strength: 
Will be assessed bilaterally using load cells that will record the force generated by the subject.  Force will 
be applied by the thumb and index finger and will be recorded in Newtons (N). 
Modified Ashworth Scale and Pendulum Test: 
Will be used to measure spasticity level in subjects with SCI during soft tissue stretching. 
 (Modified Ashworth Scale; Bohannon and Smith, 1987) 
 
 
Phase 3 
Experiment 2 (Aim 2b) : 
Individuals with SCI and healthy controls will be randomly assigned to two groups:  (1) training + rTMS, 
and (2) training + sham rTMS. Randomization will be the same as describes above. Training will be 
complete in approximately 15 sessions over approximately 3 weeks. In each session, stimulation or sham 
stimulation (approximately 25 minutes) will be applied during precision grip and wrist visuo-motor 
training (approximately 1 hour). 
Training + rTMS group- Training will consist of executing three different grip forces with one hand and 
simultaneously wrist flexion and extension movements while the contralateral hand is at rest.  
Subjects will be instructed to follow a target line on a computer screen as accurately as possible while 
performing precision grips with simultaneously maximal wrist flexion and extension. Stimulation will be 
triggered if both movements are performed. See Experiment 1 for rTMS parameters. At each time three 
targets will be presented separated by approximately 2 seconds of reset on the screen for a total duration 
of 10 seconds. The period of stimulation will last approximately 24 minutes. Subjects will be randomly 
assigned to two groups: training + rTMS, and training + sham rTMS. A train of rTMS will be applied 
during each of the target presentations. The coil will be positioned over the optimal scalp position for 
activating finger and wrist muscles. Here, 5 pulses at 5 hz will be applied each time that a target appears 
on the computer screen. In a control task individuals will be asked to perform to follow the same  cursor 
using their lower limb muscles. A total of 1200 rTMS pulses will be applied at80% of AMT intensity (see 
more details about rTMS application in AIM 2a). 
Training+sham rTMS group- Training will be conducted as described above. For sham rTMS, TMS coil 
will be positioned in the same location as described above. A second coil will be placed behind the 
subjects head, and it will discharge in the air using the same stimulation parameters that will be used in 
the TMS application. During sham stimulation only the coil located behind the subjects head will be 
triggered. Participants may feel small pressure from the coil positioned on top of their head and hear the 
click sound during triggering.  
Measurements before and after rTMS protocols: 
Physiology- We will examine: (a) MEPs, SICI, IHI, and F-wave (See procedures in Aim 1). Precision 
grip motor performance: We will quantify the following outcomes: (a) Force onset [the time point at 
which force increases 2SD above force baseline], (b) Force rate (maximum derivative of force (force/s) 
between force onset and target force), (c) Force area (area between force onset and force decay to zero), 
and (d) Total force duration  (time between force onset and force decay to zero). 

Internal Reference Number: 6961.01 
Date: 03/01/19 
 
8 
Motor function- We will use range of motion (ROM), JTT, Pinch force, Chedoke arm and Hand 
inventory, and sensory function of the upper and lower extremities using the American Spinal Injury 
Association (ASIA) sensory scores and Electrical Perceptual Threshold (EPT). These functional and 
sensory tests are described in in detail in Aim 2a. 
Plan for multiple rTMS sessions using Brainsight for MRI co-registration: to ensure that the same area of 
the motor cortex is stimulated during multiple rTMS sessions we will use the Brainsight co-registration 
system. We will use an MRI scanner located at the University of Miami Applebaum MRI center or at the 
Miami VA Medical center. Individuals will be asked to participate in the scan session at their 
convenience as soon as they are enrolled in Aim 1 of this proposal. Individuals who only participate in 
Aim 2 of the study will be asked to have the MRI session after they have signed the consent form. 
Plan for assessment of long-term effects of rTMS: Physiological and behavioral measurements will be 
acquired before and after sessions 1,5,and 10. 
Phase 3- Follow up  
Follow up measurements will be taken after 1, 2, and 3 months after Phase 3 testing to measure any 
sustained improvements in hand function. This assessment will be competed in a single session. These 
assessments will be the same as in Phase 1-3 of this research study. Each session will last about 1 hour. 
Physiological measurements- We will examine MEPs, SICI, IHI, and F-waves (see procedures in Aim1). 
Precision Grip motor performance: we will examine Force onset, rate, area and total force duration (see 
procedures in Aim 2a.) Hand motor function: we will examine JTT, Pinch force, Chedoke Arm and Hand 
inventory, and sensory function of the hand using the American Spinal Injury Association (ASIA) sensory 
scores (see procedures in Aim 2a).  
Assessment of quality of life and functional independence after SCI- the following measurements will be 
conducted before and after training sessions in Aim 2B, and at the follow up visits 1,2, and 3 months after 
training.  
(a) Self-care subscale of the spinal cord independence measure- Version III (SCIM; itzkovich et al., 2007) 
(b) The Capabilities of upper Extremities (CUE; Marino et al., 1998) 
Demographics will be collected in all subjects. This will include variable such as age, gender, race, 
height, weight, and veteran status. For individuals with SCI, we will also collect level of injury and date 
of injury.   
Target population: 
Male and female veterans with spinal cord injury at least 1 year after injury was sustained.  We also plan 
to enroll control subjects who do not have any history of spinal cord injury. 
Inclusion/Exclusion Criteria : 
Participants who are unimpaired healthy controls: 
(1) Male and females between ages 18-85 years  
(2) Right handed  
(3) Able to complete precision grips with both hands  

Internal Reference Number: 6961.01 
Date: 03/01/19 
 
9 
(4) Able to complete full wrist flexion-extension bilaterally 
(5) Able to walk unassisted 
(6) Able to complete full ankle flexion-extension bilaterally 
 
Participants who have had a spinal cord injury: 
(1) Male and females between ages 18-85 years  
(2) Chronic SCI (≥ 6 months of injury) 
(3) Spinal Cord injury at or above L5  
(4) The ability to produce a visible precision grip force with one hand  
(5) Individuals who have the ability to pick up a small object (large paperclip) from a table independently 
(6) Able to perform some small wrist flexion and extension (measured by a goniometer) 
(7) The ability to perform a small visible contraction with dorsiflexor and hip flexor muscles 
(8) No subjects will be excluded based on their race, religion, ethnicity, gender or HIV status.   
Exclusion criteria for enrollment For SCI and Healthy Control Subjects (for stimulation): 
(1) Uncontrolled medical problems including pulmonary, cardiovascular or orthopedic disease 
(2) Any debilitating disease prior to the SCI that caused exercise intolerance 
(3) Premorbid, ongoing major depression or psychosis, altered cognitive status  
(4) History of head injury or stroke 
(5) Metal plate in skull 
(6) History of seizures 
(7) Receiving drugs acting primarily on the central nervous system, which lower the seizure threshold 
(see appendix 2) 
(8) Pregnant females 
(9) Ongoing cord compression or a syrinx in the spinal cord or who suffer from a spinal cord disease such 
as spinal stenosis, spina bifida, MS, or herniated cervical disk 
(10) Individuals with scalp shrapnel, cochlear implants, or aneurysm clips.  
Qualified subjects can participate in up to 190 visits for this study.  Visit range from 1-3 hours in length. 
Start date:  11/2015. 
Completion Date: 12/2019 
 
E. Risks  

Internal Reference Number: 6961.01 
Date: 03/01/19 
 
10
This is a minimal risk proposal. 
TMS procedures:  
The TMS system stimulates the brain non-invasively. It generates a small magnetic field across the 
subject. TMS is widely used in clinical research, and the risks of TMS are believed to be very low. 
However, there is the very slight chance that TMS can cause a seizure. There is no ionizing radiation 
exposure involved and the studies are non-invasive. All participants will be screened before enrollment to 
assure that they meet study criteria and that there are no contraindications to TMS. 
Subjects will be instructed that they can discontinue the TMS experiment at any time. In the unlikely 
event of a seizure, a medical physician will be contacted for immediate response. If a headache or mild 
scalp discomfort occurs, subjects will be directed to use over the counter pain medication at their own 
discretion. Earplugs will be utilized to minimize any type of hearing damage that might possibly occur 
due to the sound generated by the TMS equipment. Dr. Perez (PI) and/or an authorized team member will 
conduct TMS procedures as needed.  
Dr. Perez has been working with TMS procedures for the last 13 years and has extensive experience in 
the use of TMS procedures. Although very unlikely, it is theoretically possible that the participant may 
have a seizure induced by the TMS. Considering the large number of subjects and patients who have 
undergone TMS studies since 1998 and the small number of seizures, we can assert that the risk of TMS 
to induce seizures is certainly very low (see review by Rossi et al., 2009). However, we will inform the 
participant about this unlikely risk. If a seizure occurs, it will occur during the TMS application itself, not 
after. When a seizure happens the participant’s brain starts acting strangely and participants may feel 
dizzy and have repetitive rhythmic movements of any part of their body. If this unlikely event happens, 
we will immediately call an attending physician. On weekends, the subject should call the emergency 24 
hour pager 305-243-1000 to get in touch with Dr. Alberto Martinez-Arizala, and let him know that he is a 
research subject from the Miami VA in Enhancement of Motor Function after Spinal Cord Injury. 
In the unlikely event of a seizure, a standard seizure protocol will be followed: 
1. Cushion the head and area so subject does not injure themselves. 
2. Turn the subject on their side to prevent aspiration 
3. Monitor the duration of the seizure 
4. If the seizure ends in less than 60 seconds, monitor and contact the primary care MD to rule our 
predisposing factors. 
5. If the seizure lasts more than 60 seconds, activate emergency services. 
In the event that a seizure occurs on premises and we are unable to reach the physician, 911 will be 
called for emergency services.  
Risks of Muscle Activity Recording (EMG): Mild discomfort, such as an itching sensation may be felt 
under the electrodes that register the response in your muscles. There may be some pain or bleeding from 
the needles used for intramuscular recording. The possibility of this is infrequent (occurring in 1-10%, or 
1-10 out of 100 people).  We will clean the area with alcohol and use standard, hospital grade electrodes, 
and sterile needles.  
Peripheral Nerve Stimulation intensity will be increased gradually during the evaluations when necessary. 
Mild discomfort, such as an itching sensation may be felt under the electrode that stimulates your wrist or 
under the electrodes that register the response in your muscles.  The possibility of this is infrequent 
(occurring in 1-10%, or 1-10 out of 100 people). We will clean the area with alcohol and use standard, 

Internal Reference Number: 6961.01 
Date: 03/01/19 
 
11
hospital grade electrodes. Another risk of the nerve stimulation used in this research is that you might feel 
mild pain, if pain fibers could be activated.   
MRI scan: Subjects, investigators, and facility staff will be examined by a hand-held screening device for 
magnetic material before entry and each re-entry to the scan room. Warning signs, including the specific 
dangers of high magnetic fields, are posted in the necessary location. The standard 3 Tesla Magnet will be 
used for testing. The MRI exam involves no exposure to x-rays or radioactivity, and is safe. The FDA 
approved the Siemens 3-T scanner, which time varying magnetic fields (gradient), specific absorption rate 
and acoustic noise levels. FDA guidelines will be strictly enforced at our 3T scanner. 
JTT/CAHA/pinch grip/ASIA: individuals will have resting periods as needed, all procedures will be 
explained in detail and subjects will be informed that they can stop the experiment at any time 
Screening Interview: Identifiable information collected during either the screening interview will be 
destroyed if the potential subject does not qualify. If the subject does qualify and ultimately enrolls into 
this research, all information collected will become part of their research record. All security precautions 
that are reflected in this protocol will apply. 
Data Collection and Storage: Research records will be retained in accordance with the Veterans Health 
Administration (VHA) Records Control Schedule. The Federal Privacy Act protects the confidentiality of 
medical records. Electronically-stored medical information collected from study participants will be kept 
on a VA server. Electronic data recorded during experimental sessions will be kept on fully-secured 
computers (password protected) on a VA server. Unique subject identifiers (i.e., a code accessible only to 
the PI and AI) will be used to label all electronic data files.  
F. Sample Size 
Up to 500 participants (250 SCI, and 250 control subjects) will be recruited to participate in this 
study at the VAMHS and at the University of Miami. Based on our previous protocols testing 
spinal cord injured subjects and healthy control subjects, we have added a 25% attrition rate to 
the number of subjects we plan to enroll in the study.  
 All participants will be between 18 and 85 years of age. We plan to recruit both veterans and non-
veterans.  
G. Data analysis is consistent with the study objective 
Aim 1: Repeated-measures ANOVA and Tukey post hoc test will be used to assess the effect of TASK 
(rest, precision grip/wrist flexion, and precision grip/wrist extension) and GROUP (SCI, controls) on 
physiological measurements. 
Aim 2a: Repeated measures ANOVA and Tukey post hoc test will be used to determine the effect of 
TIME (0,10, 30, 60 min after a single rTMS session), STIMULATION (rTMS, sham rTMS over control 
brain area) on physiological and behavioral measurements. 
Aim 2b: repeated measures of ANOVA and Tukey post hoc analysis will be used to determine effects of 
GROUP (training + rTMS, training + sham rTMS), TIME (sessions number 1,5,10 and follow up 1,2,and 
3 months) on physiological outcomes and motor performance.  
H. Privacy and Confidentiality:   

Internal Reference Number: 6961.01 
Date: 03/01/19 
 
12
Every effort will be made to make sure that the information about you obtained from this study 
will be kept strictly confidential. Private information is collected about participants as part of 
this study. Screening forms are filled out by the study coordinator or other approved study team 
member by phone or in person. Please see all specific questions asked to participants listed in 
our “SCI Subject Screening Questions” and “HV Screening Questions” forms. Screening forms  
are used during the screening session to collect both identifiable information as well as non-
identifiable information. The research staff will take every precaution to protect all identity and 
the confidentiality of the information collected about each subject.  Any electronic or 
hard/paper copies of the information collected will be stored in a secured location. Any copies 
that contain information that could be used to identify participants (such as their name, address, 
date of birth, etc.), will be stored separately from any information that does not contain 
identifiers. Only those individuals who are authorized to review the information will have 
access to it.  Identifiable electronic information related to participants’ involvement will be 
stored on restricted access password protected servers. In order to protect their confidentiality, 
data that we record about subjects may be sent to the organizations listed above via a secure 
website, courier and or facsimile. The data that will be shared with the study sponsor will not 
include any names or any information that may directly identify participants. All data will be 
coded with the study number, which may include participants’ initials. 
Information may also be disclosed to the VA Miami Healthcare System Research and Development 
Office Staff in order to perform duties related to research administration. 
 
References: 
1.0  * Please provide a list of references (Multi-site protocols: You may reference the page numbers in the 
original protocol): 
Ackerley SJ, Stinear CM, Barber PA, Byblow WD. Combining theta burst stimulation with training after 
subcortical stroke. Stroke 41: 1568-1572, 2010. 
 
Barker AT, Jalinous R, Freeston IL. Non-invasive magnetic stimulation of human motor cortex. The 
Lancet 1: 1106-1107, 1985.  
 
Barreca S, Gowland C, Stratford P, et al. Development of the Chedoke Arm and Hand Activity Inventory: 
Theoretical constructs, item generation, and selection. Top Stroke Rehabil 11: 31-42, 2004.  
 
Barthélemy D, Willerslev-Olsen M, Lundell H, Conway BA, Knudsen H, Biering-Sørensen F, Nielsen 
JB. Impaired transmission in the corticospinal tract and gait disability in spinal cord injured persons. J 
Neurophysiol 104: 1167-1176, 2010. 
 
Belci M, Catley M, Husain M, Frankel HL, Davey NJ. Magnetic brain stimulation can improve clinical 
outcome in incomplete spinal cord injured patients. Spinal Cord 42: 417-419, 2004. 

Internal Reference Number: 6961.01 
Date: 03/01/19 
 
13
 
Benninger DH, Berman BD, Houdayer E, Pal N, Luckenbaugh DA, Schneider L, Miranda S, Hallett M. 
Intermittent theta-burst transcranial magnetic stimulation for treatment of Parkinson disease. Neurology 
76: 601-609, 2011. 
 
Beres-Jones JA, Johnson TD, Harkema SJ. Clonus after human spinal cord injury cannot be attributed 
solely to recurrent muscle-tendon stretch. Exp Brain Res 149: 222-236, 2003. 
 
Bridgers SL, Delaney RC. Transcranial magnetic stimulation: an assessment of cognitive and other 
cerebral effects. Neurology 39: 417-419, 1989.  
 
Bruehlmeier M, Dietz V, Leenders KL, Roelcke U, Missimer J, Curt A. How does the human brain deal 
with a spinal cord injury? Eur J Neurosci 10: 3918-3922, 1998. 
 
Bunday KL, Perez MA. Impaired Crossed Facilitation of the Corticospinal Pathway after Cervical Spinal 
Cord Injury. J Neurophysiol (In press): 2012. 
 
Butler JE, Thomas CK. Effects of sustained stimulation on the excitability of motoneurons innervating 
paralyzed and control muscles. J Appl Physiol 94: 567-575, 2003. 
 
Butler JE, Larsen TS, Gandevia SC, Petersen NT. The nature of corticospinal paths driving human 
motoneurones during voluntary contractions. J Physiol 584: 651-659, 2007.  
 
Cotelli M, Manenti R, Cappa SF, Geroldi C, Zanetti O, Rossini PM, Miniussi C (2006) Effect of 
transcranial magnetic stimulation on action naming in patients with Alzheimer disease. Arch Neurol 
63:1602–1604 
 
Daly JJ, Wolpaw JR. Brain-computer interfaces in neurological rehabilitation. Lancet Neurol 7: 1032-
1043, 2008. 
 
Davare M, Rothwell JC, Lemon RN. Causal connectivity between the human anterior intraparietal area 
and premotor cortex during grasp. Curr Biol 20: 176-181, 2010.  
 

Internal Reference Number: 6961.01 
Date: 03/01/19 
 
14
Davey NJ, Smith HC, Savic G, Maskill DW, Ellaway PH, Frankel HL. Comparison of input-output 
patterns in the corticospinal system of normal subjects and incomplete spinal cord injured patients. Exp 
Brain Res 127: 382-390, 1999. 
 
Defrin R, Grunhaus L, Zamir D, Zeilig G. The effect of a series of repetitive transcranial magnetic 
stimulations of the motor cortex on central pain after spinal cord injury. Arch Phys Med Rehabil 88: 
1574–1580, 2007. 
Di Lazzaro V, Oliviero A, Saturno E, Pilato F, Insola A, Mazzone P, Profice P, Tonali P, Rothwell JC. 
The effect on corticospinal volleys of reversing the direction of current induced in the motor cortex by 
transcranial magnetic stimulation. Exp Brain Res 138: 268-273, 2001. 
 
Donoghue JP, Nurmikko A, Black M, Hochberg LR. Assistive technology and robotic control using 
motor cortex ensemble-based neural interface systems in humans with tetraplegia. J Physiol 579: 603-
611, 2007. 
 
Dum RP, Strick PL. Frontal lobe inputs to the digit representations of the motor areas on the lateral 
surface of the hemisphere. J Neurosci 25: 1375-1386, 2005.  
 
Ellaway PH, Catley M, Davey NJ, Kuppuswamy A, Strutton P, Frankel HL, Jamous A, Savic G. Review 
of physiological motor outcome measures in spinal cord injury using transcranial magnetic stimulation 
and spinal reflexes. J Rehabil Res Dev 44: 69-76, 2007.  
 
Ehrsson HH, Fagergren A, Jonsson T, Westling G, Johansson RS, Forssberg H. Cortical activity in 
precision- versus power-grip tasks: an fMRI study. J Neurophysiol 83: 528-536, 2000. 
 
Epstein CM, Schwartzberg DG, Davey KR, Sudderth DB. Localizing the site of magnetic brain 
stimulation in humans. Neurology 40: 666-670, 1990.  
 
Ferbert A, Priori A, Rothwell JC, Day BL, Colebatch JG, Marsden CD. Interhemispheric inhibition of the 
human motor cortex. J Physiol 453: 525-546, 1992. 
 
Fleischmann A, Sternheim A, Etgen AM, Li C, Grisaru N, Belmaker RH. Transcranial magnetic 
stimulation downregulates beta-adrenoreceptors in rat cortex. J Neural Transm 103: 1361-1366, 1996.  
 
Fregni F, Boggio PS, Valle AC, Rocha RR, Duarte J, Ferreira MJ, Wagner T, Fecteau S,Rigonatti SP, 
Riberto M, Freedman SD, Pascual-Leone A. A sham-controlled trial of a 5-day course of repetitive 

Internal Reference Number: 6961.01 
Date: 03/01/19 
 
15
transcranial magnetic stimulation of the unaffected hemisphere in stroke patients. Stroke 37: 2115-2122, 
2006.  
 
Freitas C, Mondragón-Llorca H, Pascual-Leone A (2011) Noninvasive brain stimulation in Alzheimer’s 
disease: systematic review and perspectives for the future. Exp Gerontol 46:611–627 
 
García-Alías G, Barkhuysen S, Buckle M, Fawcett JW. Chondroitinase ABC treatment opens a window 
of opportunity for task-specific rehabilitation. Nat Neurosci 12: 1145-1151, 2009. 
 
Grafman J, Pascual-Leone A, Alway D, Nichelli P, Gomez-Tortosa E, Hallett M (1994) Induction of a 
recall deficit by rapid-rate transcranial magnetic stimulation. NeuroReport 5:1157–1160. 
 
Hadley D, Anderson BS, Borckardt JJ, Arana A, Li X, Nahas Z, George MS. Safety, tolerability, and 
effectiveness of high doses of adjunctive daily left prefrontal repetitive transcranial magnetic stimulation 
for treatment-resistant depression in a clinical setting. J ECT: 18-25, 2011. 
 
Hawthorne G. Assessing utility where short measures are required: development of the short Assessment 
of Quality of Life-8 (AQoL-8) instrument. Value Health 12: 948-957, 2009.  
 
Hawthorne G, Richardson J, Osborne R. The Assessment of Quality of Life (AQoL) instrument: a 
psychometric measure of health-related quality of life. Qual Life Res 8: 209–224, 1999. 
 
Herrmann KH, Kirchberger I, Biering-Sørensen F, Cieza A. Differences in functioning of individuals 
with tetraplegia and paraplegia according to the International Classification of Functioning, Disability and 
Health (ICF). Spinal Cord 49: 534-543, 2010.  
 
Hochberg LR, Serruya MD, Friehs GM, Mukand JA, Saleh M, Caplan AH, Branner A,  
Chen D, Penn RD, Donoghue JP. Neuronal ensemble control of prosthetic devices by a human with 
tetraplegia. Nature 442: 164-171, 2006. 
 
Hoffman LR, Field-Fote EC. Cortical reorganization following bimanual training and somatosensory 
stimulation in cervical spinal cord injury: a case report. Phys Ther 87: 208-223, 2007.  
 

Internal Reference Number: 6961.01 
Date: 03/01/19 
 
16
Hoffman LR, Field-Fote EC. Functional and corticomotor changes in individuals with tetraplegia 
following unimanual or bimanual massed practice training with somatosensory stimulation: a pilot study. 
J Neurol Phys Ther 34: 193-201, 2010. 
 
Huang YZ. The modulation of cortical motor circuits and spinal reflexes using theta burst stimulation in 
healthy and dystonic subjects. Restor Neurol Neurosci 28: 449-457, 2010.  
 
Hummel FC, Cohen LG. Drivers of brain plasticity. Curr Opin Neurol 18: 667-674, 2005. 
 
Irlbacher K, Brocke J, Mechow JV, Brandt SA. Effects of GABA(A) and GABA(B) agonists on 
interhemispheric inhibition in man. Clin Neurophysiol 118: 308-316, 2007.  
 
Itzkovich M, Gelernter I, Biering-Sorensen F, Weeks C, Laramee MT, Craven BC, Tonack M, Hitzig SL, 
Glaser E, Zeilig G, Aito S, Scivoletto G, Mecci M, Chadwick RJ, El Masry WS, Osman A, Glass CA, 
Silva P, Soni BM, Gardner BP, Savic G, Bergstrom EM, Bluvshtein V, Ronen J, Catz A. The Spinal Cord 
Independence Measure (SCIM) version III reliability and validity in a multi-center international study. 
Disabil Rehabil 29: 1926–1933, 2007.  
 
Jankowska E, Stecina K, Cabaj A, Pettersson LG, Edgley SA. Neuronal relays in double crossed 
pathways between feline motor cortex and ipsilateral hindlimb motoneurones. J Physiol 575: 527-541, 
2006.  
 
Kakuda W, Abo M, Shimizu M, Sasanuma J, Okamoto T, Yokoi A, Taguchi K, Mitani S, Harashima H, 
Urushidani N, Urashima M; The NEURO Investigators. A multi-center study on low-frequency rTMS 
combined with intensive occupational therapy for upper limb hemiparesis in post-stroke patients. J 
Neuroeng Rehabil 9: 4, 2012. 
 
Kandler R. Safety of transcranial magnetic stimulation. Lancet 335: 469-470, 1990.  
 
Kang BS, Shin HI, Bang MS. Effect of repetitive transcranial magnetic stimulation over the hand motor 
cortical area on central pain after spinal cord injury. Arch Phys Med Rehabil 90: 1766–1771, 2009. 
 
Khedr EM, Ahmed MA, Fathy N, Rothwell JC. Therapeutic trial of repetitive transcranial magnetic 
stimulation after acute ischemic stroke. Neurology 65: 466-468, 2005.  
 

Internal Reference Number: 6961.01 
Date: 03/01/19 
 
17
Koch G, Rossi S, Prosperetti C, Codecà C, Monteleone F, Petrosini L, Bernardi G, Centonze D. 
Improvement of hand dexterity following motor cortex rTMS in multiple sclerosis patients with cerebellar 
impairment. Mult Scler 14: 995-998, 2008.  
 
Kokotilo KJ, Eng JJ, Curt A. Reorganization and preservation of motor control of the brain in spinal cord 
injury: a systematic review. J Neurotrauma 26: 2113-2126, 2009.  
 
Kouchtir-Devanne N, Capaday C, Cassim F, Derambure P, Devanne H. Task-dependent changes of motor 
cortical network excitability during precision grip compared to isolated finger contraction. J Neurophysiol 
107: 1522-1529, 2012.  
 
Krajacic A, Weishaupt N, Girgis J, Tetzlaff W, Fouad K. Training-induced plasticity in rats withcervical 
spinal cord injury: effects and side effects. Behav Brain Res 214: 323-331, 2010. 
 
Kujirai T, Caramia MD, Rothwell JC, Day BL, Thompson PD, Ferbert A, Wroe S, Asselman P, Marsden 
CD. Corticocortical inhibition in human motor cortex. J Physiol (Lond) 471: 501-519, 1993. 
 
Kumru H, Murillo N, Samso JV, Valls-Sole J, Edwards D, Pelayo R. et al. Reduction of spasticity with 
repetitive transcranial magnetic stimulation in patients with spinal cord injury. Neurorehabil Neural 
Repair 24: 435–441, 2010.  
 
Kuppuswamy A, Balasubramaniam AV, Maksimovic R, Mathias CJ, Gall A, Craggs MD, Ellaway PH. 
Action of 5Hz repetitive transcranial magnetic stimulation on sensory, motor and autonomic function in 
human spinal cord injury. Clin Neurophysiol 122: 2452-2461, 2011. 
 
Kwon YH, Jang SH. The enhanced cortical activation induced by transcranial direct current stimulation 
during hand movements. Neurosci Lett 492: 105-108, 2011. 
 
Lefaucheur JP, Drouot X, Von Raison F, Ménard-Lefaucheur I, Cesaro P, Nguyen JP. Improvement of 
motor performance and modulation of cortical excitability by repetitive transcranial magnetic stimulation 
of the motor cortex in Parkinson's disease. Clin Neurophysiol 115: 2530-2541, 2004. 
 
Lemon RN. Descending pathways in motor control. Annu Rev Neurosci 31: 195-218, 2008.  
 

Internal Reference Number: 6961.01 
Date: 03/01/19 
 
18
Levy WJ Jr, Amassian VE, Traad M, Cadwell J. Focal magnetic coil stimulation reveals motor cortical 
system reorganized in humans after traumatic quadriplegia. Brain Res 510: 130-134, 1990. 
 
Lisanby SH, Luber B, Perera T, Sackeim HS (2000) Transcranial magnetic stimulation: applications in 
basic neuroscience and neuropsychopharmacology. Int J Neuropsychopharmacol 3:259–273. 
 
Mhalla A, Baudic S, Ciampi de Andrade D, Gautron M, Perrot S, Teixeira MJ, Attal N, Bouhassira D. 
Long-term maintenance of the analgesic effects of transcranial magnetic stimulation in fibromyalgia. Pain 
152: 1478-1485, 2011. 
 
Macklin RA, Brooke VJ, Calabro FJ, Ellaway PH, Perez MA. Discrepancies between clinical assessments 
of sensory function and electrical perceptual thresholds after incomplete chronic cervical spinal cord 
injury 2015 Jun 30. doi: 10.1038/sc.2015.104. [Epub ahead of print] PubMed PMID: 26123212. 
 
Mansur CG, Fregni F, Boggio PS, Riberto M, Gallucci-Neto J, Santos CM, Wagner T, Rigonatti SP, 
Marcolin MA, Pascual-Leone A. A sham stimulation-controlled trial of rTMS of the unaffected 
hemisphere in stroke patients. Neurology 64: 1802-1804, 2005. 
 
Mantovani A, Lisanby SH (2004) Applications of transcranial magnetic stimulation to therapy in 
psychiatry. Psychiatric Times 21:1–2  
 
Marino RJ, Shea JA, Stineman MG. The Capabilities of Upper Extremity instrument: reliability and 
validity of a measure of functional limitation in tetraplegia. Arch Phys Med Rehabil 79: 1512–1521, 
1998.  
 
Miniussi C, Rossini PM. Transcranial magnetic stimulation in cognitive rehabilitation. Neuropsychol 
Rehabil 30: 1-23, 2001.  
 
Minks E, Mareček R, Pavlík T, Ovesná P, Bareš M. Is the cerebellum a potential target for stimulation in 
Parkinson's disease? Results of 1-Hz rTMS on upper limb motor tasks. Cerebellum 10: 804-811, 2011. 
 
Müller-Putz GR, Zimmermann D, Graimann B, Nestinger K, Korisek G, Pfurtscheller G. Event-related 
beta EEG-changes during passive and attempted foot movements in paraplegic patients. Brain Res 1137: 
84-91, 2007.  
 

Internal Reference Number: 6961.01 
Date: 03/01/19 
 
19
Nishikiori O. Studies on transcranial magnetic stimulation--Part 2. Pathological findings of rabbit brain 
after long-term stimulation based on characteristics of intracerebral induced voltage. Nippon Ganka 
Gakkai Zasshi 100: 489-495, 1996.  
 
Norton JA, Bennett DJ, Knash ME, Murray KC, Gorassini MA. Changes in sensory-evoked synaptic 
activation of motoneurons after spinal cord injury in man. Brain 131: 1478-1491, 2008. 
 
Nudo RJ. Functional and structural plasticity in motor cortex: implications for stroke recovery. Phy Med 
Rehabil Clin N Am 14: 57-76, 2003. 
 
Oberman L, Edwards D, Eldaief M, Pascual-Leone A. Safety of theta burst transcranial magnetic 
stimulation: a systematic review of the literature. J Clin Neurophysiol. 2011 Feb;28(1):67-74. Review. 
 
Oudega M, Perez MA. Corticospinal reorganization after spinal cord injury. J Physiology (In press): 
2012. 
 
Pascual-Leone A, Tormos JM, Keenan J, Tarazona F, Cañete C, Catalá MD (1998) Study and modulation 
of human cortical excitability with transcranial magnetic stimulation. J Clin Neurophysiol 15:333–334 
 
Perez MA, Lungholt BK and Nielsen JB. Short-term adaptations in spinal cord circuits evoked by 
repetitive transcranial magnetic stimulation: possible underlying mechanisms. Exp Brain Res 162: 201-
212, 2005. 
 
Perez MA, Tanaka S, Wise SP, Sadato N, Tanabe HC, Willingham DT and Cohen LG. Neural substrates 
of intermanual transfer of a newly acquired motor skill. Current Biology 17: 1896-1902, 2007. 
 
Perez MA and Cohen LG. Mechanisms underlying functional changes in the primary motor cortex 
ipsilateral to an active hand. J Neuroscience 28: 5631-5640, 2008. 
 
Perez MA, Tanaka S, Wise SP, Willingham DT and Cohen LG. Time-Specific Contribution of the 
supplementary motor area to intermanual transfer of procedural knowledge. J Neuroscience 28: 9664-
9669, 2008. 
 
Perez MA, Cohen LG. Scaling of motor cortical excitability during unimanual force generation. Cortex 
45: 1065-1071, 2009a. 

Internal Reference Number: 6961.01 
Date: 03/01/19 
 
20
 
Perez MA and Cohen LG. The Corticospinal System and Transcranial Magnetic Stimulation in Stroke. 
Topics in Stroke 16: 254-269, 2009b.  
 
Peinemann A, Reimer B, Löer C, Quartarone A, Münchau A, Conrad B, Siebner HR. Long-lasting 
increase in corticospinal excitability after 1800 pulses of subthreshold 5 Hz repetitive TMS to the primary 
motor cortex. Clin Neurophysiol 115: 1519-1526, 2004. 
 
Plautz EJ, Barbay S, Frost SB, Friel KM, Dancause N, Zoubina EV, Stowe AM, Quaney BM, Nudo RJ. 
Post-infarct cortical plasticity and behavioral recovery using concurrent cortical stimulation and 
rehabilitative training: a feasibility study in primates. Neurol Res 25: 801-810, 2003. 
 
Quartarone A, Bagnato S, Rizzo V, Siebner HR, Dattola V, Scalfari A, Morgante F, Battaglia F, Romano 
M, Girlanda P. Abnormal associative plasticity of the human motor cortex in writer’s cramp. Brain 126: 
2586–2596, 2003. 
 
Ravnborg M, Knudsen GM, Blinkenberg M. No effect of pulsed magnetic stimulation on the blood-brain 
barrier in rats. Neuroscience 38: 277-280, 1990.  
 
Reis J, Schambra HM, Cohen LG, Buch ER, Fritsch B, Zarahn E, Celnik PA, Krakauer JW. Noninvasive 
cortical stimulation enhances motor skill acquisition over multiple days through an effect on 
consolidation. Proc Natl Acad Sci USA 106: 1590-1595, 2009. 
 
Ridding MC, Rothwell JC. Is there a future for therapeutic use of transcranial magnetic stimulation? Nat 
Rev Neurosci 8: 559-567, 2007. 
 
Rosenzweig ES, Courtine G, Jindrich DL, Brock JH, Ferguson AR, Strand SC, Nout YS, Roy RR, Miller 
DM, Beattie MS, Havton LA, Bresnahan JC, Edgerton VR, Tuszynski MH. Extensive spontaneous 
plasticity of corticospinal projections after primate spinal cord injury. Nat Neurosci 13: 1505-1510, 2010. 
122: 1387-1395. 
 
Rossi S, Hallett M, Rossini PM, Pascual-Leone A, Safety of TMS Consensus Group (2009) Safety, 
ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in 
clinical practice and research. Clin Neurophysiol 120:2008–2039 
 

Internal Reference Number: 6961.01 
Date: 03/01/19 
 
21
Schieppati M, Trompetto C, Abbruzzese G. Selective facilitation of responses to cortical stimulation of 
proximal and distal arm muscles by precision tasks in man. J Physiol 491: 551-562, 1996. 
 
Sehm B, Perez MA, Xu B, Hidler J & Cohen LG. Functional neuroanatomy of mirroring during a 
unimanual force generation task. Cereb Cortex 
 
Snoek GJ, IJzerman MJ, Hermens HJ, Maxwell D, Biering-Sorensen F. Survey of the needs of patients 
with spinal cord injury: impact and priority for improvement in hand function in tetraplegics. Spinal Cord 
42: 526-532, 2004. 
 
Soteropoulos DS, Perez MA. Physiological changes underlying bilateral isometric arm voluntary 
contractions in healthy humans. J Neurophysiology 105: 1594-15602, 2011. 
 
Spooren AI, Janssen-Potten YJ, Kerckhofs E, Seelen HA. Outcome of motor training programmes on arm 
and hand functioning in patients with cervical spinal cord injury according to different levels of the ICF: a 
systematic review. J Rehabil Med 41: 497-505, 2009. 
 
Talelli P, Greenwood RJ, Rothwell JC. Exploring Theta Burst Stimulation as an intervention to improve 
motor recovery in chronic stroke. Clin Neurophysiol 118: 333-342, 2007. 
 
Taylor JL, Martin PG. Voluntary motor output is altered by spike-timing-dependent changes in the human 
corticospinal pathway. J Neurosci 29: 11708-11716, 2009. 
 
Tinazzi M, Farina S, Tamburin S, Facchini S, Fiaschi A, Restivo D, Berardelli A. Task-dependent 
modulation of excitatory and inhibitory functions within the human primary motor cortex. Exp Brain Res 
150: 222-229, 2003. 
 
Thompson AK, Chen XY, Wolpaw JR. Acquisition of a simple motor skill: task-dependent adaptation 
plus long-term change in the human soleus H-reflex. J Neurosci 29: 5784-5792, 2009. 
 
Touge, W. Gerschlager, P. Brown and J.C. Rothwell. Are the after-effects of low frequency rTMS on 
motor cortex excitability due to changes in the efficacy of cortical synapses? Clin Neurophysiol 112: 
2138- 2145, 2001. 
 

Internal Reference Number: 6961.01 
Date: 03/01/19 
 
22
Vaillancourt DE, Mayka MA, Thulborn KR, Corcos DM. Subthalamic nucleus and internal globus 
pallidus scale with the rate of change of force production in humans. Neuroimage 23: 175-186, 2004.van 
Tuijl JH, Janssen-Potten YJ, Seelen HA. Evaluation of upper extremity motor function tests in 
tetraplegics. Spinal Cord 40: 51-64, 2002. 
 
Wang W, Collinger JL, Perez MA, Tyler-Kabara EC, Cohen LG, Birbaumer N, Brose SW, Schwartz AB, 
Boninger ML, Weber DJ. Neural interface technology for rehabilitation: exploiting and promoting 
neuroplasticity. Phys Med Rehabil Clin N Am 21: 157-178, 2010. 
 
Wallace DM, Ross BH, Thomas CK. Characteristics of lower extremity clonus after human cervical 
spinal cord injury. J Neurotrauma 29: 915-924, 2012.  
 
Wang RY, Tseng HY, Liao KK, Wang CJ, Lai KL, Yang YR. rTMS Combined With Task-Oriented 
Training to Improve Symmetry of Interhemispheric Corticomotor Excitability and Gait Performance 
After Stroke: A Randomized Trial. Neurorehabil Neural Repair 26: 222-230, 2012. 
 
Yedimenko JA, Perez MA. The effect of bilateral isometric forces in different directions on motor cortical 
function in humans. J Neurophysiol 104: 2922-2931, 2010. 
 
Yanagisawa T, Hirata M, Saitoh Y, Kishima H, Matsushita K, Goto T, Fukuma R, Yokoi H, Kamitani Y, 
and Yoshimine T. Electrocorticographic control of a prosthetic arm in paralyzed patients. Ann Neurol 
2011.