Maximizing Spike - Timing Dependent Plasticity After Spinal Cord Injury
Phase: NA
Conditions: Spinal Cord Injury
Sponsor: VA Office of Research and Development

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PROTOCOL TITLE: Targeted Neuroplasticity after Spinal Cord Injury
PRINCIPAL INVESTIGATOR:
Monica Perez
Neuromodulation Lab 
Shirley Ryan AbilityLab (22nd floor)
355 East Erie St.
Chicago, IL 60611
Site(s) where study will be performed:
Version Date
Investigational Agent(s) 
(Drugs or Devices)
IND / IDE / HDE # 
Indicate
Special Population(s)
Children 
 Children who are wards of the state 
 Adults Unable to Consent  
 Cognitively Impaired Adults 
 Neonates of Uncertain Viability 
 Pregnant Women 
 Prisoners (or other detained/paroled individuals) 
 Students/Employees 
N/A
Sample Size
500
Funding Source
Institutional funds/Northwestern University
Indicate the type of consent 
to be obtained
Written 
Verbal/Waiver of Documentation of Informed Consent
Waiver of HIPAA Authorization 
Waiver/Alteration of Consent Process  
Site
 Lead Site ( For A Multiple Site Research Study)
 Data Coordinating Center (DCC)
Research Related 
Radiation Exposure
Yes 
 No 
DSMB / DMC / IDMC
Yes 
No
OBJECTIVES:
The purpose of this study is to test a strategy to restore upper and lower-limb motor function in 
individuals with spinal cord injury (SCI). We have the following two specific aims: 
8/5/2021

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Aim 1. Maximize exercise-mediated recovery of limb muscles by using stimulation induced spinal 
plasticity. We will study the effect of limb training combined with Spike-Timing Dependent Plasticity 
(STDP) on motor function recovery. We will test the effect of three groups: (1) stimulation, (2) training
+stimulation, and (3) training+sham stimulation. We hypothesize that the ability of training to promote 
recovery of limb motor function will be enhanced by eliciting STDP in upper and lower-limb. An 
important strength of this aim is the combination of training and STDP, which aims at enhancing the 
beneficial effects of motor training by promoting plasticity in the corticospinal pathway (Ellaway et al., 
2007; Castel et al., 2009). Training effects on physiological pathways will be explored and correlated 
with hand/arm motor function and the site and extent of the lesion defined by structural MRI.
Aim 2. Maximize exercise-mediated recovery of limb muscles by using stimulation induced spinal 
plasticity. STDP has been shown to be effective in enhancing the recovery of residual limb function in 
humans with chronic incomplete SCI (Urbin et at., 2017). In this aim we will investigate the effect of 
the combination of extended STDP and training. We hypothesize the ability of training to promote 
recovery of motor function will be enhanced by eliciting STDP in the corticospinal pathway.
BACKGROUND: 
After a SCI, many individuals present deficits in upper-limb and/or lower-limb function. Most SCIs are 
contusions and ~50% occur at the cervical level causing anatomically incomplete damage and 
bilaterally functional deficits to lower- and upper-limbs (Kakulas, 1999). Arm and leg function deficits 
limit daily-life activities, such as reaching and grasping, eating, writing, and walking which decreases 
the quality of life (Snoek et al., 2004). Regaining arm and leg function is considered the highest 
priority for improving the quality of life of individuals with SCI (Anderson, 2004). 
Rehabilitation strategies in humans with SCI rely on the use of exercise (Harkema et al., 2012; 
Behrman et al., 2017). Exercise training aims to drive neural networks in an activity-dependent 
manner to elicit plasticity and facilitate functionally relevant muscle activity below the level of injury 
(Knikou, 2010). Studies using animals (Courtine et al., 2009; Hill et al., 2009; McPherson et al., 2015) 
and humans (Rejc et al., 2017; Gad et al., 2018; Gill et al., 2018) agree that physiological and 
functional effects of exercise can be augmented by the use of neural stimulation, which is thought to 
increase the likelihood of activating spared neural pathways. Even though these approaches have 
facilitated exercise-mediated recovery, the overall effects remain limited. Clearly, there is a need to 
develop interventions that can more effectively engage spared neural connections to further improve 
functional recovery due to rehabilitative exercise in humans with SCI.
Evidence has shown that corticospinal transmission can be enhanced by precisely timing pairs of 
presynaptic and postsynaptic action potentials arriving at the spinal cord (Taylor & Martin, 2009), 

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which can enhance voluntary motor output in humans with (Bunday and Perez, 2012) and without 
(Taylor & Martin 2009) SCI. Evidence has shown that the activity in upper-limb muscles can be 
enhanced by activations of the lower limb (Zhou et al., 2017). Therefore a strategy that combine 
upper and lower limb stimulation and activity might be more effective to enhance upper limb function. 
In this protocol, we will test the effect of training combined with stimulation to facilitate upper and 
lower limb function. 
How STDP and training might contribute to recovery of upper-limb and lower-limb function: The 
physiological basis for these protocols comes from animal studies showing that an increase or 
decrease in synaptic strength can be elicited by repeated pairs of presynaptic and postsynaptic action 
potentials that are precisely timed with respect to each other (Bi & Poo, 1998; Dan & Poo, 1998; Bi & 
Poo, 2001). If antidromic stimulation of a postsynaptic cell is paired with timed orthodromic stimulation 
of a presynaptic cell, bidirectional plasticity can be induced (Bi & Poo, 1998; Markram et al., 1997). In 
humans, corticospinal neurons can be activated by transcranial magnetic stimulation (TMS), and 
antidromic action potentials can be elicited in sensorimotor cortex and motoneurons by peripheral 
nerve/ spinal cord stimulation. STDP has been used successfully to precisely pair pulses to arrive at 
the spinal cord (Taylor & Martin, 2009). How to strengthen synaptic plasticity in corticospinal 
connections targeting the spinal cord (spinal synapses) of upper-limb and lower-limb muscles after 
SCI combined with training and its effect on voluntary output, remains unknown and will be 
investigated in this study.
STUDY ENDPOINTS:
The primary outcome measure utilized in this part of study is the Graded Redefined Assessment of 
Strength, Sensibility and Prehension (GRASSP see below). GRASSP is an extensive and validated 
impairment and functional measure which is able to detect subtle neurologic changes in individuals 
with spinal cord injury. Specifically, it evaluates the domains of sensation, strength, quality of different 
grip patterns and the ability to complete a variety of functional tasks.
The primary outcome measure utilized in this part of study the 10-meter Walk test. In the group 
receiving lower-limb exercises, we will use the 10-meter walk test to assess walking speed in meters 
per second. The same percentage of body-weight support will be used during pre- and post-
assessments. A stopwatch will be used to measure the time to execute the task. The 10-meter walk 
will be repeated 3 times and the average will be used.
Participants may complete the following secondary endpoint measurements before and after the 
STDP protocol as outlined below. 
A). MEPs: Transcranial magnetic stimuli (TMS) will be delivered from a Magstim 200 stimulator 
(Magstim Company) through either a figure-of-eight coil (loop diameter, 7 cm) or a double-cone coil 
(used for the tibialis anterior muscle) with a monophasic current waveform. TMS will be delivered to 

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the optimal scalp position for activation of dominant muscles in controls and the furthest muscle with 
residual connectivity below the level of injury in individuals with SCI. The optimal scalp position will be 
determined by moving the coil in small steps along the hand/arm/leg representation of the primary 
motor cortex to find the region where the largest MEP can be evoked with the minimum intensity in 
the targeted muscle(s). The muscles to be activated will be the first dorsal interosseous, abductor 
pollicis brevis, flexor and extensor carpis radialis, biceps and triceps brachii, deltoid, quadriceps 
femoris, hamstrings, tibialis anterior and soleus. Measurements: resting (minimum intensity required 
to induce MEPs greater than 50 μV in 5/10 consecutive trials at rest), and active (minimum intensity 
able to evoke an MEP bigger than 200 μV in 5/10 consecutive trials during 5-10% of MVC) motor 
threshold. Thirty MEPs will be average in each condition. 
B). CMEPs: Supramaximal electrical stimulation will be administered posterior to the mastoid process 
or thoracic spine to elicit motor evoked potentials to upper- and lower-limb muscles.
C). Motoneuronal excitability (reflected by F-wave persistence and amplitude): Using 
supramaximum stimulus intensity (120% of the maximal motor response, M-max; 0.2 ms duration, 20 
trials (88)) to the ulnar nerve at the wrist for the first dorsal interosseous, median nerve at the wrist for 
abductor pollicis brevis, brachial plexus at the erb’s point for the deltoid and biceps brachii, femoral 
nerve for quadriceps, and common peroneal nerve under the head of the fibula for the tibialis anterior 
and posterior tibial nerve behind the knee joint for the soleus. We will quantify latency, peak-to-peak 
amplitude of each F-wave, and F-wave persistence (number of F-waves present on each set).
D)
H-reflex: Quadriceps femoris H-reflex and M-max: Participants are comfortably seated in an
armchair. Percutaneous electrical stimulation of the femoral nerve will be delivered (using 1 ms
rectangular electrical stimulus, DS7AH, Digitimer Ltd.) through a cathode (10-mm diameter Ag-AgCl
electrode) placed in the femoral triangle and an anode (Ag-AgCl plaque) placed over the posterior
aspect of the thigh. Stimulus intensities will be increased in steps of 0.05 mA, starting below H-reflex
threshold and increasing up to measure the H-max and M-max at rest (0.25 Hz). The H-max and
Mmax will be measured as peak-to-peak amplitude of the non-rectified response in control subjects
and both legs of individuals with and without spasticity as determined by the MAS. MAS this clinical
scale will be used by measuring resistance encountered during manual passive muscle stretching
using a six-point ordinal scale (0=no increase in tone, 1/+1=slight increase in tone with a catch and
release or minimal resistance at the end or less than half of the range of movement, respectively,
2=more marked increased tone through most of the range of movement but affected parts easily
moved, 3=considerable increase in tone and passive movement difficultly, and 4=affected parts rigid;
Bohannon and Smith, 1987). Tibialis anterior H-reflex and M-max: Participants will be comfortably
seated in an armchair. Percutaneous electrical stimulation of the common peroneal nerve will be
delivered (using 1 ms rectangular electrical stimulus, DS7AH, Digitimer Ltd.). Stimulus intensities will
be increased in steps of 0.05 mA, starting below H-reflex threshold and increasing up to measure the
H-max and M-max at rest (0.25 Hz). The H-max and M-max will be measured as peak-to-peak

E)
EMG and force voluntary output: Individuals will perform a maximum voluntary contraction
(MVC) of the targeted muscles (deltoid, biceps brachii, first dorsal interosseous, abductor pollicis
brevis, quadriceps femoris, tibialis anterior and/or soleus) through surface electrodes secured to the
skin over the belly of each muscle (Ag-AgCl, 10 mm diameter). The signals will be amplified, filtered
(20–1000 Hz), and sampled at 10 kHz for offline analysis.
F)
Nine Hole Peg Test (9HPT): This test measures finger dexterity. The board is placed at the
participant’s midline, with the container holding the pegs facing toward the hand being tested. Nine
small pegs are placed in a container and subjects are instructed to pick up each of the pegs and put
them back as fast and accurately as possible. The time to complete the task is measured in seconds.
G). Jebsen Taylor Test (JTT): This test measures hand function. The time in seconds to complete 
subcomponents of the JTT will be measured for both hands. 
H) Chedoke Arm and Hand inventory (CAHAI): This test measures upper-limb motor recovery.
Quantitative scale with 13 items (each item is given a score: 1 to 7).
I) Electrical Perceptual Threshold (EPT): This test provides a quantitative measure of sensory
function by using small pulses of electricity on the surface of the skin and will be used to evaluate
sensory threshold in the hands/arms and legs.
J) Kinematics: These will be measured during self-paced and fast grasping or walking movements
recorded by OptiTrack V100 cameras (120 Hz) and by Opti Track, V120: Trio camera,
NaturalPoint, Inc., with cameras respectively for the locomotor training. Subjects will be seated
and grasp with the less affected (participants) and dominant (controls) arm. Cameras will be
positioned in front/sides of subjects with markers on the tip of the thumb and index finger, inner
side of the wrist, lateral size of the elbow and shoulder joints. Variables: 1) Movement onset (MO):
time between the GO signal and start of forward arm velocity. 2) Total movement duration (MD):
time between MO and grasp (Gr=time when index and thumb contact target). MD will be broken in
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amplitude of the non-rectified response in control subjects and both legs of individuals with and 
without spasticity as determined by the MAS. Soleus H-reflex and M-max: Participants will be 
comfortably seated in an armchair. Percutaneous electrical stimulation of the posterior tibial nerve will 
be delivered (using 1 ms rectangular electrical stimulus, DS7AH, Digitimer) through a cathode (10mm 
diameter Ag-AgCl electrode) placed in the popliteal fossa over the posterior tibial nerve and an anode 
(Ag-AgCl plaque) placed over superior to the patella. Stimulus intensities will be increased in steps of 
0.05 mA, starting below H-reflex threshold and increasing up to measure the H-max and Mmax at rest 
(0.25 Hz). The H-max and M-max will be measured as peak-to-peak amplitude of the non-rectified 
response in control subjects and both legs of individuals with and without spasticity as determined by 
the MAS. 

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time to reach maximum velocity (MV), maximum hand aperture (MA), and the first finger contact 
(FC), and Gr. 
K) Startle: We will test the StartReact response to assess contributions from the reticulospinal tract.
Participants will be asked to observe a red LED located ~1 m in front of them. When the LED is
illuminated, individuals will be asked to perform as fast as possible isometric muscle contractions.
In some trials, the LED will be presented with a quiet (<95 dB; 50 ms) or a startling (SAS, >115 dB;
50 ms) acoustic stimulus. We will measure: (a) visual reaction time (defined as the onset of the
EMG burst in the contracted muscle after the LED), (b) auditory reaction time (time delay between
the presentation of the quiet acoustic stimulus and the onset of the EMG response), and (c)
visual+startle reaction time (time between the SAS and the EMG onset).
L) Pendulum Test: As part of the physical exam, we will use the pendulum test to measure muscle
tone at the knee by using gravity to provoke muscle stretch reflexes during passive swinging of the
lower limb.
M) Portable Spasticity Assessment Device (PSAD): The PSAD combine biomechanical and
electrophysiological measurements for an objective quantification of active and passive
component of muscle stiffness (Lorentzen et al., 2017). The device functions as a dynamometer
integrating measurement of force, joint movement, and reflex-mediated muscle activity.
N) Toronto Rehabilitation Institute-Hand Function Test (TRI-HFT): This exam measures gross
motor function frequently used to manipulate objects that participants may encounter in their daily
lives. The first part of the test evaluates manual hand dexterity through the ability to use
lateral/pulp pinch and palmar grasp to manipulate common objects in three different gravity-related
positions: against gravity (supination), toward gravity (pronation), and in a gravity-eliminated plane
(mid-prone position). To test the palmar grasp, participants are presented with a: mug, book, soda
can, isosceles triangular sponge, and wireless telephone. To test lateral pinch and precision grip,
participants are presented with a: paper sheet, Ziploc bag filled with five golf balls, dice, credit
card, and pencil. The second part of the test measures the strength of their lateral/pulp pinch and
palmar grasp. Participants are presented with nine rectangular blocks, instrumented cylinder,
credit card attached to a dynamometer and wooden bar used to measure the torque generated by
palmar grasp, the force that the pinch (lateral or pulp) grasp could resist, and the eccentric load
that the palmar grasp could sustain. There is no time limit within which the task must be
performed. The scoring system is designed to emphasize the type of grasp used to accomplish the
task: an active (i.e. ability to develop active finger) or passive (i.e. positioning of the proximal
joints) grasp (Kapadia et al., 2012).
O) Neuromechanical hand testing: This exam will measure stretch reflexes flexor and extensor
carpi radialis and first dorsal interosseous using a previously described method (Kamper et
al., 2001). Stretch reflexes will be elicited by rotation of the wrist joint for flexor and extensor carpi

radialis, and by rotation of the metacarpophalangeal joint for first dorsal interosseous. The arm will 
be positioned along the trunk, with the elbow flexed at 90° and secured to the device. The wrist 
and metacarpophalangeal joint will be aligned with the forearm in a neutral position and secured to 
the motor shaft through a jig such that rotation of the shaft produced rotation of the targeted joint. 
Rotation will be performed from the maximal joint flexion/extension position. Ten trials will be 
performed with a few minutes between trials to minimize effects of repeated stretching on 
subsequent responses. 
P) Stretch reflexes: We will use a Kinesiological Instrument for Normal and Altered
Reaching Movements (KINARM) to examine elbow stretch reflexes change related to spasticity.
The KINARM is capable of applying loads at elbow joints using torque motors while angular
position and angular velocity are recorded. Briefly, participants will sit with their arms resting in
troughs with shoulders abducted ~85°. Shoulder and elbow joints will be aligned with the linkages
of the robot and movement will be permitted in the horizontal plane. Physical stops do not allow
the elbow to hyperextend. Elbow angle, fingertip position, and segment length for both arms will
be calibrated for each participant. The kinematic assessment of spasticity consists of elbow joint
stretches by moving the forearm from maximal elbow extension to maximal elbow flexion and in
the opposite direction to assess passive and active muscle stiffness, respectively. EMG activity
will be recorded from biceps and triceps brachii of the right arm through bipolar surface
electrodes (Ag-AgCl, 10-mm diameter, 1 cm apart) secured on the skin. Ten trials will be
performed with a few minutes between trials to minimize effects of repeated stretching on
subsequent responses. Elbow angular position and velocity will be sampled at 1000 Hz using
Dexterit-E (BKIN Technologies Ltd., Kingston, Canada) and analyze with MATLAB (MathWorks,
Natick, MA). Range-of-motion, torque, and stretch reflex will be analyzed as well as first angle
(i.e., the angle at an angle (i.e., angle at the final position following the release after the “catch”).
Q) Modified Ashworth Scale (MAS): This scale measures resistance encountered during
manual passive muscle stretching using a six-point ordinal scale. During testing of elbow flexor
and extensor muscle, subjects will sit comfortably in a chair with their arm in a supine position. The
elbow joint will be stretched by moving the forearm from maximal elbow extension to maximal
elbow flexion (triceps brachii spasticity assessment) and in the opposite direction (biceps brachii
spasticity assessment). The knee extension and ankle extension and flexion will performed to
assess spasticity in quadriceps and tibialis anterior and soleus respectively. The same rater will
perform all MAS assessments.
R) Participant reported spasticity: Individuals with SCI will grade the severity of spasticity with a
four-point nominal scale (0=none; 1=mild; 2=moderate; 3=severe) to answer questions: 1) how
would you rate the severity of your spasticity in your right biceps brachii, 2) triceps brachii, 3)
quadriceps, and 4) tibialis anterior, 5) soleus?
S) Surveys: All SCI participants will be asked to complete the following SCI-CAT surveys during
the pre-assessment and at the post-40 visits:
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(a) Ambulation: This questionnaire will ask the participant about their ability to do thing like walk,
run and jump.
(b) Basic Mobility: This questionnaire will ask the participant about their ability to perform their daily
routine.
(c) Fine Motor: This questionnaire will ask the participant about their ability to pick up small
objects.
(d) Manual and Power Wheelchair Mobility: This questionnaire ask the participant about their
ability using a wheelchair.
(e) Self-Care: This questionnaire will ask the participant about their ability to do activities of daily
living such as getting dressed, bathing, and eating.
STUDY INTERVENTION(S) / INVESTIGATIONAL AGENT(S):
STDP protocol: 
STDP and sham-STDP: During STDP, participants will have a maximum of 360 paired pulses of 
stimuli delivered every 1-10 s (~60 min) and a small cohort of participants (n=10) will have a 
maximum of 720 paired pulses of stimuli (up to 4 times per day) using the same delivery period. 
Corticospinal volleys will be evoked by TMS over the primary motor cortex and/or the spinal cord will 
be timed to arrive at corticospinal-motoneuronal synapses of each muscle ~1-2 ms before antidromic 
potentials evoked in motoneurons by peripheral nerve stimulation (PNS) and/or spinal root 
stimulation. During sham-STDP, a coil will be placed on the scalp of the participant to provide the 
participant with the feeling of having the coil on their head. This coil will not be connected to a TMS or 
any other device. A second coil will be placed ~10 cm behind the subject’s head and triggered in the 
air every 1-10s for up to 720 stimuli to provide the subject with the same auditory sound produced by 
the TMS as the non-sham.
TMS: Transcranial magnetic stimuli will be delivered from a Magstim 200 stimulator through either a 
figure-of-eight coil or a double-cone coil (used for the tibialis anterior muscle) with a monophasic 
current waveform. TMS will be delivered to the optimal scalp position for activation of the targeted 
muscle. The optimal scalp position will be determined by moving the coil in small steps along the 
hand/arm/leg representation of the primary motor cortex to find the region where the largest MEP can 
be evoked with the minimum intensity in the targeted muscle. This scalp position will be saved using 
a stereotaxic neuro-navigation system (Brainsight 2). 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 stimuli will be delivered at an intensity from motor threshold to 100% of the 
maximum stimulator output. 
PNS/Spinal root Stimulation: Supra-maximum electrical stimulation (200 μs pulse duration, using 
Digitimer DS7AH or DS7R, Cosyma BioStim-5 ) will be delivered to the ulnar nerve at the wrist for the 
first dorsal interosseous, median nerve at the wrist for abductor pollicis brevis, brachial plexus at the 
erb’s point for the deltoid and biceps brachii, common peroneal nerve under the head of the fibula for 
the tibialis anterior, posterior tibial nerve for soleus, and/or spinal cord segments in the 
thoracic/lumbar spine. The anode and cathode will be placed approximately 3 cm apart and 1 cm in 

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diameter with the cathode positioned proximally. The stimuli will be delivered at an intensity of 120% 
of the M-max for each muscle. 
TMS and PNS/spinal root interstimulus interval (ISI). The ISI between TMS and PNS/spinal root 
stimulation will be set to allow descending volleys elicited by TMS to arrive at the presynaptic terminal 
of corticospinal neurons ~1-2 ms before antidromic PNS/spinal root volleys reach the motoneurons 
reach during STDP. The methods for timing the arrival of volleys at the spinal cord have been 
described previously (Bunday and Perez, 2012; Urbin et al., 2017; Bunday et al., 2018). Briefly, the 
ISI will be tailored to individual subjects based on conduction times calculated from latencies of 
MEPs, F-wave, and M-max. MEP latencies will be recorded during isometric ~10% of MVC of the 
target muscle to determine the shortest and clearest response for our estimations. The onset latency 
will be defined as the time when each response exceeds 2 SD of the mean rectified pre-stimulus 
activity (100 ms) in the averaged waveform. Peripheral conduction time (PCT) will be calculated using 
the following equation:
PCT = (F-wave latency – M-max latency) × 0.5
Central conduction time (CTT) will be calculated using the following equation:
CCT = MEP latency – (PCT + M-max latency)
Upper limb training
All participants will exercise immediately after the stimulation paradigm. Upper-limb exercises will 
involve gross grasping, fine grasping, and hand cycle using an arm ergometer. During gross 
grasping, subjects will be asked to reach and grasp cylinders, blocks, cups and lids randomly 
presented on a table located in front of them at a height of ~20 cm. Then, subjects will be asked to 
reach and grasp the object to put it back on the table. These sets of movements will be repeated 20 
times for each object with breaks as needed. During fine grasping, participants will perform similar 
movements but they will be asked to reach and grasp smaller objects (peg, bead, pinch pin, cube). 
During hand cycle, the arm ergometer will be used for 15 minutes and grasping gloves will be used 
as needed. Movements will be passive, active-assisted, or active depending on participant’s ability to 
perform tasks. In addition, training will consist of grasping with the thumb and index finger targets of 
different diameters (1, 2.5, and 6 cm) in a vertical board (36x30”) positioned in front of them. The 
board will contain 6 panels (12x15”) which will light up individually by a computer cue. Each panel will 
have three LED lights to indicate grip strength to be exerted (red=30% MVC, 
blue=20% MVC, yellow=5% MVC). A reflective line in each target will identify the place to grasp, 
which will be modified to increase task difficulty. Force transducers will run along the sides of each 
target to communicate with LEDs. Kinematics and EMG signals will be acquired through surface 
electrodes. Subjects will be instructed to grasp the object between index finger and thumb as fast and 
accurately as possible holding the final posture for 3 s until the light disappear. 300 trials will be 
completed.
Lower Limb Training

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All participants exercised immediately after STDP or sham-STDP. Lower-limb exercises will involve 
over-ground walking, treadmill walking, and stair climbing training. During locomotor training, subjects 
will use a body-weight support system with ~0-70% of body weight support. During treadmill training, 
subjects will walk at a speed of 0.1-0.3 m/s for 10 minutes using the body-weight support system. 
During stair climbing, subjects will climb up and down 4 steps with 3 full repetitions. Locomotor 
training+STDP protocol: In each session, STDP stimulation will be targeting the leg muscles at rest, 
and their effects will be tested on voluntary contractions. Locomotor training will be preceded by the 
STDP protocol. The locomotor training will consist of walking. The amount of weight support will be 
provided as needed by a body-weight support system and the level of support will be associated with 
gait kinematics which resemble unsupported walking. The body-weight support system is a robotic 
over ground arrangement for practicing a wide range of activities without the risk of falling. The 
support will be adjusted within and between sessions as necessary to prevent excessive knee flexion 
during stance phase or toe dragging during swing phase (Finch et al., 1991). Subjects will be 
encouraged to walk at their comfortable speed at which step kinematics are acceptable (no toe 
dragging, an adequate knee flexion during swing phase, adequate knee extension at initial stance 
phase, etc.). All subjects will be allowed to rest as needed during the training sessions. The starting 
and end points and guiding path will be marked with lines on the floor. Thirty five retro-reflective 
markers will be attached to the participant’s body according to the Plug-In-
Gait market set. While the participant is walking on the path, joint movements will be acquired by a 
3dimensional motion capture system. The locomotor training session will consist of at least 3 
sessions are expected to be completed per week as the participant is able. Missed sessions will be 
rescheduled according to the subject’s availability. 
STUDY TIMELINE:
Participants will be initially screened over the phone or in person to ensure eligibility based on 
established inclusion and exclusion criteria. 
If eligible, participants will be asked to complete pre, post, and follow-up assessment sessions in 
addition to the training sessions. Each assessment will require 2-5 sessions. Participants will 
complete up to 135 training sessions with a maximum of 360 paired pulses of stimulation and a small 
cohort of participants (n=10) will complete up to 270 training sessions with a maximum of 720 paired 
pulse of stimulation (up to 4 times per day). This will be determined based on preliminary data. In Aim 
1, participants will be tested before and after at least 10 training sessions with single site stimulation. 
In Aim 2, participants will be tested before and after at least 40 training sessions with multisite 
stimulation. If a training session is not completed or missed participants will be asked to recover that 
session in a timely manner. 

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We anticipate that each participant will take about 2-10 months to complete the study 
procedures/testing. Follow-up assessments will be done 1-9 months after completion of protocol, 
one follow-up in the first 3 months and the last follow-up in the 4-9 months following the last 
completed session. We will evaluate the subject’s ability to move their hands, arms, legs, feet and/or 
toes using the different physiological and functional tests as mentioned above. TMS measurements, 
CMEPS and EMG recordings may also be done at these follow-up assessments.
INCLUSION AND EXCLUSION CRITERIA:
We anticipate the screening of  500 subjects across the two aims (60 subjects for Aim 1, and 40 for 
Aim 2) who have incomplete SCI at the cervical/thoracic/lumbar level (C2-L2). This number accounts 
for an attrition rate of 50%. To account for screen failures we would like to ask for a total of 200 
subjects. 
▪
Inclusion criteria for SCI subjects:
(1) Male and females between ages 18-85 years
(2) SCI at least 4 weeks post injury
(3) Spinal Cord injury at or above L2
(4) ASIA A,B,C, or D, complete or incomplete
(5) Possess the following abilities
(Aim 1) The ability to produce a visible precision grip force with one hand,
and/or the ability to perform some small wrist flexion and extension (Aim
2) The ability to perform a small visible contraction with dorsiflexion and
hip flexor muscles

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▪
Exclusion criteria for SCI Subjects:
(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)
Vascular, traumatic, tumoral, infectious, or metabolic lesion of the brain,
even without history of seizure, and without anticonvulsant medication
(6)
History of seizures or epilepsy
(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 disk
(10) Metal plate in skull
(11) Individuals with scalp shrapnel, cochlear implants, or aneurysm clips
RECRUITMENT METHODS:
We anticipate screening of  500 subjects to complete the study (see description above). We will be 
using the IRB approved SCI registry for recruitment. A letter granting access to the registry is 
included in the submission. Subjects who have previously expressed an interest in participating in 
research studies at the Shirley Ryan AbilityLab complete a questionnaire and request that their 
information be entered into the research volunteer database. This database is searchable based on 
criteria such as age, time-post injury and injury level. Potential subjects will be called by the study 
coordinator. If the individuals have not agreed to be contacted by phone for future studies then the 
treating physician will be the one contacting them. The phone call will be to provide information about 
the study to the individual to determine if they are interested in the study. We will not be collecting 
any information from the individual. All the screening will be done after written consent is collected 
and before enrollment. 
COMPENSATION FOR PARTICIPATION IN RESEARCH ACTIVITIES:
Participants will be paid $30 for each testing/assessment session (anticipated to last up ~2-3 hours). 
Participants will be compensated an additional $10/hour for each additional hour, if it is surpassed. 
There is not compensation for each of the stimulation+training sessions. The funds will be issued to 
your ClinCard when the visit is complete. The funds will be available within 1 day after being loaded 
and can be used at your discretion.

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Due to the ongoing circumstances of COVID-19, we would like to avoid having the subjects travel 
to and from the hospital with public transportation. In the event that public transportation is the 
subjects only transportation, we will ask the subject to take a Taxi/Uber/Lyft and the cost of the 
Taxi/Uber/Lyft will be reimbursed if a receipt is provided. 
Upon enrollment in the study participants will be issued a ClinCard, which is a specially designed 
debit card for clinical research. When a visit is completed, funds will be approved and loaded onto the 
card. The funds will be available within 1 day after being loaded and can be used at the participant’s 
discretion. Participants be issued one card for the duration of their participation. If the participant 
already possess a ClinCard, no new card will be issued and the funds will be loaded as appropriate. If 
the card is lost or stolen, please call (866) 952-3795 or ask a coordinator for a replacement ClinCard.
Fees are incurred if used at an ATM (fees vary by location). However, if the card is used for in-store 
or online purchases via credit or debit, or presented to a bank teller, there are no associated fees and 
no expiration date.
Please be advised: Inactivity on the card for more than 3 months will incur a monthly fee. However, 
as long as there is activity on the card within 3 months (funds are added or a transaction is 
completed), the month period will reset and no monthly fee will be assessed. If the participant do 
incur a monthly fee, please contact Greenphire Support at the number on the back of the card and 
they will reverse the fee. See “Tips for Using the Attached ClinCard” for more information. The 
Finance Department at the Rehabilitation Institute of Chicago will be provided with the participant’s 
information, including their Social Security Number, in order to issue payment for the study 
participation. Study payments are considered taxable income and reportable to the Internal 
Revenue Service (IRS). An IRS Form 1099 will be sent to the participant if the total payments are 
$600 or more in a calendar year.
The participant may be given access to new inventions that are being developed by the investigator, 
the study sponsor, or other people involved in the study. Certain laws can make it harder to obtain 
legal protection for a new invention shared with a study participant, unless the study participant 
agrees to keep information about the invention confidential. The participant agree to keep confidential 
information they may receive about new inventions, such as new drugs, new devices, or new 
methods.
WITHDRAWAL OF PARTICIPANTS:
Subjects will be allowed to withdraw from the study at any time upon request. Their participation will 
be terminated if any of the inclusion criteria ceases to be valid or if any exclusion criteria will manifest 
after enrollment. Occurrence or participant reporting of any of the following during the course of the 
study may lead to withdrawal by study team:

Page 14 of 22 IRB #: STU00209714
●Change in dosage for neuro-active medications (Baclofen, Lyrica, Celebrex, Cymbalta, Gabapentin, 
Naprosyn, Diclofenac, Diazepam, Tramadol, etc.) within 2 weeks of any study visit.
●Skull fractures, skull deficits or concussion within the last 6 months
●Unexplained recurring headaches
●Sleep deprivation, alcoholism
●Claustrophobia precluding MRI
●Pregnancy
RISKS TO PARTICIPANTS:
Muscle Activity Recording (EMG): Mild discomfort, such as tingling, an itching sensation may be felt 
under the electrodes that register the response in the participants muscles. We will clean the area 
with alcohol and use standard, hospital grade electrodes. 
Peripheral Nerve Stimulation/Spinal stimulation/MEPs/CMEPs/H-Reflex: Intensity will be increased 
gradually during the electrical stimulation evaluations when necessary. Mild discomfort, such as an 
itching sensation may be felt under the electrode that stimulates the targeted nerve(s) or under the 
electrodes that register the response in the muscle(s). We will clean the area with alcohol and use 
standard, hospital grade electrodes. Another risk of the nerve stimulation used in this research is that 
participants might feel mild pain, if pain fibers could be activated. Skin irritation due to the use of self-
adhesive surface electrodes is possible but will be minimized by cleaning the skin with alcohol before 
and after the application of the electrodes.
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. Subject Screening. The magnetic field will affect any metallic object. In order to avoid risks 
associated to heating or motion of metallic parts in the body, all individuals will be carefully screened 
and will have to complete a safety check form (separate file uploaded in the documents list). Potential 
Risks. Some individuals feel uncomfortable in enclosed spaces, as in the MRI (claustrophobia). The 
individual can stop the test at any time by squeezing an emergency stop squeeze ball he/she will hold 
in their unimpaired hand. 
JTT/9HPT/CAHAI/GRASSP/EPT/TRI-HFT: 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.
Portable Spasticity Assessment Device (PSAD): Mild discomfort, such as tingling, an itching 
sensation may be felt under the electrodes that register the response in the participants muscles. We 

Page 15 of 22 IRB #: STU00209714
will clean the area with alcohol and use standard, hospital grade electrodes. Possible skin irritation 
from the attachment of arms straps.
Neuromechanical Testing: There is the potential to cause too much stretching, which may cause pain 
or damage to the joint. A number of safety features are implemented to attempt to reduce these risks, 
such as mechanical stops and limit switches. Research staff will monitor the subject while using this 
equipment.
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, ROC stat will be contacted immediately. 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 available to minimize any type of hearing damage that might possibly occur due to 
the sound generated by the TMS equipment. An authorized study team member will be present 
during all 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 individuals 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 ROC stat. 
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 ROC stat. 
5. If the seizure lasts more than 60 seconds, activate emergency ROC stat services.
Spinal stability for inpatient subjects with cervical injuries: TMS over the primary motor cortex and 
cervical roots and also electrical stimulation applied over the brachial plexus and the spinal cord 
can general neck muscle contractions and head movement. Therefore, testing will be conducted 
using head and neck support. We will use the patient’s own cervical-collar/neck brace during 

Page 16 of 22 IRB #: STU00209714
testing. In the event a patient is not using a cervical collar/neck brace, we will provide a neck 
brace for use during testing. In addition, to ensure that there are no concerns about spine stability, 
prior to enrolling a patient with any injury level, we will get a written authorization from the patient’s 
neurosurgeon and/or SCI care physician at the SRALab approving the patients’ participation in all 
study procedures. 
Subjects Screening: Individuals with brain and spinal cord injury are commonly recruited for 
noninvasive brain stimulation studies, and providing they have no history of seizure disorder and 
do not meet any of the other exclusion criteria as determined by the TMS safety check (separate 
file uploaded in the documents list), they are a clinical population to which TMS can be safely 
applied. All individuals will be carefully screened for the following contraindications to TMS (as 
listed in the protocol, consent form, and separate TMS safety checklist): pacemakers, metal 
implants in the head region, history of epilepsy or seizures, skull fractures or skull deficits, 
concussion within the last 6 months, unexplained recurring headaches, medications that lower 
seizure threshold, and pregnancy), changes in neuro-active medication dosing within 2 weeks of 
baseline assessments and across the duration of the study. Individuals with any such 
contraindications will be excluded from the study. Therefore those individuals included will only be 
those to which TMS can be safely applied. A majority of the studies conducted by our 
collaborators over the last 10 years have included patients with brain and/or spinal cord injury, and 
no reportable adverse events have occurred during TMS interventions similar to this proposal.
Statistical Analysis:
Aim 1: Repeated-measures ANOVA and Tukey post hoc analysis will determine effects of GROUP 
(stimulation, training+stimulation, and training+sham), TIME (before, immediately after, and follow-
ups around 3 and 6 months post intervention) on physiological and behavioral outcomes. For 
alpha (type I error) of 0.05 and 1-beta (power) of 0.8, 45 SCI participants (15/group) will be 
included.
Aim 2: Repeated-measures ANOVA and Tukey post hoc analysis will determine effects training 
stimulation, TIME (before, immediately after, and follow-ups around 9 months post intervention) on 
physiological and behavioral outcomes. For alpha (type I error) of 0.05 and 1-beta (power) of 0.8, 
11 SCI participants will be included.
Audio/Video Taping: 
We plan to audio and video taping some parts of the experimental session, upon subject consent 
(optional in the consent form). Recordings will be only of the experimental activities described in 
the protocol. The subjects’ identity will be hidden if subjects do not explicit consent to be 
recognized from the video or audio. The audio and video records will be stored in a password-
protected file on a USB drive in a locked cabinet in the PI's office at the Rehabilitation Institute of 
Chicago.
The audio and video records will be used only for:

Page 17 of 22 IRB #: STU00209714
a) Medical or scientific publications;
b) Presentation at conferences;
The audio and video records will be destroyed after the time period chosen in the consent form.
This study does not involve any other risk to the subject, beyond some sense of effort and mild 
fatigue. Fatigue will be assessed based on the subjects’ verbal report. They will be explicitly 
invited to interrupt the experiment if they experience fatigue. All studies will be carried out in the 
hospital environment were medical care is immediately available if needed.
POTENTIAL BENEFITS TO PARTICIPANTS:
Participation in the experiment may result in no direct improvement or, in the rare and 
unanticipated event, worsening of the subject’s condition, including prolonged recovery time.
DATA MANAGEMENT AND CONFIDENTIALITY:
Every effort will be made to make sure that the information about the participant obtained from 
this study will be kept strictly confidential. Private information is collected about participants 
during the screening sessions as part of this study. Once the necessary information is 
collected it is placed into a secure cabinet in a locked room. 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.
PROVISIONS TO PROTECT THE PRIVACY INTERESTS OF PARTICIPANTS:
Interviews and research procedures will be conducted by approved members of the research 
team in private areas within the Shirley Ryan Abilitylab. Information to be collected will be limited 
to the amount necessary and specified in this submission to complete research specific aims and 
study goals.
COMPENSATION FOR RESEARCH-RELATED INJURY:
No compensation is available in the event of research related injury.
ECONOMIC BURDEN TO PARTICIPANTS:
Taking part in this research study will not lead to any costs to the participant. 

Page 18 of 22 IRB #: STU00209714
CONSENT PROCESS:
Subjects will be given or sent a copy of the Informed Consent form to be read before the 
consenting procedure begins. When the subject (and his/her family/friends) have had a chance to 
read the consent form a meeting will be scheduled to review the consent form, discuss study 
procedures in detail, and answer any questions the subject may have. The consent process will 
be done with either Principal Investigator or another member of the approved study team. 
NON-ENGLISH SPEAKING PARTICIPANTS:
Non-English speaking participants are excluded from our study population as we will not be 
utilizing a translator. 
PROTECTED HEALTH INFORMATION (PHI AND HIPAA):
Participants will first complete written informed consent and complete appropriate HIPPA forms 
prior to participation. A HIPPA form will be obtained from all participants. We are committed to 
respect the participant’s privacy and to keep their personal information confidential. When 
choosing to take part in this study, the participant is giving us the permission to use their personal 
health information that includes health information in their medical records and information that 
can identify them. For example, personal health information may include their name, address, 
phone number or social security number. The participant’s health information we may collect and 
use for this research includes:
•
Medical history
•
Results of physical examinations
•
Questionnaires
•
Records about study devices
•
Billing information

Page 19 of 22 IRB #: STU00209714
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Appendix 2
Medications that may lower seizure threshold
Intake of one or a combination of the following drugs forms a strong potential hazard for application of 
TMS due to their significant seizure threshold lowering potential: imipramine, amitriptyline, doxepine, 
nortriptyline, maprotiline, chlorpromazine, clozapine, foscarnet, ganciclovir, ritonavir, amphetamines, 
cocaine, (MDMA, ecstasy), phencyclidine (PCP, angel’s dust), ketamine, gamma-hydroxybutyrate 
(GHB), alcohol, theophylline.