Recovery of Cardiovascular Function With Epidural Stimulation After Human Spinal Cord Injury
Phase: NA
Conditions: Spinal Cord Injury
Sponsor: University of Louisville

Protocol Title: Recovery of cardiovascular function with epidural stimulation after 
human spinal cord injury 
 
Version Date: 09/27/2017 
 
 
NCT Number: NCT02037620 

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Applicant’s 
Name: 
Susan J. Harkema, Ph.D. 
Institution: 
Christopher & Dana Reeve 
Foundation 
Project Title: 
Recovery of cardiovascular function with epidural stimulation after human 
spinal cord injury. 
 
Overall Objective: We propose to demonstrate that epidural stimulation (ES) can be used to 
recover significant levels of autonomic control of cardiovascular and respiratory function as well 
as the ability to voluntarily control leg movements below the injury level. This intervention 
would provide an immediate therapeutic alternative to individuals who now have no recourse for 
treatment. The reduction in the cost to the health care system, care givers and society would be 
dramatic. 
Introductory Statement and Background:  In the context of studies of human locomotion, we 
made the astonishing observation that three individuals who had been diagnosed as clinically 
motor complete (unable to voluntarily activate muscles below their level of lesion) developed the 
ability to voluntarily move their toes, ankles, knees and hips only in the presence of tonic ES of 
the lumbosacral spinal cord when also receiving intense locomotor training [1]. Even more 
surprising, over a period of months, they reported improved temperature regulation, bowel and 
bladder function, and normalized sexual activity. We also measured significant improvements in 
cardiovascular and respiratory function that persisted throughout the day even without 
stimulation. 
Cardiovascular Function. Cardiovascular diseases are the leading cause of morbidity for 
individuals with SCI [2]. Reduction in peripheral blood flow increases the risk of pressure ulcers, 
parasympathetic imbalance increasing vasovagal syncope, fatigue and cognitive dysfunction, and 
symptomatic orthostasis which are manifestations of the reduced quality of life experienced by 
these patients [3-5]. With time, post injury episodes of orthostatic hypotension and autonomic 
dysreflexia become more prominent and persist in many individuals with cervical and high 
thoracic injury for the rest of their lives [3, 5, 6]. The causes of orthostatic hypotension in 
individuals with SCI are multifactorial and can be classified into either neurogenic (related to 
injury to the autonomic nervous system which controls cardiovascular function and has tracts 
through the spinal cord) or other physiologic consequences of SCI [3-5] . Other conditions that 
could contribute to orthostatic hypotension following SCI include altered baroreceptor 
sensitivity, lack of skeletal muscle pumps, cardiovascular deconditioning, altered salt and water 
balance and altered cerebral vascular autoregulation. A combination of sympathetic agonists and 
venous compression devices are the only measures available for treatment of these symptoms. 
We propose that cardiovascular control is mediated by the spinal cord as the key integrator of 
complex signals from the periphery and from supraspinal centers in the brain stem (Figure 1). 
This spinal circuitry is moment by moment driven by peripheral input modulated plasticity to 
optimize the systemic blood pressure and heart rate. We have demonstrated in rats with chronic 
SCI that the sacral cutaneous or visceral afferents produced significant activation of the 
sympathetic activity within the renal nerve and correspondingly significant alteration in arterial 
blood pressure [6]. ES in the absence of descending input can modify the excitability of the 
relevant spinal interneuronal pools allowing them to respond to peripheral autonomic input and 
approximate normal cardiovascular control. It is also possible that ES restores conduction 
properties of residual damaged or non-functional, but anatomically intact axons across the spinal 
injured segment. If this is the case, then ES alone without the cardiovascular stress of stand 
training should restore near normal cardiovascular control. If, however, the spinal cord circuitry 

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is the key controller, then stand training with ES will be needed to optimize autonomic function. 
The ultimate goal is to develop appropriate parameters for ES that will activate spinal 
sympathetic circuits sufficient to maintain a more normal arterial blood pressure. If we can 
improve the management of this secondary complication of SCI, we would not only improve the 
health of this disadvantaged population but also dramatically reduce health care expenditures. 
Respiratory function. Respiratory complications result in death and ongoing health problems in 
people with chronic SCI [2]. Following SCI, control of respiratory muscles innervated from 
within and below the injury zone is altered leading to paralysis [7, 8] and respiratory function 
deficits [9] which significantly impede recovery [10] and diminish quality of life [11]. Exercise 
programs involving limb muscles are known to increase fitness and improve ventilatory function 
in individuals with chronic SCI [12, 13]. However, none of the respiratory rehabilitative 
modalities have yet been proven to be clinically effective in patients with chronic SCI [14]. 
Preliminary results of locomotor training studies from our center indicate that the locomotor step 
training in individuals with motor complete SCI leads to increased spinal motor output to 
respiratory muscles, but does not improve the voluntary initiated respiratory muscle activating 
patterns. It has been shown that spinal networks for locomotion and respiration are closely 
related [15]. However, the three individuals who received ES increased their respiratory 
capacity. Therefore, based on our observations, we hypothesize that ES of the lumbosacral spinal 
cord will lead to re-activation of respiratory motor control and task specific training may enhance 
this effect in individuals with clinically motor complete SCI. 
Restoration of voluntary control of movement. The critical role of the corticospinal tract in 
generating voluntary movements with the spinal cord simply being a conduit of these signals in 
primates has long been a widely held belief. This premise then limits the options for recovery to 
paralysis only occurring with repair or regeneration of these pathways. Our recent observations 
of three individuals with motor complete injury regaining the ability to voluntarily move their 
hips, knees and ankles upon command only in the presence of ES (Figure 2) challenges this 
theory and provides a novel treatment strategy for paralysis. The conceptual basis of our 
approach is that epidural stimulation combined with task-specific training re-engages existing 
spinal circuits and challenges novel post-injury circuitry to reorganize in functionally significant 
ways [1, 16, 17]. We provide a cellular environment that enables sensory-motor and autonomic 
circuits to recover significant levels of function. We are capitalizing on the inherent functional 
capacity that is built into these systemic circuits. Another point of significance in our approach is 
the high level of functional interdependence among the many physiological systems impacted by 
complete motor paralysis. The first motor complete subject studied, who has trained to stand and 
to voluntarily move his legs with ES for over 2 years, showed restoration of cardiovascular, 
respiratory, bladder, bowel, temperature regulation and sexual function in addition to recovery of 
movement and ability to stand. 
Preliminary Data: Preliminary data in one motor complete quadriplegic patient with chronic 
hypotension and symptomatic orthostasis have shown that with optimized epidural stimulation 
parameters, we can maintain systolic blood pressure (SBP) 20% above his nadir and prevent 
symptomatic hypotension. 
  
 

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Rationale: We propose to determine the functional gain that can be achieved in voluntary 
control of movements below the level of injury and autonomic nervous system function as a 
result of activation of spinal circuits with epidural stimulation (ES) in humans with paralysis. In 
addition to the scientific advances, the proposed experiments are essential to translating this 
therapeutic approach to a larger scale, which is needed to have a meaningful clinical impact. ES 
for recovery of neurological function in patients with severe SCI is not widely used because of 
uncertainty regarding the mechanisms of action and convincing evidence of efficacy in a larger 
numbers of subjects. Our approach will allow us to determine specific types of ES needed for 
Figure 1. Continuous 
blood pressure and 
heart rate recordings 
from the individual with 
cervical motor complete 
SCI during standing (A) 
and sitting (B) with and 
without epidural 
stimulation. 
Figure 2. Lower extremity EMG activity 
during voluntary movement occurred only 
with epidural stimulation in three 
individuals with motor complete spinal 
cord injury. EMG activity from a subject 
B07 during voluntary attempts of left hip and 
knee flexion (A) without stimulation at 27 
and 7 months prior to implantation; (B) 
without out stimulation (left panel) and with 
stimulation (right panel). EMG activity during 
attempts of ankle dorsiflexion without 
stimulation (top panels) and with stimulation 
(bottom panels) (C) from B07 (D) from 
subject A45 and (E) from subject B13. 
Muscles, surface EMG: Upper trapezius 
(UT), intercostal (IC), adductor magnus (AD), 
vastus lateralis (VL), medial hamstrings 
(MH), tibialis anterior (TA), soleus (SOL); 
fine wire EMG: iliopsoas (IL), extensor 
digitorum longus (EDL), extensor halluces 
longus (EHL). Black bars represent the 
command to flex and white bars represent the 
command to relax. Gray highlighted indicates 
verbal command to ‘flex’. Blue indicates 
tonic stimulation. 

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voluntary movement and autonomic nervous system dysfunction which lays the groundwork for 
expedient translation to larger numbers of individuals with SCI. 
Current clinical methods of diagnosis of clinically complete SCI may not be sensitive enough 
to detect residual functional synapses across the lesion [18]. We propose to use a series of 
neurophysiological approaches that can detect different sources of supraspinal influence on 
spinal circuitry and identify specific pathways including vestibulospinal, reticulospinal, 
corticospinal and long propriospinal pathways that may remain viable or emerge with ES and 
task specific training after complete motor paralysis [19-32]. Such residual connectivity would 
be identified by the presence of voluntarily controlled movement or evoked motor potentials 
occurring only in the presence of epidural stimulation. Identifying the essential supraspinal-
spinal pathways needed to recover these voluntary movements will advance our knowledge of 
human neural control of movement and provide critical information for developing repair and 
regeneration strategies and in determining the type and severity of patient that could benefit most 
readily in regaining voluntary control using epidural stimulation. 
 
Research Plan: 
1. 
Specific Aims 
a. Specific Aim 1. Demonstrate whether cardiovascular dysfunction improves in 
response to ES and stand training. 
Hypothesis 1.1: ES and stand training will significantly increase resting 
systolic blood pressure (SBP) and diastolic blood pressure (DBP) and 
decrease heart rate (HR) to a greater extent than ES alone. 
Hypothesis 1.2: Serum catecholamine levels will increase with ES and to a 
greater extent with ES and stand training. 
Hypothesis 1.3 Cardiac structure and function will improve with ES and to 
a greater extent with ES and stand training. 
a. End systolic and end diastolic volumes 
b. Systolic function and ejection fraction  
c. Cardiac Output 
Hypothesis 1.4 Orthostatic hypotension and orthostatic tolerance will 
improve with ES and to a greater extent with ES and stand training. 
Hypothesis 1.5 Arterial stiffness will decrease with ES and to a greater 
extent with ES and stand training. 
Hypothesis 1.6 Metabolic indices will improve with ES and to a greater 
extent with ES and stand training. 
The changes in cardiovascular function in individuals who received stand training and ES could 
have been induced by the ES alone or may have required the combination of ES and stand 
training. Since these individuals had received extensive stand and step training without these 
changes in cardiovascular parameters prior to the ES implant, the changes could not be attributed 
to the training alone. Thus ES in combination with stand training may be needed to regain 
vascular tone and reactivity. Peripheral autonomic control is lost with spinal cord damage above 

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the level of sympathetic output to the sympathetic ganglia. In individuals without neurologic 
injury who were subjected to weightlessness, experienced loss of cardiovascular control as 
observed with astronauts experiencing orthostatic hypotension, syncope on standing, and 
tachycardia [3]. Changes in blood distribution occur with postural changes. These blood 
distribution changes stimulate peripheral autonomic nerves that activate smooth muscles, 
reducing the capacitance of the vasculature and increasing cardiac return, preventing decreases in 
SBP and increases in heart rate. 
b. Specific Aim 2. To evaluate whether task specific training combined with ES can 
improve pulmonary function and restore activation of respiratory muscles in 
individuals with SCI. 
Hypothesis 2.1: Task specific stand training using ES parameters optimized 
for standing will result in more successful generation of voluntary 
respiratory muscle activation than ES without this task specific training. 
The combination of stand training, specific for functional spinal proprioceptive activation, with 
ES, needed to increase the locomotor and respiratory spinal network responsiveness, might be 
required for successful respiratory reactivation. If voluntary movement training and stand 
training with ES will lead to the bigger respiratory effect, it will indicate that ES might facilitate 
both the strengthening of supraspinal and spinal pathways specific for locomotion and 
respiration. 
c. Specific Aim 3. Identify mechanisms of restoration of voluntary movement with 
ES after paralysis. 
Hypothesis 3.1: Task specific voluntary movement training using ES 
parameters optimized for voluntary movement will result in more 
successful voluntary movements than ES for cardiovascular function. 
Hypothesis 3.2: Task specific stand training using ES parameters optimized 
for standing will result in more successful generation of voluntary 
movements than ES without task specific training. 
We propose that the spinal circuitry is the key integrator of complex signals from the periphery 
and supraspinal centers that drive the final motor pool output. We predict that the circuitry is 
continuously adapting to activity-dependent events that functionally configure the spinal 
networks to optimize generation of a specific motor task. Another possibility is that the ES 
retrogradely stimulates residual axons that anatomically crossed the lesion but were not 
functional. Also, the ES could restore the conduction properties that were lost with 
demyelination or other consequences of damage [1, 16, 33-36]. If only the restoration of the 
conduction of the residual supraspinal connections is needed, then the ES alone without 
voluntary or stand training should be sufficient to restore voluntary movement of the legs. 
However, if the spinal cord circuitry is a key controller, then task specific training of voluntary 
movement in the presence of ES will also be required to optimally generate voluntary movement. 
Stand training with ES may also be required for the recovery of voluntary movement given 
that the nervous system evolved in an anti-gravity environment and information related to load 
bearing has been shown to be a critical factor in modulation of neural activity [1, 37, 38]. 
Astronauts and research animals who are neurally intact return to earth with neural disorders 
such as spasticity and clonus that are common to individuals with spinal cord injury [39], 

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indicating that loss of load related sensory information drives neural plasticity that results in 
deleterious effects. Then weight-bearing with ES would also result in successful voluntary 
movement. The most efficacious approach may be the combination of ES with voluntary training 
and ES with stand training. 
Given that each of our subjects to date has received stand training as well as training for 
voluntary movement of the limbs it may require the combination of stand training and ES to 
recover and improve voluntary movement. To some degree, even when standing, there is 
undoubtedly some critical element of voluntary control of posture and balance, and it seems 
almost inevitable that there will be some overlap of the circuitries of voluntarily moving the 
lower limbs when bearing weight as well as when one is not load bearing. 
 
d. Specific Aim 4. Identify supraspinal descending pathways that could contribute to 
the restoration of voluntary movement with ES after paralysis. 
Hypothesis 4.1: Stand training using ES parameters optimized for stand 
and voluntary training using ES parameters optimized for voluntary 
movement will significantly increase the amplitudes and decrease the 
latencies of evoked potentials of the leg muscles using transcortical 
electromagnetic stimulation (corticospinal) as well as facilitate the 
monosynaptic excitability of motoneuron pool of m.Soleus (H- reflex) after 
conditioning galvanic vestibular stimulation vestibular stimulation 
(vestibulospinal), an audio startle reaction (reticulospinal), and stimulation 
of the ulnar nerve (propriospinal).  
Hypotheses 4.2: Voluntary movement training using ES parameters 
optimized for voluntary training will significantly increase the amplitudes 
and decrease the latencies of evoked potentials of the leg muscles induced 
by stimulation of the cortex (transcortical electromagnetic stimulation). 
Hypotheses 4.3: Stand training using ES parameters optimized for stand 
training will significantly facilitate H-reflex and/or increase the amplitudes 
and decrease the latencies of evoked potentials of the leg muscles after 
conditioning with galvanic vestibular stimulation (vestibulospinal), 
induction of an audio startle reaction (reticulospinal), stimulation of the 
ulnar nerve (propriospinal) or by applying transcortical electromagnetic 
stimulation (corticospinal), demonstrating an activity-dependent effect on 
all supra-spinal pathways connectivity. 
Hypotheses 4.4: The anatomical and axonal integrity of the neural tissue in 
the spinal cord (according to MRI) will have a positive relationship to the 
degree of restoration of voluntary movement after complete motor 
paralysis. 
Experimental activation of descending motor tracts on leg muscles and the soleus H-reflex have 
been studied extensively in humans using cortical stimuli to activate the corticospinal tract [27, 
30, 32], galvanic stimulation to activate the vestibulospinal tract [19, 21-24], auditory stimulation 
to activate the reticulospinal tract [29], and sensory stimuli to activate long propriospinal tracts 
[20, 25, 26, 28, 31]. The unique aspect of this proposal is that we will customize these 
experimental paradigms by conducting the neurophysiological assessments of all three prominent 

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descending pathways and the long propriospinal pathways together to comprehensively assess 
the extent of residual descending and long propriospinal pathways’ viability in the spinal cord 
injury population [19-21, 23-25, 28, 40-65]. A soleus H-reflex recruitment curve and the 
conditioning stimulation paradigms (i.e. transmagnetic, galvanic, auditory startle, or ulnar nerve) 
specific to each pathway will be conducted. The amplitudes and latencies of the soleus H-reflex 
will be calculated. 
2. Methods and Procedures 
a. General Experimental Design. We will enroll 5 research participants who have 
sustained a SCI to participate in the proposed experiments. Our novel approach of conducting 
repeated experiments with comprehensive assessments in a smaller cohort of patients rather than 
a more traditional approach of including a large number of patients and focusing on a single 
outcome allows advancing both clinical and scientific knowledge. We have found success with 
the smaller cohort approach because we can employ more rigorous, quantitative and sensitive 
outcomes that not only inform us about the potential clinical efficacy but also provide further 
knowledge of the mechanisms of neural control of movement and other physiological 
mechanisms related to cardiovascular, respiratory and function and voluntary control of 
movement. 
b. Research participant enrollment. Each research participant will be screened for 
medical eligibility by the neurosurgeon and physiatrist and for scientific eligibility by the site 
principal investigator (see Human Subjects section below). After eligibility is determined and 
consent procedures are implemented, the individual will undergo all clinical and 
neurophysiological assessments for voluntary movement, cardiovascular and respiratory 
function. Magnetic resonance imaging (MRI) will be conducted at the time of enrollment to 
establish structural integrity of the nerve tissue and to establish the severity of injury and diffuse 
tensor imaging to establish the axonal integrity. A standard MRI of the area of injury will be 
conducted and it will be read by a radiologist and the following measures will be made: 1) the 
number of sagittal cuts in which the signal change is present, 2) maximum height of signal 
change, 3) maximum area of signal change, 4) maximal canal compromise will calculated 
(MCC) and 5) maximal spinal cord compression (MSCC). All of these measurements will be 
made on the mid sagittal view. 
Participants will continue with their current daily activities for 80 consecutive days without 
any intervention (usual care) followed by all assessments. Surgical implantation of the 5-6-5 
Specify or  5-6-5 Specify SureScan MRI electrode, and Restore Advanced or RestoreAdvanced 
SureScan MRI Pulse generator, (MEDTRONIC, Minneapolis, MN, USA) encompassing the 
lumbosacral spinal cord guided by neurophysiological mapping will then occur (implant). 
Surgical  Procedure  (Implantation of Medtronic Specify™ 5 -6-5 or  Medtronic Specify™ 5 -6-5 
SureScan MRI):  Thoracic epidural stimulation is an operation that is commonly performed by 
neurosurgeons or pain management physicians for the treatment of intractable pain and spasticity 
involving the lumbar spine and legs. In this study, we will be inserting electrodes into the 
thoracic epidural space below the level of a spinal cord injury. 
The Medtronic Specify 5-6-5 or Specify 5-6-5 SureScan MRI (Minneapolis, MN) 16-electrode 
epidural arrays and battery pack will be used and the operation will be performed at University 
Hospital in Louisville, KY. Two large bore IV cannulas, a urinary catheter, and endotracheal 
tube will be inserted. Muscle relaxant medications will be avoided which will allow motor 
evoked potentials to be performed intraoperatively. Prophylactic antibiotics will be administered 
intravenously with maintenance of adequate blood pressure. The patient will be placed in the 

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prone position on the operating table with all pressure points being well-padded, particularly 
over the pelvis, knees, abdomen, and eyes. A midline incision will be made in the thoracolumbar 
area, with dissection carried deeply to the laminae. A cross-table lumbar spine X-ray will be 
performed to confirm the correct level. An L2-L3 laminectomy will be performed to provide a 
site for insertion of the epidural electrodes. The Specify 5-6-5 or Specify 5-6-5 SureScan MRI 
electrode will be passed along the dorsal aspect of the epidural space in a cephalic direction to 
the T11-L1 level. Fluoroscopy using the O-arm will be used to confirm the position of the 
electrode. Neurophysiological parameters will be utilized to determine optimal lead placement 
by monitoring the motor system using electrical stimulation of the spinal cord at the T11-L1 
spinal segmental levels. Electrophysiological tests will be performed under the direction of Dr. 
Harkema. If appropriate motor responses cannot be obtained initially, the electrode will be 
repositioned as many times as required in order to obtain optimal motor responses from the legs. 
Optimal position of the electrode will cover L1-S1spinal levels. The wire lead connected to the 
Specify 5-6-5 or Specify 5-6-5 SureScan MRI electrode will be sutured tightly to muscle to 
prevent its being dislodged. The surgical incision will be closed in layers, and a wire connected 
to the epidural electrode will be passed through the subcutaneous layer and tunneled 
subcutaneously to exit through the skin about 4 inches to the right of the midline. A sterile 
dressing will cover the external wire, and the midline incision will be closed. 
The next part of the operation will be performed while the patient is in the supine or side 
position. The patient will be turned from the prone to the supine/side position keeping the area of 
the external wire exit sterile. The abdomen, lower thoracic area, and right flank will be prepped 
using betadine soap. A lower abdominal incision will be made approximately 4 inches in length 
and will be carried to the subcutaneous area directly external to the abdominal muscle layer. A 
wire passer will be threaded circumferentially to the lateral flank incision to the site of exit of the 
electrode wire to allow the distal portion of the electrode wire to be threaded through the wire 
passer. The distal (abdominal) aspect of the electrode wire will be attached to the battery pack of 
the Specify 5-6-5 or Specify 5-6-5SureScan MRI electrode. The battery back will be buried in 
the subcutaneous tissue directly external to the abdominal muscle. The battery pack will be 
sutured to muscle in order to prevent its migration. The surgical field will be irrigated using 
antibiotic solution to minimize infection. The abdominal incision will be closed in layers. The 
patient will be taken from the operating room and transferred to the recovery room. 
The patient will be kept in the recovery room for 4-6 hours. He or she will stay overnight at 
University Hospital for monitoring and then will be transferred to the Frazier Rehab Institute or 
home. The patient will be monitored for blood pressure, pulse, and temperature changes. Fluid 
output will be recorded hourly to maintain appropriate homeostasis. The dressing over the 
incision will be changed 24 hours postoperatively. The patient will be discharged home and a 
research nurse will make daily visits to change dressings and check on the incision. The patient 
will recover at home for 2-3 weeks prior to any testing or stimulation is started. 
ES is administered by a multi-electrode array implanted in the epidural space over the dorsum of 
cord. An implanted package containing stimulating circuits, rechargeable battery, and wireless 
communication activates the electrodes (16 platinum electrodes arranged in three columns of [5-
6-5]). The pattern of electrically active electrodes, as well as electrode voltage, stimulating 
frequency, and stimulating pulse width can be remotely programmed. Since different spatial 
activation patterns and different frequency parameters affect different spinal circuits, the array 
can be reconfigured, within limits, to bias its facilitating effects toward different activities, such 
as cardiovascular control or voluntary movement. 

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Clinical and neurophysiological assessments will be repeated post implantation. Mapping of the 
motor evoked responses in response to spatial and amplitude/frequency responses [66] will be 
conducted and the specific configurations and parameters optimal for voluntary movement, 
standing and cardiovascular function will be identified.  
The individual will then undergo ES stimulation optimizing cardiovascular function for 80 days 
for 2-6 hours per day (Appendix A). In our pilot data from the first three individuals, we 
observed in two individuals that as they continued stimulation they were able to maintain normal 
blood pressure levels without stimulation for some periods of time.  In one individual, the 
stimulation was always needed to maintain systolic blood pressure within normal ranges, 
however if allowed to stimulate for longer periods of time they may have reached normal ranges 
without needing ES.  Thus, the protocol now reflects ES time periods customized to the actual 
modulation of the blood pressure for each individual.  The individual will monitor their blood 
pressure and use the stimulator during those periods when their systolic blood pressure is outside 
the targeted range.  The individual chooses the time periods during the day they will use the 
stimulator with a minimum of 2 hours each day.  In situations that 2 hours of continuous 
stimulation occurs, a break of at least 15 minutes of no stimulation should occur before resuming 
stimulation again. Cardiovascular ES is limited to 6 hours each day.  Each session of ES can be 
less than 2 hours if the blood pressure remains within the targeted range without stimulation.  
Stimulation periods will be conducted and observed in the laboratory before being approved to 
be done in the home. 
The same clinical and neurophysiological assessments again will be repeated (Post CV 
Training). The research participant will then undergo ES for voluntary movement (VM) sessions 
for 80 days for 2 sessions  per day, in addition to continuation of ES for CV function. The CV 
sessions can be conducted at home. The voluntary sessions will be conducted both in the 
laboratory and at home.  Each voluntary session will be focused on the leg and/or trunk.   The 
remote device records the minutes of stimulation and parameters used so these will be collected 
on those days the research participants are not in the laboratory. For approximately the first 5 
sessions of each intervention (CV or VM), the sessions may be conducted in the laboratory under 
the supervision of the investigators. The optimal parameters will be identified and programmed 
into the remote device. For the following sessions, the research participants will come to the 
laboratory at least once every 2 weeks and CV and VM parameters will be evaluated. The final 5 
sessions may also be conducted in the laboratory (monitoring purposes, if necessary). The 
research participant will then complete the same clinical and neurophysiological assessments 
(Post VM Training).  
In our previous early feasibility studies we have found that the intensity (daily session number) is 
a critical factor in the recovery of voluntary and independent standing recovery.  The first three 
research participants in this pilot study did not regain sufficient independent standing to be able 
to take the Stand-ES to their home environment unlike those in our other study who had training 
twice a day.  Thus, now in the final intervention we will include daily stand training sessions 
once or twice a day (1-hour each) with ES stimulation parameters optimized for standing for 80 
sessions. Research participants will participate in 2-6 hours of cardiovascular and 2-4 hours of 
voluntary parameters outside of the stand training session.  Total daily stimulation time will be 6-
10 hours. All stand training and ES sessions will be conducted in the laboratory. Approximately 
every 10 sessions the cardiovascular and voluntary sessions may be conducted in the laboratory 
(monitoring purposes, if necessary). Then the final clinical and neurophysiological assessments 
will be conducted (Post Stand Training). 

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After the training and experiment period has ended, research participants will be released with a 
list of approved programs based on investigator review. When the individual returns for a 
follow-up visit, the time the research participant used each program will be downloaded from the 
stimulator. 
Cardiovascular Function (Specific Aim 1): 
Orthostatic Stress Test (with and without catecholamine blood draw) will be assessed in the 
morning in a quiet, temperature-controlled (~22 C) room. After arriving, participants will be 
asked to empty their bladder before beginning the study. A butterfly catheter will be inserted into 
an antecubital vein during instrumentation to allow the collection of blood without additional 
stress to the participant by appropriate clinical staff. Continuous arterial BP will be acquired 
from a finger cuff placed around the ring, middle, index finger or thumb (Finapres Medical 
Systems). The hand will be placed in an arm sling and kept at the level of the heart throughout 
the study. Manual arterial blood pressure measurements will be taken throughout the study with 
a digital blood pressure measurement device or via the auscultation method. A three or twelve-
lead ECG (ML132, AD Instruments) will be placed for ECG monitoring. Rib cage and abdomen 
kinematics (respiratory kinematics) will be acquired using an inductive plethysmograph. 
Baseline recording for 15 minutes will begin after a 3-5 minute rest period that will follow 
subject preparation. At the end of 15-minute recording in the supine position, participants will be 
passively moved into the upright seated position (tilt chair) or upright position (tilt table). This 
position will be maintained for 15-18 minutes. Then the participants will be passively moved to 
the supine position for 10-15 minutes. Eight milliliters of venous blood will be drawn from an 
antecubital vein at the end of 15-minute supine to assess baseline catecholamine levels. Blood 
draw will be repeated at 3 min and at the end of 15 minutes of upright position. The test will be 
aborted if subjects become lightheaded or symptomatic of syncope. The Hemodynamic Test 
during standing, upright, sitting and supine positions with and without ES will be recorded using 
a Finapres system as described above. This assessment may be performed with and without 
epidural stimulation. 
 
Blood pressure lability: 24-hour blood pressure monitoring (Specific Aim 1) and Heart Rate 
Variability: ECG Holter Monitor 
Continuous blood pressure monitoring will be recorded over a period of 24 hours outside the 
lab (Meditech ABPM, Budapest, Hungary). In regards to the severity of AD, the participant’s 
signs of OH (e.g. yawning, pallor) and subjective symptoms (e.g. light-headedness, dizziness) 
will also be assessed using validated autonomic questionnaires. Continuous ECG will be 
recorded over a period of at least 24 hours outside the lab with a 3,7 or 12 lead Holter monitor 
(EDAN Instruments, Inc). 24-hour measurements will be repeated throughout the training 
interventions.   
 
Ultrasound: Measurements will be taken with and without epidural stimulation. 
Arterial Stiffness (Specific Aim 1) 
Arterial Pulse Wave Velocity (aPWV m/s) will be measured non-invasively and 
calculated by dividing the distance between measurement sites by the pulse transit time. 
Distance between the arterial measurement points will be measured using measuring tape 
along the surface of the body, held parallel to the testing table. The pulse transit is 
determined from the arterial blood pressure waves, which are collected at each arterial site. 
A pen-like device (model SPT-301; Millar Instruments Inc., Houston, TX) or Complior 

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Pulse Wave and Central Pressure Analyzer (Alam Medical, Vincennes, France) sensors will 
be applied to the carotid, femoral, brachial and other arterial sites using a light pressure to 
obtain arterial pressure waves. Heart rate will be recorded using a single-lead (lead I) 
electrocardiogram (ECG) (model ML 123, AD Instruments Inc., Colorado Springs, CO). 
Arterial structure: Wall thickness and lumen diameter (Specific Aim 1) 
Brachial and femoral arterial images will be collected using B-mode ultrasound for 10 
cardiac cycles. Images will be analyzed using internal ultrasound software to determine 
lumen diameter and intima-media thickness. 
Cardiac structure and function (Specific Aim 1) 
Cardiac images will be collected non-invasively using Doppler ultrasound (GE 
Healthcare or Philips Healthcare) in a supine and seated position. Briefly, apical four and 
two-chamber views, and parasternal short and long-axis views will be collected and stored 
on the ultrasound for offline analysis. Indices of interest will include but not limited to: 
volumes (end systolic (ESV), end diastolic (EDV), diameters (intraventricular septum 
systole (IVSs) and diastole (IVSd), left ventricular internal diameter systole (LVIDs)), 
systolic function (left ventricular posterior wall systole (LVIDd) and diastole (LVPWd), 
ejection fraction (EF), cardiac output (CO), fractional shortening, mitral regurgitation 
(dP/dT)) and diastolic function (E/A, E/e’ ratio, IVRT, DT). 
International Autonomic Standards Evaluation (Specific Aim 1) 
Until recently individuals with SCI were only examined with use of motor and sensory 
neurological standards in order to establish the level and the severity of the neurological 
impairment or AIS (American Spinal Injury Association Impairment Scale) resulting from the 
SCI. During the last decade, International Autonomic standards for evaluation of individuals 
with SCI were developed and implemented around the world (76). These short standardized 
forms collect data on cardiovascular (AD and OH) as well as other autonomic dysfunctions 
including bladder bowel and sexual dysfunctions. 
Body Composition (Specific Aim 1) 
DXA: Weight, height, and total body fat will be determined from a dual energy x-ray 
absorptiometry (DXA) scan (Hologic QDR 4500W, APEX System Software Version 2.3) at 
Jewish Hospital, performed in the supine position. Waist circumference will be measured in the 
supine position following a normal expiration, to the nearest 1cm midway between the lowest 
lateral border of the ribs and the uppermost lateral iliac crest. Waist circumference is considered 
the most practical bedside measurement of visceral adipose tissue. Hip circumference will be 
measured supine over the widest part of the femoral great trochanter. Waist/hip ratio and body 
mass index (measured weight in kilograms divided by the measured height [meters2]) will be 
calculated. Total body fat will be reported as total body fat in kilograms, and as a percent of total 
body weight determined by DXA scan. Height (length) will be measured using the electronic 
ruler function and weight from the DXA scan table scale feature. This is the preferred measure 
for assessing total body fat and has strong agreement with cadaver and chemical composition 
studies. Recent studies comparing DXA to CT and MRI have confirmed the validity and 
reliability of DXA to assess abdominal adiposity [26]. In addition, its ease of use makes it ideal 
for  studying large populations. All scans will be performed with a (Hologic Discovery QDR 
4500W (Hologic Inc., Bedford, MA), which has an error of less than 1% for body fat scans. An 
experienced technician will conduct scans according established protocol. All participants will be 
scanned with this methodology to ensure high internal validity (Intervention Protocol Version 
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BOD POD Body Composition:  
Procedure:  The BOD POD is an air displacement plethysmograph that measures body 
composition, fat mass, fat-free mass, thoracic gas volume, and estimates resting metabolic rate. 
Participants will be asked to sit in the scanner, remaining still during the test. The full test requires 
only about 5 minutes and includes multiple short (about 40 seconds) volume calculations. The last 
scan for thoracic gas volume will only be conducted with individuals capable of holding the 
breathing tube to their mouth. Men will be asked to wear a form-fitting Lycra/spandex-type swim 
suit or single-layer compression shorts with no padding. Women will be asked to wear a form-fitting 
Lycra/spandex-type swim suit or single-layer compression shorts without padding and a single layer 
(not padded) sports bra.  Participants may be asked to repeat the procedure. 
Analysis: Body composition, fat mass and fat-free mass will be calculated by the Cosmed BOD 
POD software package based upon the measured or predicted thoracic gas volume and the equation 
of the chosen model. Resting Metabolic Rate is estimated from the thoracic gas volume and the 
activity level that the research participant self-reports. The Brozek and Siri models (based on sex 
and ethnicity) are standard with the software package. Additional models can be built into the 
software.  
Metabolic Parameters (Specific Aim 1) 
Blood draws: A trained technician will draw a venous blood sample. Participants will 
undergo a 12-hour fast the night before, including no food or drink including alcohol or 
caffeine (water is permitted). A complete blood count (white blood cells and differentials, 
erythrocytes, packed cell volume, hematocrit, platelets, hemoglobin and red cell indices) 
will be performed. Blood glucose control (HbA1c), fasting glucose, fasting insulin, 
atherogenic dyslipidemia (triglycerides, TC, LDL-c, HDL-c, TC/HDL-c), a pro-thrombotic 
state (PAI-1 and TAFI), a pro- inflammatory state (IL-6, and TNF-α), leptin, adrenal control 
(angiotensin, aldosterone and renin) will also be measured. Blood samples for PAI-1, TAFI, 
IL-6, and TNF-α will be analyzed using enzyme-linked immunosorbent assays (ELISA). 
Plasma levels of lipid and hemoglobin A1c will be analyzed through laboratory services 
using a Dade Behring RxL Max analyzer. This system has demonstrated very good intra and 
interassay reliability for lipid and glucose measures. A comprehensive drug screen 
(urinalysis or blood draw) will be done to assess the use of combustible drugs (nicotine and 
other drugs that can be smoked) 
Aerobic Fitness Evaluation: Peak oxygen uptake test (VO2peak) (Specific Aim 1) 
Participants will perform an exercise regimen. Participants will be asked to not perform 
any moderate or heavy exercise 12 hours prior to the test. Resting ECG, blood pressure 
(DinamapCarescape V100; GE Healthcare, Buckinghamshire, UK) and respiratory measures 
(ParvomedicsTruemax 2400, Sandy, UT, USA) will be collected two minutes prior to 
exercise. Heart rate will also be monitored with a chest strap heart rate monitor (Polar T31 
heart rate monitor, Polar Electro Inc., Woodbury, NY, USA). Continuous blood pressure 
and heart rate will also be measured using the Finapres acquisition described in the 
orthostatic stress test. Each participant will perform a graded exercise test (GXT) on a total 
body recumbent stepper (NuStep T4 ergometer, Ann Arbor, MI) to measure VO2max. For 
participants with tetraplegia who have limited handgrip function, tensor bandages will be 
used to secure hands to the ergometer handles. For those participants unable to perform the 
test on the NuStep, an arm ergometer test protocol will be administered [29, 53]. 
Participants will be instructed to maintain a cycling rate of 60 rev/min for the duration of the 
test. After an initial warm-up at 0W, power output will be increased at a rate of 5 W/min for 

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participants with tetraplegia, or 10 W/min for participants with paraplegia, until volitional 
exhaustion (i.e. dropping below 30 rev/min). Participants will be asked to identify their 
ratings of perceived exertion (RPE) on the Borg scale every minute until the completion of 
exercise. Heart rate and oxygen uptake will be recorded on a breath-by-breathe basis for the 
duration of the test. The highest 15-second average of oxygen uptake during the test will be 
recorded as VO2peak. 
Basal Metabolic Rate (BMR) (also called Resting Metabolic Rate – RMR) (Specific Aim 1) 
BMR is the rate of energy expenditure by humans at rest (reported as kilocalories). The 
release, and using, of energy in this state is sufficient only for the functioning of the vital 
organs: the heart, lungs, nervous system, kidneys, liver, intestine, sex organs, muscles, brain 
and skin. BMR is measured under very restrictive circumstances when a person is awake, 
without moving or talking while the person is lying down in a best for about 45 minutes 
after fasting for 10-12 hours. A canopy hood will be placed to cover the participant head and 
shoulder, and BMR will be measured by expired gases through indirect calorimetry and will 
be analyzed with a Parvo Medic TrueOne 2400 (Sandy, UT). Analysis of the oxygen and 
carbon dioxide composition of the expired air will occur every 10 seconds. The cart will be 
calibrated with a 3-liter syringe for flowmeter calibration and the ambient air for gas 
calibration at least 30 minutes before testing as recommended by the manufacturer’s 
guidelines. An accurate BMR measurement requires that the person's sympathetic nervous 
system not be stimulated, thus, it requires complete rest. BMR generally decreases with age 
and with the decrease in lean body mass. Increases in muscle mass and mitochondrial 
proliferation (for example: as a result of endurance training) result in increases in BMR. 
Pulmonary Function Test, PFT (Specific Aim 2): PFT’s will be performed in the participant’s 
wheelchair using BreezeSuite System (MedGraphics, St. Paul, MN). Forced vital capacity (FVC) 
and forced expiratory volume in 1 second (FEV1) will be obtained. Three acceptable spirograms 
will be obtained and the result of their best attempt will be used [67]. MP45-36-871-350 
Differential Pressure Transducer (Validyne Engineering, Northridge, CA) will be used to 
measure the maximum inspiratory pressure (PImax) and the maximum expiratory pressure 
(PEmax). The PImax will be measured during maximal inspiratory effort beginning at near 
residual volume and PEmax will be measured during maximal expiratory effort starting from 
near total lung capacity. The assessment will require a sharp, forceful effort be maintained for a 
minimum of 2 seconds. The maximum pressure will be taken as the highest value that can be 
sustained for one second. The maximum value from three maneuvers that varied by less than 
20% will be averaged. 
Respiratory Motor Control Assessment (RMCA) (Specific Aim 2): 
Procedure:  This assessment combines standard spirometry and airway pressure measurements 
(as described in the Pulmonary Function Test /PFT/ section), 3-lead Electrocardiography (ECG) 
(ML132, AD Instruments), beat-by-beat arterial Blood Pressure (BP) recordings from a finger 
cuff (Finapres Medical Systems), respiratory kinematics using inductive plethysmography 
(lnductotrace, Ambulatory Monitoring), and  surface Electromyography (sEMG) (Motion Lab 
Systems, Inc, Baton Rouge, LA) of the muscles of respiration.  This assessment may be 
performed with and without epidural stimulation. 
Respiratory muscle activation patterns will be evaluated using sEMG of respiratory-related 
muscles using the MA300 System (Motion Lab Systems, Baton Rouge, LA) [68]. sEMG input 
will be amplified with a gain of 2000, filtered at 4-1000 Hz and sampled at 2000-10000 Hz. The 

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electrodes will be centered over the muscle belly parallel to the muscle fibers.  The skin will first 
be prepped with a sterile alcohol swab before electrode placement and held in place with either 
Tegaderm Film (3M Req#1624W) or Cover-Roll Stretch Tape (BSN Medical, Hamburg, 
Germany).  The ground electrode(s) will be placed over the acromion process bilaterally. 
The RMCA will utilize a multi-muscle sEMG-based measure of motor output from the central 
nervous system recorded during voluntary tasks attempted in the supine and sitting position [69, 
70].  The protocol begins in the seated position and consists of the following maneuvers followed 
by 5 minutes of relaxation in supine position:  Spirometry, PEmax, PImax, PEmax and PImax 
sustained for 5 seconds, deep breath, coughing, and a Valsalva maneuver.  Each maneuver will 
be cued by an audible tone and repeated three times.  After the 5 minute relaxation period, the 
aforementioned maneuvers will be repeated in the supine position.  The supine position protocol 
will exclude the Valsalva maneuver, while adding a neck flexion against resistance, shoulder 
shrug, hip and knee flexion, and a sit-up task.  sEMG of left and right neck, trunk, limb muscles 
including but not limited to submental, sternocleidomastoid, scalene, upper trapezius, lower 
trapezius, upper portion of pectoralis major, intercostals, the diaphragm, rectus abdominus, 
obliques, and the paraspinals will be recorded using a multi-channel EMG system MA300 with 
pre-amplified electrodes (MotionLab Systems Inc., Baton Rouge, LA) or an Eclipse 
Neurological Workstation (Axon Systems Inc., Hauppauge, NY) with pairs of recessed, FE9 
silver-silver chloride cap surface electrodes (Grass Instruments, W Warwick, RI).  
Analysis:  The envelope of EMG activity for each muscle will be calculated using a root mean 
square (RMS) algorithm [69].  Analysis windows will be determined from the event marker 
recorded with the cuing tone that signaled the subject to begin the task. The overall amount of 
EMG Magnitude (µV, Mag) and the Similarity Index (SI), that quantitate the multi-muscle 
distribution of activation during Maximum Expiratory Pressure Task (MEPT) in research 
participants compared to that of healthy subjects will be calculated using a vector-based analysis 
as previously described [69, 70]. In brief: multi-muscle activity parameters will be calculated 
using averaged RMS amplitudes from each SCI subject for comparison to group values from 
non-injured (NI) subjects. The resulting Mag parameter is the amount of combined sEMG 
activity during MEPT calculated as a length of the resultant vector. The SI provides a value 
between 0.0 and 1.0 (most similar) equal to the cosine of the angle between the resultant multi-
muscle distribution vectors in SCI subject to that of NI subjects. To perform the maximum 
airway pressure tasks, subjects will produce maximum respiratory efforts for 5 seconds blowing 
into the Airlife 001504 circuit (Allegiance Healthcare Corp., McGaw Park, IL). Airway pressure; 
sEMG; breathing rate and chest wall kinematics will be monitored simultaneously by using 
Powerlab acquisition system (ADInstruments, Colorado Springs, CO). 
For the bursts analysis, EMG data will be full wave rectified and filtered using a 4th order 
bandpass Butterworth filter (40 Hz - 500 Hz) representing the relative number and frequencies of 
the motor units recruited per burst. Integrated EMG will assess the total EMG activity generated 
during specific phases of the motor tasks. Co-activation values of inspiratory and expiratory 
muscles and the degree of coordination in the breathing-related oscillations will be evaluated 
through principal component analysis. 
 
EMG, kinematics and kinetics experiments (Specific Aim 3): During the experiments, the 
research participants will be placed on the treadmill in an upright position and suspended by a 
cable in a harness (i.e. BWST) or on an overground standing device. Voluntary leg movements 
will be performed on a mat or seated in a chair. Following standard skin preparation techniques, 
bipolar surface EMG electrodes may be placed bilaterally on the following muscles: soleus 
(SOL), medial gastrocnemious (MG), tibialis anterior (TA), medial hamstrings (MH), quadriceps 

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(VL and RF) and adductor (AD) muscles. Fine-wire EMG electrodes may be used for deep 
muscles of the hip and foot. Limb and trunk kinematics including hip, knee and ankle angles will 
be acquired using high speed passive marker motion capture (Motion Analysis, Santa Rosa, CA). 
When appropriate we will measure individual ground reaction forces (GRF) using HRMat 
(TEKSCAN, Boston, MA) or forces during movement with a force transducer (Kistler, Amherst, 
NY). These experiments will be performed with and without epidural stimulation. 
NeuroRecovery Assessment using EMG activity: Standing, Stepping, and Overground motor tasks: 
(Specific Aim 3)  
Procedure: Assess the level of muscle activation and amount of external assistance required 
during standing and stepping in a body-weight supported treadmill environment, as well as 
overground motor tasks. Efficacy of arm, trunk and leg movement recovery and incorporation of 
independent motor tasks will be measured by the NRS [71, 72], comprised of fourteen motor tasks, 
and combined with EMG, kinematic, and kinetic analyses. This population has ongoing medical 
issues related to their spinal cord injury and so in some cases we may not complete the assessments 
with EMG depending on the physical status of the research participant. This will not affect the 
overall integrity of the data set. The research participant will be asked to perform these tasks as 
independently as possible with and without epidural stimulation 
Materials: EMG, kinematic, and kinetic analysis will be performed on the upper and lower 
extremities and/or trunk during stepping, standing, and overground motor tasks. Muscle activation 
patterns will be evaluated using EMG that may include but is not limited to the following 
combinations of muscles: sternocleidomastoid (SCM), upper trapezius (UT), biceps brachii (BB), 
triceps brachii (TB), extensor carpi radialis (ECR), flexor digitorum profundus (FDP), abductor 
digiti quniti (ADQ), external intercostal (IC6 - 6th intercostal space), rectus abdominus (RA), 
external oblique (EO), erector spinae (ES), rectus femoris (RF), vastus lateralis (VL), medial 
hamstrings (MH), adductor (AD), tibialis anterior (TA), peroneous longus (PL), medial 
gastrocnemius (MG), soleus (SOL), flexor hallucis brevis (FHB) or longus (FHL), extensor 
hallicus longus (EHL), and extensor digitorum longus (EDL) using the MA300 System (Motion 
Lab Systems, Baton Rouge, LA). We may also use fine-wire EMG to acquire activity from the 
illio-psoas (IL), or other deep muscles, including the hand and feet muscles listed above. Standard 
needle insertion sites for each muscle will be used [73].  
EMG input will be amplified with a gain of 2000, filtered at 4-1000 Hz and sampled at 2000-
10000 Hz. The bipolar surface electrodes will be placed over the muscle belly parallel to the 
muscle fibers. The skin will first be prepared by shaving and cleaning the area with a sterile 
alcohol swab before electrode placement. The ground electrode(s) will be placed over a bony 
surface of the lower leg(s). Limb kinematics will include trunk, and upper and lower extremity 
angles that will be acquired using high speed passive marker motion capture (Motion Analysis, 
Santa Rosa, CA). When appropriate, we will measure individual ground reaction forces (GRF) 
using a zebris FDM-T System (zebris Medical GmbH, Isny, Germany) or forces during movement 
with a force transducer (Kistler, Amherst, NY). Blood pressure and heart rate may be measured 
using either a manual blood pressure monitor (Dinamap V100, GE Medical) or by a finger cuff 
(Finapres Medical Systems). Temperature may be monitored using a customized sensor system. A 
NIRS optode may be placed on a muscle of the leg to measure muscle oxygenation and 
hemodynamics. 
The research participant will be asked to perform motor tasks as independently as possible. 
Research staff will score each of these tasks based on the algorithm. The following tasks may be 
performed in separate sessions (e.g. overground tasks, standing, or stepping on different days). 

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Sit: The research participant will be sitting unsupported at the edge of the therapy mat with 
both feet touching the ground with hips and knees in 90-degree angles. The research staff will then 
ask the participant to sit without upper extremity support to attain or maintain best posture. 
Depending on participant abilities, participant may be asked to maximally reach forward and to 
each side while maintaining appropriate posture and balance. 
Reverse Sit Up: From an unsupported sitting position at the edge of the mat with feet on the 
ground with hips and knees in 90-degree angles, the research participant will be asked to slowly 
lower his/her trunk down to the mat without assisting the movement with his/her arms. 
Depending on participant abilities, participant may be asked to maintain trunk position, rotate 
trunk, and return to upright sitting. 
Sit Up: From a supine position on the mat with feet on the ground with hips and knees in 90-
degree angles, the research participant will be asked to return to a sitting position without the 
use of his/her arms. 
Trunk Extension in Sitting: The research participant will be sitting with feet flat on the floor 
with hips and knees in 90-degree angles and chest resting on his/her lap. The research participant 
will be asked to return to an upright sitting position without the use of arms. Depending on 
participant abilities, participant may be asked to slowly lower trunk down to chest and return to 
upright sitting without use of arms. 
Overhead Press: The participant will begin the task by sitting with their best posture at the 
edge of the therapy mat with both feet touching the ground with hips and knees in 90-degree angles 
and hands down by their sides. The participant will be asked to curl their hand towards the 
shoulder then press their hand towards the ceiling while straightening the elbow. As the participant 
progresses through the task with appropriate kinematics, they may be asked to perform the task 
while holding a one, three or five pound dumbbell. Each upper extremity will be performed and 
scored separately. Stability assistance can be given to the participant at the trunk, up to the level of 
the inferior borders of the scapulae while they are performing this task. 
Forward Reach and Grasp: The participant will begin the task by sitting with their best 
posture at the edge of the therapy mat with both feet touching the ground with hips and knees in 
90-degree angles and hands down by their sides. A table will be placed in front of the participant 
with the height adjusted to be one inch below the wrist crease with their elbow flexed to 90 
degrees. An empty 12 oz. can, will be placed on the table, arm’s length away. The participant will 
be asked to reach forward, grab the can, bring it to their mouth, and set it back down on the table. 
As the patient progresses through the task with appropriate kinematics, they will be asked to 
perform the task with a full 12 oz. can. Each upper extremity will be performed and scored 
separately. Stability assistance can be given to the participant at the trunk, up to the level of the 
inferior borders of the scapulae while they are performing this task.  
Door Pull and Open: The participant will begin the task by sitting with their best posture at 
the edge of the therapy mat with both feet touching the ground with hips and knees in 90-degree 
angles and their arm resting on the table. The table height will be adjusted to be one inch below the 
wrist crease with their elbow flexed to 90 degrees. The participant will be instructed to pull their 
hand back to the side of their body as if opening a door. As the participant progresses through the 
task, they will be instructed to perform additional movements, including pronation and supination. 
Once the participant performs the movements with appropriate kinematics, they will be asked to 
perform the task with a 3 pound dumbbell and to pick up a key, insert it in a lock and turn the key 
90 degrees. Each upper extremity will be performed and scored separately. Stability assistance can 
be given to the participant at the trunk, up to the level of the inferior borders of the scapulae while 
they are performing this task.  

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Can Open and Manipulation: The participant will begin the task by sitting with their best 
posture, at the edge of the therapy mat with both feet touching the ground with hips and knees in 
90-degree angles and hands down by their sides. A table will be placed in front of them with the 
height adjusted to be one inch below the wrist crease. The participant will be asked to 
simultaneously reach and place both hands around a container with a lid. As the participant 
progresses through the task with appropriate kinematics, they will be asked to perform more 
advanced skills, including stabilizing the can with one hand while using a lateral pinch to remove 
the lid with the other. There will be items in the can that the participant will be asked to remove 
and translate with the tips of their fingers. Each upper extremity will be performed and scored 
separately. Stability assistance can be given to the participant at the trunk, up to the level of the 
inferior borders of the scapulae while they are performing this task.  
Sit to Stand: The research participant will be asked to stand up from a seated position at the 
edge of the mat, with hips and knees in 90-degree angles, without the assistance of his/her arms. If 
the participant is able to raise his body 50% off the mat, the research staff will assist as needed 
during the latter 50% of standing. Depending on participant abilities, participant may be asked to 
stand up while holding 20 pounds and to stand up from a seated position with hips at 100-degree 
flexion angles. 
Stand: The research participant will be asked to stand overground with proper posture. 
Assistance will be provided by research staff only as needed. Depending on participant abilities, 
participant may be asked to reach maximally reach forward and laterally, achieve and maintain 
tandem stance, and achieve and maintain single-limb stance while maintaining proper posture and 
balance. 
Walking: From a standing position, the research participant will be asked to shift weight 
laterally and forward while in a stride position. Assistance will be provided by research staff only 
as needed. Depending on participant abilities, participant may be asked to take repetitive steps, 
step over an object, descend an incline, complete a pivot turn all while walking as well as run 10 
meters while maintaining proper posture and balance. 
Stand Adaptability: From a standing position over a treadmill with overhead body weight 
support, the research participant will be asked to maintain best posture without use of upper 
extremity support. The research staff will assist only as needed at body segments not being 
assessed. Body weight support will then be lowered until the research participant can no longer 
maintain proper posture without assist. Depending on participant abilities, participant may be 
asked to resist perturbations at the trunk with body weight support less than 20%, perform squats, 
and maintain single-limb stance all while maintaining proper posture and balance with body 
weight support less than 10%. 
Step Retraining: From a standing position over a treadmill with overhead body weight 
support, the research participant will be asked to maintain proper posture and natural arm swing 
while the research staff assists him/her to walk at speeds of 2.0 mph or greater. The research staff 
will provide assist to maintain proper stepping kinematics. Body weight support will then be 
lowered until the research participate is unable to maintain proper posture and/or the research staff 
are unable to maintain proper stepping kinematics. Depending on participant abilities, participant 
may be asked to step over objects, adjust to varying random treadmill speeds, and achieve a 
running pattern all while maintaining proper posture, with support from research staff to maintain 
stepping kinematics, at various levels of body weight support. We may step continuously for up to 
10 minutes. 
Step Adaptability: From a standing position over a treadmill with overhead body weight 
support, the research participant will be asked to maintain proper posture and natural arm swing 
while walking at speeds of 0.6-1.2 mph. The research staff will provide assist to provide proper 

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posture and stepping kinematics only as needed. Body weight support will then be lowered until 
the research participate is unable to maintain proper posture or stepping kinematics. Depending on 
participant abilities, participant may be asked to step over objects, adjust to varying random 
treadmill speeds, and achieve a running pattern all while maintaining proper posture and stepping 
kinematics at various levels of body weight support. 
Analysis: Based on the performance across categories, 4 phase scores can be assigned. Phase 1 
represents the greatest impairment relative to normal movement patterns with most people being 
non-ambulatory. In Phase 2, people begin to stand and weight support independently. Phase 3 
denotes walking with varying skill levels. Phase 4 reflects normal locomotor and transfer 
performance with marked adaptability to varying conditions. EMG data will be full wave rectified 
and filtered using a 4th order bandpass Butterworth filter (40 Hz - 500 Hz) representing the relative 
number and frequencies of the motor units recruited per burst. Integrated EMG will assess the total 
EMG activity generated during specific phases of the motor tasks. Co-activation values of agonists 
and antagonist muscles and the degree of coordination in the movements will be evaluated through 
principal component analysis. 
 
MG and Soleus H-reflex (Specific Aim 4): All EMG data will be collected at 2000 Hz with 
custom-written acquisition software (National Instruments, Austin, TX, USA). We will record 
bilateral EMG (Motion Lab Systems, Baton Rouge, LA, USA) from same muscles as above. The 
soleus H-reflex will be evoked by monopolar electrical stimulation of the posterior tibial nerve at 
the popliteal fossa using a 1-ms pulse, generated by a constant current stimulator (DS7A, 
Digitimer, UK) and will be recorded by surface monopolar differential electrodes placed over the 
soleus muscle. A minimum 10 control and conditioned reflexes will be recorded in every trial. 
The indifferent electrode will be placed above the patella for selective stimulation of the nerve 
trunk. The EMG signal will be amplified and band-pass filtered (10 Hz-500 Hz) before being 
sampled at 2 kHz (1401 plus running Spike 2 software). The digitized EMG signals will be 
rectified and the size of M-wave and H-reflex responses will be measured as the area under the 
full-rectified waveforms. Soleus H-reflexes will be recorded as designated by each specific 
supraspinal pathway protocol (described in detail below). For all conditioning experiments, 
amplitude and latency changes of the soleus H-reflex will be used to quantify the effects of the 
TMS, galvanic, auditory or ulnar nerve stimulation. Control H-reflexes will be evoked 
interleaved with those conditioned by the respective stimulation. 
Corticospinal pathways (Specific Aim 4): We will administer single pulse transmagnetic 
stimulation using a Magstim 200 single-pulse stimulator with a double cone coil for activating 
lower extremity musculature while the research participants are in the supine position. We will 
position the coil approximately 0-2 cm anterior to the vertex to locate the hotspot left and right 
tibialis anterior and quadriceps muscles. We will position the coils tangentially to the scalp with 
intersection of both wings at 45 degrees to midline for optimal motor cortex stimulation. We will 
use Signal software (Cambridge electronic design, UK) to trigger motor evoked potential (MEP) 
data acquisition. We will perform MEP data analysis using Signal software (Cambridge 
electronic design, UK). Mean peak-to-peak MEP amplitudes (average of 8-10 trials) at intensities 
10%, 20%, 30%, 40%, 50%, 60% and 70% above rMT will be used to generate stimulus 
response curves. Using SigmaPlot curve-fitting software, stimulus response curves will be fitted 
with the Boltzmann function: MEPa= P/1+exp ((I50-I)/k), where P is the Plateau amplitude, I is 
the intensity, I50 is the amplitude at 50% of plateau and k is slope parameter of the steepest 
portion of the curve. 

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Research participants will be in a supine position with a fixed hip, knee and joint angle. For 
those individuals who can maintain a voluntary contraction, an additional series of tests will be 
conducted with background EMG activity. For soleus H-reflex modulation single pulses will be 
used to condition the H-reflex induced by posterior tibial nerve stimulation at interstimulus 
intervals ranging between 0 and 100 s (see 8,33,61,68). We will measure the MEP’s in response 
to incrementing levels of TMS over the leg area of the primary motor cortex and generate 
recruitment curves. We will measure changes in threshold, slope and the maximum amplitude of 
the recruitment curve to determine if severity of injury, time since injury, or locomotor training 
influences the excitability or functional connectivity of the corticospinal pathways. We will also 
compare the reproducibility of these parameters in non-disabled research participants to verify 
these changes are not attributed to inherent variability of the measurements. We will calculate 
peak-to-peak values for the MEP response and those responses at a given stimulation frequency 
will be averaged and plotted versus the stimulation intensity. If background EMG is elicited we 
will average the amplitude from a 25 ms window prior to stimulation. 
Vestibulospinal pathways (Specific Aim 4): We will administer galvanic stimulation (rectangular 
pulses, 300 ms, 2-4.5 mA) with Digitimer DS5 Isolated Bipolar Constant Current Stimulator 
using 2.5 cm diameter electrodes placed over the mastoid processes for the assessment of the 
vestibulospinal pathways. The digitimer will be externally triggered by our Labview program 
and used to condition the soleus H-Reflex. The research participants will be lying with the head 
of the mat fixed (30 degrees) because posture influences the responses. Control H-reflexes will 
be evoked interleaved with those conditioned by auditory stimulation with the time randomly 
between 10 and 20 seconds to allow adequate recovery of the motoneuron pool. A minimum of 5 
responses of control and condition will be measured and averaged with conditioned responses 
expressed as percentage of control values. Peak-to-peak amplitude will be calculated and the 
mean amplitude and standard deviation for each of the conditioned and control reflexes. The 
conditioned reflexes will be expressed as a percentage of the control reflexes. 
Reticulospinal pathway (Specific Aim 4): The reticulospinal pathway will be evaluated using 
soleus H-reflex amplitude under conditioning stimulation via auditory stimulus (30 ms tone of 90 
dB at 700 Hz) that will be delivered using binaural earphones. EMG will be recorded from the 
sternocleidomastoid muscle to confirm the startle response (10). The soleus H-reflex will be 
elicited 50 ms after the sound to peak after 75-125 ms and return to baseline values after 250 ms 
(24). Amplitude changes of the soleus H-reflex will be used to quantify the effects of the 
auditory stimulation. Control H-reflexes will be evoked interleaved with those conditioned by 
auditory stimulation with a time separation of at least 2 minutes. A minimum of 5 responses of 
control and condition will be measured peak-to-peak and averaged with conditioned responses 
expressed as percentage of control values. 
Long propriospinal pathway (Specific Aim 4): The long propriospinal system will be 
evaluated using soleus H-reflex amplitude under conditioning stimulation of the ipsilateral 
ulnaris nerve at the wrist joint via surface electrodes with trains of 3 rectangular pulses (pulse 
duration: 0.5 ms, pulse interval: 3 ms) (20,47). The soleus H-reflex will be elicited 100 ms after 
the ulnaris nerve stimulation. The intensities of the stimuli will be expressed as multiples of the 
threshold for the direct M response of the abductor pollicis brevis muscle. The stimulus will be 
applied every 3 s in a randomized, interleaved conditioned and unconditioned stimuli sequences. 
Somatosensory Evoked Potential: 

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Procedure: Somatosensory evoked potentials (SEPs) - Somatosensory evoked potentials are 
recorded through surface electrodes to measure conduction in the peripheral nerves, cervical and 
lumbosacral spinal cord, deep brain structures, and sensory cortex (Asanuma 1981. Skin is cleaned 
with alcohol and prepared using mild abrasive conductive paste for the placement of surface 
electrodes on the scalp over the Fz, CZ, C3 and C4 locations of the International 10-20 System for 
EEG electrode placement. Electrodes are also placed over the 7th cervical, 12th thoracic, right or 
left side of iliac crest and on popliteal fossa medially and distally. Stimulation electrodes are 
placed over the median nerve at the wrist and tibial nerve of the right and left upper and lower 
limbs. Ground electrodes are placed on the forearms and thighs. Repeated single-pulse electrical 
stimulation is delivered at intensities of 1 and 1.5 times motor threshold for the recorded muscles 
for each of the four nerves evaluated. Averaged responses for up to 256 stimuli will be recorded 
for each of these two intensities for the right and left median and tibial nerves. Simultaneous 
bilateral stimulation will be applied if no recognizable responses are recorded from the scalp leads. 
Stimulation delivery rates will not exceed 2 per second. 
Analyses: Average latencies will be calculated for N20 & P23 peaks for the Median nerve and N45 
& P37 peaks for the Tibial nerve using Natus (Viking).The peak to peak amplitude can also be 
calculated using Natus (Viking). 
 
Sympathetic Skin Responses (SSR):  
Procedure:  Sympathetic skin responses (SSR): The SSR will be elicited by stimulation of supra-
orbital, median and/or tibial nerves, and recorded bilaterally and simultaneously from both hands 
and feet to assess the extent of disruption to spinal autonomic pathways. Five to ten electrical 
stimuli (duration 0.2 ms; intensity 3-60mA) will be applied Supra orbital nerve, the median nerve 
and posterior tibial nerve, in random order and with variable and long-time delays to minimize 
habituation. 
Analysis: The SSR recordings are among the frequently utilized techniques for the evaluation of 
integrity and functional capacity of the autonomic circuits after SCI [74-77]. The outcomes will be 
calculated as a number of recognizable responses out of 10 stimulations, and averaged latency and 
averaged amplitude [78]. 
 
Interventions: 
1) ES Cardiovascular Parameters during sitting or lying supine  
2) ES Voluntary Parameters during voluntary leg movement training  
3) ES Stand Parameters during stand training overground or on BWST 
c.    Significance. The prognosis for those who suffer a devastating spinal cord injury 
(SCI) that results in complete paralysis, cardiovascular, respiratory, and bladder dysfunction is 
extremely poor. The combined medical and personal economic impact of these complications of 
the average spinal cord injured patient over the average life span are devastating, with an 
estimated 1,275,000 Americans with a SCI (1). The current paradigm is to provide compensatory 
therapeutic interventions which focuses on improved function above the lesion, with the singular 
hope that in the future some regenerative approach, perhaps using stem cell technologies, will 
reach clinical trials; because, it is thought that reestablishing anatomical connectivity of 
supraspinal input to the spinal cord is essential for recovery of movement and autonomic 
function. In this proposal, we challenge 1) the concept that movement and autonomic function 
can only be restored by re-establishing anatomical connections from supraspinal to spinal 

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neurons; and 2) that those with the diagnosis of clinically motor complete SCI indicates a 
prognosis of essentially no recovery. Individuals with complete motor paralysis suffer from a 
myriad of complications that result in mortality, morbidity, hospitalization, high burden of care 
and health care costs and a drastically lowered quality of life. 
d. Human Subjects 
Human Subjects Involvement and Characteristics: There are approximately 1,275,000 
Americans with a SCI. Fifty-six percent of the injuries occur in people aged 16 to 30, with an 
average age of 31, and 82% of the total population are male. Minorities make up 38% of SCI 
cases and while every effort will be made to recruit minorities, based on the incidence rates, their 
participation may be limited. Every effort will be made to recruit women, though only about 
18% of SCI patients are female. Although many people have secondary health issues after SCI, 
such as spasticity and frequent urinary tract infections, they are otherwise healthy individuals. 
Standing and activity dependent training is considered beneficial for people with SCI, who are 
otherwise confined to a wheelchair, as immobilization can contribute to secondary pathologies 
such as osteoporosis, leg muscle contractures, decreased cardiovascular health, pressure sores 
and muscle atrophy. Pregnant women with SCI will not be studied because the risks to the fetus 
are unknown. No other vulnerable subjects will be included. 
We will enroll five research participants who have sustained a SCI (AIS A, B or C) to 
participate in the proposed experiments. Frazier Rehab Institute evaluates approximately 300 
chronic SCI outpatients each year. We also have a database of over 200 people with SCI who 
have expressed interest in participating in our research programs. 
All  research  participants,  irrespective of  gender,  will  be selected  based  on  the  following 
Inclusion criteria.   
1)  non-progressive  SCI  with  motor  paralysis  above  T1;  American  Spinal  Injury 
Association Impairment Scale (AIS) A, B or C; 2) 21 – 70 years of age;  3) greater than 2 years 
post injury; 4) stable medical condition; 5) unable to voluntarily move all single joints of the 
legs;  6) cardiovascular dysfunction including presence of persistent resting low blood pressures 
and/or symptoms of autonomic dysreflexia and/or orthostatic hypotension; 7) respiratory 
dysfunction including at least 15% deficit in predicted pulmonary function outcomes; and 8) 
presence of functional segmental reflexes. 
Exclusion criteria: 
1) ventilator dependent; 2) painful musculoskeletal dysfunction, unhealed fracture, severe 
contracture, or untreated pressure sore/wound that might interfere with training; 3) untreated 
psychiatric disorders; 4) ongoing drug abuse; 5) cardiovascular, respiratory, bladder, or renal 
disease unrelated to SCI; 6) severe anemia (Hgb<8 g/dl) or hypovelemia; 7) HIV or AIDS 
related illness (self-reported or based on chart review); 8) ongoing use of combustible drugs (e.g. 
Nicotine and illicit: methamphetamine, marijuana, cocaine, etc); and 9) unable to wean off from 
anti-spasticity medications.  
Each research participant will be screened for medical eligibility by a neurosurgeon and 
physiatrist and for scientific eligibility by the principal investigator. After eligibility is 
determined and consent procedures are implemented, the individual will undergo clinical and 
neurophysiological assessments for voluntary movement, cardiovascular and respiratory 
function. Random drug testing will be conducted throughout the study to verify the participant is 
abstaining from the use of nicotine and other combustible drug products. 

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During the experimental stand session, participants will use an overground standing device 
or will be placed on the treadmill in an upright position and suspended in a harness by an 
overhead pulley at the maximum load at which knee buckling and trunk collapse can be 
avoided. A trainer positioned behind the participant will aid in pelvis and trunk stabilization. 
The trainer will ensure that the trunk and pelvis are not flexed or hyper-extended during 
standing. Trainer(s) positioned at the lower limb will provide manual facilitation using a 
customized technique developed by this research team that facilitates knee extension standing. 
Trainer(s) promote knee extension by applying gentle pressure at the tibial tuberosity and 
stimulation of the patellar tendon. Manual facilitation  at  the  trunk-pelvis  and  at  the  legs  
will  be  used  only  when  needed. For those participants trained on the body weight support 
system, the body weight support (BWS) will be continuously reduced over the course of the 
training sessions as the subjects increase their ability to bear weight on the lower limbs. Manual 
facilitation will be reduced with independence of standing. Assessment of standing, EMG 
activity, kinematics and kinetics during standing, pulmonary and voluntary function will be 
conducted prior to the onset of training and after approximately 4 months (80 sessions) of each 
intervention 
Experimental testing, electrode implantation and subsequent training interventions will be 
initiated after the subject has been evaluated and the research team has determined compliance 
with the selection criteria. Maxwell Boakye, MD, Joseph Neimat, MD or Camilo Castillo, MD 
will complete a medical history and neurological examination to determine medical eligibility for 
each SCI subject. Susan  Harkema,  PhD  will  determine  study  eligibility  based  on  the  inclusion  
and exclusion criteria and by the medical recommendation of Dr. Boayke and Dr. Castillo. 
Experimental testing and training interventions will be initiated after the subject has been evaluated 
and determined in compliance with the selection criteria. The subjects will not be concurrently 
enrolled in any other experimental studies unless approved by the investigators. All subjects will 
sign an informed consent that has been approved by the University Institutional Review Board 
(IRB) prior to entering the study. Each subject will be assigned a subject identification number to 
designate all evaluations.  
Sources of Materials: Data obtained will be utilized specifically for research and teaching 
purposes only. Members of the research team including research assistants, post-doctoral 
students and graduate students will have access to the materials for analyses. Only Dr. Harkema 
will have access to the coding of the identification number to the research participants. 
Potential Risk: 
Risk from Surgery and Implantation of Neurostimulator: The surgical procedure 
performed to implant the 5-6-5 Specify or Specify 5-6-5 SureScan MRI electrode, 
(MEDTRONIC, Minneapolis, MN, USA) and RestoreAdvanced or Restore Advanced SureScan 
MRI Pulse generator, (MEDTRONIC, Minneapolis, MN, USA) involves minimal risk. Both 
devices are FDA approved and meet US safety regulations. The patient will be apprised of the 
surgical risks by Dr. Boakye or Dr. Neimat. As with any routine surgical intervention there is a 
risk of bleeding and infection. Other potential risks of this procedure involve: 1) development of 
scar tissue around the electrode; 2) epidural hemorrhage; 3) seroma; 4) hematoma; 5) CSF leak; 
and 6) skin erosion. Some complications such as lead migration and breakage of electrode or 
hardware could require follow up surgery. The subjects will be monitored postoperatively and 
will stay overnight at University of Louisville Hospital. The patient will be followed during that 
period by Drs. Boakye, Neimat or Castillo to monitor any complications of surgery. 

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Risk from Interventions and Experimental Procedures: 
Stand and/or Voluntary Interventions: Because subjects must meet the criteria listed above, 
we expect that all subjects will be in good health. The studies described may involve the 
following physical risks and/or discomforts: 1) increased respiration or shortness of breath; 2) 
increased heart rate; 3) muscle and joint soreness; 4) lowering or elevation of blood pressure; 5) 
dizziness; 6) skin irritation from recording electrodes or hand placements of trainers; 7) skin 
abrasion from hand placements of trainers; 8) chest pain; 9) muscle strain or joint sprain from 
weight-bearing due to standing or stepping, or the force exerted by the trainers; and 10) fracture 
from weight-bearing due to standing or the force exerted by the trainers. 
Most subjects will have increased respiration and heart rate due to an increase in activity. 
However, we do not expect the increase in respiration and heart rate to be greater than what is 
normally experienced during regular exercise. Many SCI subjects will likely sustain skin 
irritation from the recording electrodes or hand placements of the trainers. These conditions are 
considered to be minimal risks and are reversible. 
There  is  some  chance  that  subjects  may  sustain  muscle  and  joint  soreness,  lowering  
or elevation of blood pressure, dizziness or skin abrasion from hand placements of the trainers. If 
these events occur, stand training and the experiment would cease immediately. Dr. Castillo will 
be alerted if the condition persists. These conditions are considered to be minimal risks and are 
reversible. 
It is highly unlikely that a subject would feel chest pain or high blood pressure would occur 
that did not resolve within several minutes. These events have not occurred in our past 
experience. However, if this did occur the individual would be immediately transported to the 
respective hospital’s Emergency Unit and Dr. Castillo will be notified. It is also highly unlikely 
that  a  subject  would  suffer  a  muscle  strain,  joint  sprain  or  fracture  from  standing. These 
conditions are considered to be moderate risks but rarely occur. However if these events should 
occur,  the  subject  would  immediately  stop  stand  training  and  would  be  evaluated  by  Dr. 
Castillo. Standard medical procedures will be provided. The subject’s primary physician would 
be notified as needed. These conditions are considered to be moderate risks and are reversible. 
Stimulation parameters used during training will be closely monitored by the research team. 
Subjects will undergo training about stimulator use at each site. Testing of optimal stimulation 
parameters and ranges will be performed in the laboratory to make sure stimulation is safe for the 
subject. Stimulation programs given to each participant will be restricted to those used and tested 
in the laboratory. Subjects will be instructed to call the therapist, nurse or assigned research team 
member immediately if complications from stimulation develop during home training programs. 
Dr. Castillo will be notified as needed. 
If serious adverse effects such as autonomic dysreflexia, sustained elevation or reduction in 
blood pressure,  or bradycardia or tachycardia have recurring onset on an individual or become 
present  across  the  tested sample population the research team will evaluate the  stimulation 
protocol. Stimulation parameters will be assessed initially limiting the voltage and frequency as 
well as selecting more localized configuration patterns that could reduce such effects. If a serious 
adverse event occurs as a result of stimulation, the research participant will be required to train in 
the laboratory for at least a week where they can be monitored by research staff. They will not be 
allowed to return to a home based stimulation program until they show stable responses to the 
stimulation and have been cleared by a physician. If stimulation parameters cannot be found to 
eliminate the onset of adverse effects the study will be stopped. 
Orthostatic Stress Test: While undergoing this test, participants may experience dizziness, 
changes in blood pressure and heart rate or shortness of breath. Each participant will be closely 

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monitored for any drastic changes in the recordings of their blood pressure, heart rate or 
breathing or show visible flushing of their cheeks or face. 
Blood Catecholamines: Though venipuncture is routinely done and relatively safe, participants 
may experience a feeling of light-headedness, bruising, Hematoma (blood accumulating under 
the skin), pain and/or infection. Participants will be monitored for any adverse effects or acute 
cases of the specified risks. 
Pulmonary function tests: During testing, every research participant will be slowly acclimated to 
the equipment to make him/her feel comfortable. This will help the research participants avoid 
experiencing a lowered blood pressure or dizziness. Each participant will be closely monitored 
for blood pressure and heart rate throughout each sEMG recording. Testing will immediately 
cease if these values become abnormal or if the research participant feels tired, winded or has 
chest pain. If these conditions persist, Dr. Castillo will be immediately contacted to assess the 
participant and will notify the primary care provider when necessary. Before and after every 
sEMG recording, the participant’s skin will be examined for irritations and abrasions. If skin 
irritations or abrasions are caused by the recording electrodes, placement will be modified 
appropriately. 
Transcranial Magnetic Stimulation and Peripheral Nerve Stimulation: There are no known 
significant risks with this procedure at this time, because the magnetic fields at the strengths used 
are thought to be without harm. The exception is if you have a cardiac pacemaker, or a certain 
type of metallic clip in your body (i.e., an aneurysm clip in your brain). There are no known 
long-term adverse effects reported with the use of this device; however, this test is still under 
development. There may be unforeseen risks in the long-term that are currently unknown. The 
TMS device produces a loud clicking sound.  Although studies have found no hearing 
impairments as a result of this sound, some subjects experience a mild temporary effect on their 
hearing. To minimize this possibility, participants will be given protective earplugs. In patients 
with epilepsy, activation of the brain could also activate a seizure. Patients with stroke can also 
develop seizures due to the brain scar. Therefore, magnetic stimulation of the brain could 
conceivably activate a seizure in a stroke survivor with such a scar. There may be slight 
discomfort associated with the electrical stimulation. If this becomes uncomfortable, stimulation 
will be reduced or stopped. 
There are no identifiable psychological, sociological, economical or legal risks to the 
participants. 
Adequacy of Protection against Risk: 
Recruitment and Informed Consent: The research team will utilize the Human Locomotion 
Research Center’s Potential Volunteer Database (UofL Study #06.0647) to search for potential 
research volunteers for any of our current research studies based on eligibility criteria (e.g. level 
of injury, cause of injury, etc.). Participants will be screened through IRB #07.0024 and through 
the screening consent for this protocol. All eligible subjects will be invited to the recruiting site 
to discuss the complete protocol, including its risks and benefits with Dr. Harkema (Louisville) 
and/or designated research staff. Afterwards, all potential subjects will be encouraged to read the 
informed consent and discuss the study with their physician, family and friends, before signing 
the IRB approved informed consent. The informed consent will be written in language that an 
eighth-grade student would be able to understand and will contain information on all studies to 
be performed as well as contact information if the subject and his/her associates should have any 

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questions. The original signed informed consent and two copies will be kept in Dr. Harkema’s 
office. If a participant is employed by the University, we will review and discuss a risk 
management plan.    The plan will be signed by the investigator, participant and witnessed by an 
individual outside of the study and department to ensure there is no coercion. A copy of the plan 
will be provided to the participant and placed in his employee file. 
Protection against Risk: To protect confidentiality, each research participant will be 
assigned a coded identification number with no association to their identity. This number will 
distinguish all evaluations and analyses. Data will be stored on computer media and video and 
will be secured in a locked storage area of the laboratory. Only members of the research team 
including research assistants, post-doctoral students and graduate students will have access to the 
data for analyses. Dr. Harkema will have access to the coding of the identification number to the 
research participants. No individual will be allowed to participate in the study without being 
examined by Dr. Castillo. All eligible research participants will be encouraged to discuss the 
study with their primary physician, in order to minimize physical risks. To further minimize 
risks, the following precautions will be taken: 
Stimulation: Every research participant will be slowly acclimated to stimulation. This may 
help  the  research  participants  avoid  experiencing  significant  blood  pressure  fluctuations  or 
dizziness. However, if these conditions should occur, stimulation will be modified or stopped, 
depending on the need to regulate the blood pressure. Each research participant will be closely 
monitored (blood pressure, oxygen saturation, heart rate) throughout stimulation sessions in the 
lab. Stimulation will immediately cease if these values become abnormal or if the research 
participant feels tired, winded or has chest pain. If these conditions persist, Dr. Castillo will be 
contacted immediately to assess the participant and will notify the primary care provider when 
necessary. Dr. Harkema and the research team will continually assess the appropriate stimulation 
parameters including configurations, voltage and frequency. 
Orthostatic Stress Test, Pulmonary function tests, EMG Experiments: Participants will be 
continuously monitored for any signs of risks or discomfort. If these occur the recording or 
training session will be immediately discontinued. If any complications arise, the training will 
immediately stop and Dr. Castillo will immediately be informed. He or a designated associate 
will be available on campus during all data collections. In addition, the participant’s primary care 
provider will be notified as necessary. Reports of symptoms associated with infection will be 
addressed immediately and the participant’s primary care provider will be notified as necessary. 
Transcranial Magnetic Stimulation and Peripheral Nerve Stimulation: Both during and in 
the days following the procedure, participants will be monitored for excessive discomfort, 
headaches and other adverse reactions. Reports of symptoms associated with seizures will be 
addressed immediately and the participant’s primary care provider will be notified as necessary. 
 
Data Safety and Monitoring Plan 
An independent Data Safety Monitoring Board (DSMB) has been chartered to monitor the 
safety of research participants as well as the validity and data integrity of studies conducted at 
the Kentucky Spinal Cord Injury Research Center, University of Louisville and the Frazier 
Rehab Institute. Members of the DSMB serve in an individual capacity and will convene yearly 
to provide their expertise including recommendations regarding the continuation, modification, 
or termination of any or all phases of a study. The DSMB will review cumulative study data to 
evaluate safety, study conduct, scientific validity and data integrity. DSMB members may review 
current versions of the protocol and Informed Consent Form, and any subsequent amendments to 
ensure an understanding of a study’s objectives and design. Day-to-day oversight of the study 
will be provided by the Principal Investigators. They will review all study data and any adverse 
events, and report all adverse events to the University of Louisville, IRB, DSMB chairperson and 

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sponsor as appropriate. Medical events that occur while the research participants are engaged in 
the research protocols also will be logged by a research nurse, physical therapists, physicians 
and/or staff. Any adverse events (AE) are collected on an Adverse Event Form and will be 
reported at the yearly DSMB meeting. An AE report will be generated for each event and will 
include a description of the event, when and how it was reported, as well as any official chart 
records or documentation to corroborate the event and a determination of attribution. Any AE 
that the PI determines to be definitely, probably, or possibly related to the research intervention, 
or serious in nature, and unexpected will be reported to the IRB, within 5 business days of the PI 
gaining knowledge of the event. Any unanticipated problems involving risks to research 
participants or others will include a corrective plan and measures to prevent reoccurrence. Such 
events will be reported to appropriate regulatory agencies as required within 5 business days of 
the PI gaining knowledge of the event. 
 
e. Animals - NOT APPLICABLE 
f. Biohazardous Materials - NOT APPLICABLE 
  
 
 

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Reference List 
 
1. 
Harkema, S., et al., Effect of epidural stimulation of the lumbosacral spinal cord on voluntary 
movement, standing, and assisted stepping after motor complete paraplegia: a case study. 
Lancet, 2011. 377(9781): p. 1938-47. 
2. 
Garshick, E., et al., A prospective assessment of mortality in chronic spinal cord injury. Spinal 
Cord., 2005. 43(7): p. 408-416. 
3. 
Fortrat, J.O., L. Somody, and C. Gharib, Autonomic control of cardiovascular dynamics during 
weightlessness. Brain Res.Brain Res.Rev., 1998. 28(1-2): p. 66-72. 
4. 
Krassioukov, A., et al., A systematic review of the management of orthostatic hypotension after 
spinal cord injury. Arch.Phys.Med.Rehabil., 2009. 90(5): p. 876-885. 
5. 
Rosado-Rivera, D., et al., Comparison of 24-hour cardiovascular and autonomic function in 
paraplegia, tetraplegia, and control groups: implications for cardiovascular risk. J.Spinal 
Cord.Med., 2011. 34(4): p. 395-403. 
6. 
Krassioukov, A.V., D.G. Johns, and L.P. Schramm, Sensitivity of sympathetically correlated 
spinal interneurons, renal sympathetic nerve activity, and arterial pressure to somatic and 
visceral stimuli after chronic spinal injury. Journal of Neurotrauma, 2002. 19(12): p. 1521-
1529. 
7. 
Laffont, I., et al., Breathlessness associated with abdominal spastic contraction in a patient with 
C4 tetraplegia: a case report. Arch.Phys.Med.Rehabil., 2003. 84(6): p. 906-908. 
8. 
Zimmer, M.B., K. Nantwi, and H.G. Goshgarian, Effect of spinal cord injury on the neural 
regulation of respiratory function. Exp.Neurol., 2008. 209(2): p. 399-406. 
9. 
Schilero, G.J., et al., Pulmonary function and spinal cord injury. Respir.Physiol Neurobiol., 
2009. 166(3): p. 129-141. 
10. 
Linn, W.S., et al., Pulmonary function in chronic spinal cord injury: a cross-sectional survey 
of 222 southern california adult outpatients. Arch.Phys.Med.Rehabil.2000.Jun.;81.(6.):757.-
63., 2000. 81: p. 757-763. 
11. 
Walter, J.S., et al., A database of self-reported secondary medical problems among VA spinal 
cord injury patients: its role in clinical care and management. J.Rehabil.Res.Dev., 2002. 39(1): 
p. 53-61. 
12. 
Hoffman, M.D., Cardiorespiratory fitness and training in quadriplegics and paraplegics. 
Sports Med., 1986. 3: p. 312-330. 
13. 
Foll-de Moro, D., et al., Ventilation efficiency and pulmonary function after a wheelchair 
interval-training 
program 
in 
subjects 
with 
recent 
spinal 
cord 
injury. 
Arch.Phys.Med.Rehabil.2005.Aug.;86.(8.):1582.-6., 2005. 86: p. 1582-1586. 
14. 
Nici, L., et al., American Thoracic Society/European Respiratory Society statement on 
pulmonary rehabilitation. Am.J.Respir.Crit Care Med., 2006. 173(12): p. 1390-1413. 
15. 
Goulding, M., Circuits controlling vertebrate locomotion: moving in a new direction. Nat Rev 
Neurosci, 2009. 10(7): p. 507-18. 
16. 
Courtine, G., et al., Transformation of nonfunctional spinal circuits into functional states after 
the loss of brain input. Nat.Neurosci., 2009. 12(10): p. 1333-1342. 
17. 
Ichiyama, R.M., et al., Step training reinforces specific spinal locomotor circuitry in adult 
spinal rats. J.Neurosci., 2008. 28(29): p. 7370-7375. 
18. 
Alexander, M.S., et al., Outcome measures in spinal cord injury: recent assessments and 
recommendations for future directions. Spinal Cord, 2009. 47(8): p. 582-591. 
19. 
Britton, T.C., et al., Postural electromyographic responses in the arm and leg following 
galvanic vestibular stimulation in man. Exp. Brain Res, 1993. 94(1): p. 143-151. 

Page 28 of 30 
Version: 09/27/2017 
20. 
Delwaide, P.J. and P. Crenna, Cutaneous nerve stimulation and motoneuronal excitability. II: 
Evidence for non-segmental influences. J.Neurol.Neurosurg.Psychiatry, 1984. 47(2): p. 190-
196. 
21. 
Ghanim, Z., et al., Effects of galvanic mastoid stimulation in seated human subjects. 
J.Appl.Physiol, 2009. 106(3): p. 893-903. 
22. 
Iles, J.F. and J.V. Pisini, Cortical modulation of transmission in spinal refelex pathways of man. 
Journal of Physiology, 1992. 455: p. 425-446. 
23. 
Kennedy, P.M. and J.T. Inglis, Modulation of the soleus H-reflex in prone human subjects using 
galvanic vestibular stimulation. Clin.Neurophysiol., 2001. 112(11): p. 2159-2163. 
24. 
Kennedy, P.M. and J.T. Inglis, Interaction effects of galvanic vestibular stimulation and head 
position on the soleus H reflex in humans. Clin.Neurophysiol., 2002. 113(11): p. 1709-1714. 
25. 
Meinck, H.M. and B. Piesiur-Strehlow, Reflexes evoked in leg muscles from arm afferents: a 
propriospinal pathway in man? Exp.Brain Res., 1981. 43(1): p. 78-86. 
26. 
Zehr, E.P., D.F. Collins, and R. Chua, Human interlimb reflexes evoked by electrical stimulation 
of cutaneous nerves innervating the hand and foot. Exp.Brain Res., 2001. 140(4): p. 495-504. 
27. 
Cowan, J.M., et al., The effect of percutaneous motor cortex stimulation on H reflexes in muscles 
of the arm and leg in intact man. J Physiol, 1986. 377: p. 333-47. 
28. 
Delwaide, P.J. and P. Toulouse, Facilitation of monosynaptic reflexes by voluntary contraction 
of muscle in remote parts of the body. Mechanisms involved in the Jendrassik Manoeuvre. 
Brain, 1981. 104(Pt 4): p. 701-9. 
29. 
Delwaide, P.J., J.L. Pepin, and A. Maertens de Noordhout, The audiospinal reaction in 
parkinsonian patients reflects functional changes in reticular nuclei. Ann Neurol, 1993. 33(1): 
p. 63-9. 
30. 
Goulart, F., J. Valls-Solé, and R. Alvarez, Posture-related changes of soleus H-reflex 
excitability. Muscle Nerve, 2000. 23(6): p. 925-32. 
31. 
Meier-Ewert, K., U. Hümme, and J. Dahm, New evidence favouring long loop reflexes in man. 
Arch Psychiatr Nervenkr (1970), 1972. 215(2): p. 121-8. 
32. 
Serranová, T., et al., Abnormal corticospinal tract modulation of the soleus H reflex in patients 
with pure spastic paraparesis. Neurosci Lett, 2008. 437(1): p. 15-9. 
33. 
Barthelemy, D., H. Leblond, and S. Rossignol, Characteristics and mechanisms of locomotion 
induced by intraspinal microstimulation and dorsal root stimulation in spinal cats. J. 
Neurophysiol, 2007. 97(3): p. 1986-2000. 
34. 
Gerasimenko, Y.P., et al., Epidural spinal cord stimulation plus quipazine administration 
enable stepping in complete spinal adult rats. J Neurophysiol, 2007. 98(5): p. 2525-36. 
35. 
Ichiyama, R.M., et al., Hindlimb stepping movements in complete spinal rats induced by 
epidural spinal cord stimulation. Neurosci.Lett., 2005. 383(3): p. 339-344. 
36. 
Lavrov, I., et al., Epidural stimulation induced modulation of spinal locomotor networks in adult 
spinal rats. J.Neurosci., 2008. 28(23): p. 6022-6029. 
37. 
Edgerton, V.R., et al., Theoretical basis for patterning EMG amplitudes to assess muscle 
dysfunction. Med.Sci.Sports Exerc., 1996. 28(6): p. 744-751. 
38. 
McCall, G.E., et al., Spaceflight suppresses exercise-induced release of bioassayable growth 
hormone. J Appl Physiol (1985), 1999. 87(3): p. 1207-12. 
39. 
Recktenwald, M.R., et al., Effects of spaceflight on rhesus quadrupedal locomotion after return 
to 1G. Journal of Neurophysiology, 1999. 81(5): p. 2451-2463. 
40. 
Ali, A.S., K.A. Rowen, and J.F. Iles, Vestibular actions on back and lower limb muscles during 
postural tasks in man. J. Physiol, 2003. 546(Pt 2): p. 615-624. 
41. 
Bacsi, A.M. and J.G. Colebatch, Evidence for reflex and perceptual vestibular contributions to 
postural control. Exp. Brain Res, 2005. 160(1): p. 22-28. 

Page 29 of 30 
Version: 09/27/2017 
42. 
Baldissera, F., P. Cavallari, and G. Tassone, Effects of transmastoid electrical stimulation on 
the triceps brachii EMG in man. Neuroreport, 1990. 1(3-4): p. 191-3. 
43. 
Baldissera, F., H. Hultborn, and M. Illert, Integration in spinal neuronal systems, V.B. Brooks, 
Editor. 1981, American Physiological Society: Bethesda,MD. p. 509-595. 
44. 
Balter, S.G., et al., Background on methods of stimulation in galvanic-induced body sway in 
young healthy adults. Acta Otolaryngol, 2004. 124(3): p. 262-71. 
45. 
Brown, P., et al., The effect of posture on the normal and pathological auditory startle reflex. J 
Neurol Neurosurg Psychiatry, 1991. 54(10): p. 892-7. 
46. 
Burke, D., et al., Convergence of descending and various peripheral inputs onto common 
propriospinal-like neurones in man. J Physiol, 1992. 449: p. 655-71. 
47. 
Calancie, B., M.R. Molano, and J.G. Broton, Interlimb reflexes and synaptic plasticity become 
evident months after human spinal cord injury. Brain, 2002. 125(Pt 5): p. 1150-1161. 
48. 
Carlsen, A.N., et al., Identifying visual-vestibular contributions during target-directed 
locomotion. Neurosci Lett, 2005. 384(3): p. 217-21. 
49. 
Chokroverty, S., T. Walczak, and W. Hening, Human startle reflex: technique and criteria for 
abnormal response. Electroencephalogr.Clin.Neurophysiol., 1992. 85(4): p. 236-242. 
50. 
Courtine, G., et al., Recovery of supraspinal control of stepping via indirect propriospinal relay 
connections after spinal cord injury. Nat.Med., 2008. 14(1): p. 69-74. 
51. 
Dakin, C.J., et al., Frequency response of human vestibular reflexes characterized by stochastic 
stimuli. J Physiol, 2007. 583(Pt 3): p. 1117-27. 
52. 
Davis, M., et al., A primary acoustic startle circuit: lesion and stimulation studies. J.Neurosci., 
1982. 2(6): p. 791-805. 
53. 
Delwaide, P.J., C. Figiel, and C. Richelle, Effects of postural changes of the upper limb on reflex 
transmission in the lower limb. Cervicolumbar reflex interactions in man. J Neurol Neurosurg 
Psychiatry, 1977. 40(6): p. 616-21. 
54. 
Delwaide, P.J. and B. Schepens, Auditory startle (audio-spinal) reaction in normal man: EMG 
responses 
and 
H 
reflex 
changes 
in 
antagonistic 
lower 
limb 
muscles. 
Electroencephalogr.Clin.Neurophysiol., 1995. 97(6): p. 416-423. 
55. 
Faganel, J. and M.R. Dimitrijevic, Study of propriospinal interneuron system in man. cutaneous 
exteroceptive conditioning of stretch reflexes. Journal of the Neurological Sciences, 1982. 56: 
p. 155-172. 
56. 
Fitzpatrick, R., D. Burke, and S.C. Gandevia, Task-dependent reflex responses and movement 
illusions evoked by galvanic vestibular stimulation in standing humans. J.Physiol, 1994. 478 ( 
Pt 2): p. 363-372. 
57. 
Iles, J.F., A.S. Ali, and G. Savic, Vestibular-evoked muscle responses in patients with spinal 
cord injury. Brain, 2004. 127(Pt 7): p. 1584-1592. 
58. 
Kagamihara, Y., et al., Long-loop reflex from arm afferents to remote muscles in normal man. 
Exp.Brain Res., 2003. 151(1): p. 136-144. 
59. 
Lobel, E., et al., Functional MRI of galvanic vestibular stimulation. J Neurophysiol, 1998. 
80(5): p. 2699-709. 
60. 
Lowrey, C.R. and L.R. Bent, Modulation of the soleus H-reflex following galvanic vestibular 
stimulation and cutaneous stimulation in prone human subjects. Muscle and Nerve, 2009. 40(2): 
p. 213-220. 
61. 
Orlov, I.V., Y.K. Stolbkov, and V.C. Shuplyakov, Effects of artificial feedback to the vestibular 
input on postural instability induced by asymmetric proprioceptive stimulation. 
Neurosci.Behav.Physiol, 2008. 38(2): p. 195-201. 
62. 
St George, R.J. and R.C. Fitzpatrick, The sense of self-motion, orientation and balance explored 
by vestibular stimulation. J Physiol, 2011. 589(Pt 4): p. 807-13. 

Page 30 of 30 
Version: 09/27/2017 
63. 
Voordecker, P., et al., Audiogenic startle reflex in acute hemiplegia. Neurology, 1997. 49(2): p. 
470-3. 
64. 
Wardman, D.L., J.L. Taylor, and R.C. Fitzpatrick, Effects of galvanic vestibular stimulation on 
human posture and perception while standing. J.Physiol, 2003. 551(Pt 3): p. 1033-1042. 
65. 
Wardman, D.L., B.L. Day, and R.C. Fitzpatrick, Position and velocity responses to galvanic 
vestibular stimulation in human subjects during standing. J.Physiol, 2003. 547(Pt 1): p. 293-
299. 
66. 
Minassian, K., et al., Stepping-like movements in humans with complete spinal cord injury 
induced by epidural stimulation of the lumbar cord: electromyographic study of compound 
muscle action potentials. Spinal Cord., 2004. 42(7): p. 401-416. 
67. 
Kelley, 
A., 
et 
al., 
Spirometry 
testing 
standards 
in 
spinal 
cord 
injury. 
Chest.2003.Mar.;123.(3):725.-30., 2003. 123: p. 725-730. 
68. 
American Thoracic, S., ATS/ERS Statement on respiratory muscle testing. Am.J.Respir.Crit 
Care Med, 2002. 166(4): p. 518-624. 
69. 
Aslan, S.C., et al., Evaluation of respiratory muscle activation using respiratory motor control 
assessment (RMCA) in individuals with chronic spinal cord injury. J. Vis. Exp, 2013(77). 
70. 
Ovechkin, A., et al., Evaluation of respiratory muscle activation in individuals with chronic 
spinal cord injury. Respir.Physiol Neurobiol., 2010. 
71. 
Behrman, A.L., et al., Assessment of functional improvement without compensation reduces 
variability of outcome measures after human spinal cord injury. Arch Phys Med Rehabil, 2012. 
93(9): p. 1518-1529. 
72. 
Harkema, S., et al., Assessment of functional improvement without compensation for human 
spinal cord injury: extending the Neuromuscular Recovery Scale to the upper extremities. 
J.Neurotrauma, 2016. 
73. 
Geiringer, S.R., Anatomic localization for needle electromyography. 1999: Hanley & Belfus. 
74. 
Cariga, P., et al., The prevalence and association of neck (coat-hanger) pain and orthostatic 
(postural) hypotension in human spinal cord injury. Spinal Cord., 2002. 40(2): p. 77-82. 
75. 
Claydon, V.E. and A.V. Krassioukov, Orthostatic hypotension and autonomic pathways after 
spinal cord injury. J.Neurotrauma, 2006. 23(12): p. 1713-1725. 
76. 
Claydon, V.E., et al., Cardiovascular responses and postexercise hypotension after arm cycling 
exercise in subjects with spinal cord injury. Arch.Phys.Med.Rehabil., 2006. 87(8): p. 1106-
1114. 
77. 
Elliott, S. and A. Krassioukov, Malignant autonomic dysreflexia in spinal cord injured men. 
Spinal Cord., 2006. 44(6): p. 386-392. 
78. 
Cariga, P., et al., Organisation of the sympathetic skin response in spinal cord injury. 
J.Neurol.Neurosurg.Psychiatry, 2002. 72(3): p. 356-360. 
79. 
Brozek, J., et al., DENSITOMETRIC ANALYSIS OF BODY COMPOSITION: REVISION OF 
SOME QUANTITATIVE ASSUMPTIONS. Ann N Y Acad Sci, 1963. 110: p. 113-40. 
80. 
Stocks, J., et al., Plethysmographic assessment of functional residual capacity and airway 
resistance, in Infant respiratory function testing, J. Stocks, et al., Editors. 1996, Wiley-Liss: 
New York. p. 191–239. 
 
 

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