Neuromodulation of Motor and Sensory Spinal Pathways in Subjects Undergoing Epidural Spinal Cord Stimulation
Phase: NA
Conditions: Chronic Pain
Sponsor: Medical University of South Carolina

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Neuromodulation of motor and sensory spinal pathways in subjects undergoing epidural spinal cord 
stimulation.  
 
NCT04157400  
Document Date 10/15/2019 

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Neuromodulation of motor and sensory spinal pathways in subjects undergoing epidural spinal cord 
stimulation. 
 
PROTOCOL TITLE: 
Neuromodulation of motor and sensory spinal pathways in subjects undergoing epidural spinal cord 
stimulation. 
 
 
PRINCIPLE INVESTIGATOR: 
Nathan C. Rowland, MD, PhD 
 
CO-INVESTIGATOR: 
Mark G. Bowden, PT, PhD 
 
 
 
 
 
 

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1.0 Objectives/Specific Aims 
Each year, an estimated 34,000 spinal cord stimulation (SCS) surgeries are performed worldwide for treatment 
of debilitating chronic low back and leg pain (CLBLP).1 Although the commercial application of SCS to treat 
CLBLP was approved by the FDA in 1989, only in the past decade have significant advancements in stimulator 
technology been introduced. For instance, traditional SCS devices achieved reduction in pain using a type of 
stimulation known as low-frequency tonic stimulation (LFTS, below 100 Hz), which was dependent on induction 
of paresthesias (i.e., a tingling sensation) over the areas of pain perception.2 However, we now know that 
LFTS compromises sensory information flowing back to the spinal cord, which can be important in other spinal 
cord functions such as proprioception and movement. In contrast, recent innovations in stimulator technology 
now provide the capability to apply stimulation frequencies up to 10,000 Hz along with complex waveform 
patterns – known as high frequency burst stimulation or HFBS - that can mitigate pain perception without the 
induction of paresthesias and the negative consequences on proprioception and movement.3  We propose to 
study the effects of these recently introduced features in SCS technology on motor and sensory spinal 
thresholds, proprioception and movement in subjects with CLBLP. 
 
The spinal cord relies on input from the motor cortex as well as sensory information from the extremities to 
carry out specific actions. For example, recent evidence suggests that preservation of temporally specific 
proprioceptive information via dorsal column primary afferent fibers is critical for motor behaviors such as 
ambulation.3,4 Since the spinal cord is exposed during the placement of the SCS device, information about a 
subject’s motor and sensory spinal pathways can be easily obtained during the regular course of the procedure 
and compared to proprioceptive and motor responses once the subject is awake and moving with the device 
turned on. Our lab specializes in electrophysiological recordings in subjects undergoing spinal cord stimulator 
(SCS) implantation for CLBLP, while MUSC’s Locomotion Laboratory specializes in quantifying proprioception 
and movement in human subjects. In this proposal, we will apply these techniques to subjects with CLBLP to 
determine effects of spinal neuromodulation on motor and sensory thresholds, proprioception, and 
kinematics.5,6 Our plan includes the following specific aims:  
 
Aim 1. Compare the effects of LFTS and HFBS on motor and sensory thresholds intraoperatively. 
Question: Do HFBS waveform patterns modulate motor and sensory thresholds to allow more information to 
reach the spinal cord? In this aim, we will measure sensory and motor spinal thresholds in subjects undergoing 
SCS implantation during stimulation of epidural paddle contacts. We hypothesize that HFBS will reduce motor 
and sensory thresholds relative to LFTS during epidural paddle activation. 
 
Aim 2. Determine the effect of HFBS on proprioceptive afferent signaling from lower extremity muscle 
groups. Question: Does HFBS, when compared to traditional LFTS, allow for increased spatial limb 
awareness during passive motion? In this aim, postoperative subjects from SA1 will undergo isokinetic passive 
proprioceptive testing before, during and after spinal cord stimulation with HFBS and LFTS parameters 
targeting musculature surrounding the knee. We hypothesize that subjects will have increased awareness of 
the lower limb in space through passive movement during optimal HFBS compared to optimal LFTS 
parameters. 
 
Aim 3. Determine the effect of HFBS on lower extremity musculature during gait. Question: Does HFBS, 
when compared to LFTS, differentially affect muscle synergy patterns during gait? In this aim, subjects from 
SA1 and SA2 will perform treadmill walking before, during and after SCS stimulation. Subjects will be 
monitored with surface EMG and 3-D kinematic tracking software to quantify any changes in walking pattern. 
We hypothesize that subjects will have increased EMG module complexity during gait while experiencing 
optimal HFBS compared to optimal LFTS or no stimulation. 
 
 
 
 
 

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2.0 Background 
 
Significance 
SCS is currently used to treat chronic neuropathic pain that may arise from spinal injury, disease, and/or 
previous spinal surgery, for example, in cases of post-laminectomy syndrome, the most common indication for 
SCS. SCS surgery represents 70% of all neuromodulation cases in the United States and is expected to grow 
as the intervention shows continued promise to successfully treat neuropathic pain from these and many other 
etiologies.1 With the introduction of new charging capacities, stimulation frequencies and waveform patterns, 
questions about potentially new mechanisms of pain reduction as well as effects on other spinal cord functions, 
such as movement and balance, have gained urgency. 
 
SCS was originally based on a concept known as the gate control theory of pain. Gate control theory 
postulates that central regulation of pain involves nonnociceptive fibers (large Aβ fibers in the dorsal column 
medial lemniscal pathway) that inhibit nociceptive fibers (Aδ and C fibers in the spinothalamic pathway) and 
thus reduce both pain transmission in the spinal cord as well as perception by higher brain centers.7 The SCS 
procedure involves placement of epidural electrodes that when activated recruit lower threshold Aβ fibers that 
produce a paresthetic sensation along the region of pain. The antidromic projections to dorsal horn 
interneurons influence two additional downstream targets: fibers that further inhibit pain transmission and 
ventral motor neuron pools that target specific myotomes . 8 
 
In 2009 Harkema et al investigated the motor effects from LFTS at intensities strong enough to elicit 
paresthesias, ranging from 5-60 Hz (frequency), 210 to 450 µs (pulse width) and amplitude ranging from 0.1 to 
8.0 V. Using these parameters, LFTS was found to elicit lower extremity muscle activity including co-activation 
during standing, rhythmic activation during stepping, and mechanically appropriate activation of agonist lower 
extremity muscles during weight shift in a subject with spinal cord injury.9 Additionally, Gill et al introduced the 
application of multiple independent current control (MICC) which allows for different stimulation parameters on 
the paddle to be delivered in tandem, innervating spatially distinct regions of the spinal cord. The MICC 
programs supported bilateral tasks, suggesting that complex charge delivery via MICC can enable independent 
modulation of both spinal sensory and motor neuron pools. 
 
The ability to program customized HFBS patterns may help to address another important factor in potentially 
expanding the use of SCS to other indications, including movement: preservation of proprioception. The 
amount of compromised afferent information during traditional spinal cord stimulation via LFTS is dependent 
upon the quantity of dorsal column primary afferents recruited and is proportional to increases in current and 
pulse width.3,10 Traditional stimulation parameters (15Hz-100Hz, 210µs–450µs, 4.5mA–9.0mA) were found to 
cause decreased interneuron modulation of inhibitory/excitatory interneurons from antidromic collision when 
amplitudes are high enough to innervate their homonymous motor neuron pool to activation threshold. 
However, high frequency burst stimulation (HFBS) at 600Hz was found to illicit motor neuron activation with a 
39.8% reduction in current amplitude and 15% recruitment of modeled homonymous afferents, as opposed to 
45% recruitment utilizing LFTS to elicit similar motor neuron activation.3 
 
3.0 Intervention to be studied 
 
Overview 
This study will perform the following research-specific procedures: 
1) Determination of eligibility through medical chart review  
2) Recording and stimulation of spinal potentials during insertion of epidural spinal stimulator paddle  
3) Proprioception testing 
4) Body weight support and treadmill (BWST) testing  
 

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Definitions and nomenclature 
Spinal cord stimulation (SCS) will be performed using a 32-electrode 
paddle array (Boston Scientific, Marlborough, MA) (Figure 1) implanted in 
the dorsal epidural space along the thoracolumbar region of the spinal 
cord. The array will be powered by a multiple independent current-
controlled (MICC) implantable pulse generator (IPG) connected to the 
paddle per standard of care procedures for SCS implantation. In addition, 
as per standard of care, motor evoked potential (MEP), somatosensory 
evoked potential (SSEP) and electromyography (EMG) will be performed 
via 
the 
IOMAX 
intraoperative 
neuromonitoring 
system 
(Cadwell, 
Kennewick, WA) and LR10 (Tucker Davis Technologies, Alachua, FL) 
recording device. The SCS system will be placed for clinical purposes, 
i.e., treatment of chronic pain, however, we will collect data at various 
points during the placement. The study procedures will add 15 
minutes to the surgery. MUSC’s Locomotion Rehabilitation Laboratory 
– located at the College of Health Professions Building C - houses a 
Biodex Pro System 4 isokinetic/isometric dynamometer (Biodex Medical 
Systems, Shirley, NY). The Biodex will standardize application of passive 
isokinetic knee flexion/extension trials to each blinded subject for 
proprioceptive investigations, which will be referred to as threshold to detect passive movement (TTDPM) 
throughout the rest of this document. Finally, MUSC’s Locomotor Energetics and Assessment Laboratory – 
also located at the College of Health Professions Building C – houses a dual belt Instrumental Treadmill 
(Bertec, Scotland, U.K.) that is coplanar with the floor and will be used during all walking events. The 
laboratory also has a 12-camera motion capture system (PhaseSpace, San Leandro, CA) that utilizes active 
infrared LED tracers to track kinematic positioning data and will be used during all walking events. Another tool 
offered by the lab is a 16-channel EMG system (Motion Labs, Baton Rouge, LA, model MA300-XVI) which 
utilizes surface electrodes to detect target muscle activity and will also be used during all walking events. In all, 
we expect total duration of the study to be approximately 30 days. 
 
Device use 
The epidural stimulator paddle (Boston Scientific, Marlborough, MA, model 4x8 CoverEdge™ 32) and IPG 
(Boston Scientific, Marlborough, MA, model Spectra WaveWriter™) are FDA-approved, commercially available 
devices designed to treat chronic pain of the back and lower extremities and will be used for their intended 
clinical purpose – electrical stimulation of dorsal column fibers to mitigate pain perception. The research use of 
this device, which will add approximately 15 minutes to the surgery, involves recording/stimulating from the 
device during the standard of care intraoperative neuromonitoring protocol. Regardless of study participation, 
the stimulator paddle and IPG will be implanted according to standard of care for the pre-planned SCS surgery. 
The IOMAX intraoperative neuromonitoring system (Cadwell, Kennewick, WA), equipment owned by MUSC 
and operated by MUSC neurophysiology staff, is a commercially available device used during standard of care 
spinal surgical procedures, such as SCS implantation. Regardless of study participation, intraoperative 
neuromonitoring via IOMAX will take place according to standard of care for the pre-planned SCS surgery. The 
following devices are used for research purposes only. The LR10 is a physiological signal amplifier and 
analog to digital converter that will be used to record from the stimulator paddle during standard of care 
neuromonitoring protocols. The Biodex Pro System 4 (Biodex Medical Systems, Shirley, NY), used regularly 
by physical rehabilitation researchers here at MUSC, is a commercially available device that will be used solely 
as a research tool to deliver passive isokinetic knee flexion/extension during the TTDPM. The Instrumental 
Treadmill (Bertec, Scotland, U.K), GAITRite mat (CIR Systems, Franklin, NJ), motion capture system 
(PhaseSpace, San Leandro, CA), and MA300 EMG system (Motion Labs, Baton Rouge, LA) are all 
commercially available devices that are used by MUSC researchers at the College of Health Professions to 
perform extensive gait analysis in subjects with various neurological deficits. Gait analysis is being performed 
Figure 1: Boston Scientific CoverEdge™ 32 
Surgical Lead (left) and fluoroscopic image of 
the stimulator array after implantation along 
the dorsal epidural space (right). 

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for research purposes only, and is not standard of care for patients receiving SCS surgery. All medical devices 
are to be used as they are FDA approved and marketed. 
 
 
4.0 Inclusion and Exclusion Criteria / Study Population. 
 
All diagnostic procedures will have taken place prior to recruitment as part of the routine diagnosis and care of 
patients with chronic pain. It is standard of care to require failure of conservative therapy, e.g., 6 weeks of 
physical therapy and/or 1 or more epidural steroid injections, and SCS temporary trial by a board-certified pain 
management specialist in addition to neuropsychological testing by a board-certified neuropsychologist prior 
to being considered for permanent SCS implantation. 
 
Eligibility for this study will be based on the following inclusion/exclusion criteria: 
 
Research Inclusion Criteria 
- 
Subjects diagnosed with CLBLP by a pain specialist with a documented referral for evaluation of 
SCS surgery  
- 
Subjects with the ability to walk 
- 
Age 18-80 
 
Research Exclusion Criteria 
- 
Subjects with the inability to consent for themselves. 
- 
Prior history of spinal neoplasm, infection, arteriovenous malformation and/or radiation to the spine 
 
The rationale for these research related criteria are as follows: subjects with prior history of tumor, infection, 
arteriovenous malformation and/or radiation of the tissues surrounding the epidural space may result in 
formation of scar tissue which directly alters the resistance of the tissue to passing electrical current, potentially 
confounding study data. None of the research exclusion criteria would exclude a patient from undergoing SCS 
surgery for non-research purposes, therefore the exclusion criteria apply only to the research being performed 
for this protocol. 
 
5.0 Number of Subjects 
We propose to study 5 individuals with CLBLP. A prior study conducted by Formento et al, 2018 using SCS 
and proprioceptive testing published a standard error and 95% confidence interval using successful and 
unsuccessful SCS trial attempts (p < 0.05 among LFTS parameters and no stimulation, with a minimum of 10 
trials per stimulation setting.)3 Based on this, we expect that our small population will exhibit similar variance. 
The subject sample size is in direct comparison to sample sizes of previous proof of concept studies regarding 
SCS for spinal cord physiology biomarker sampling.3,9,11 The research team plans to use a two-way repeated 
measures ANOVA model in order to investigate the varying differences in stimulation type and kinematic 
parameters. A Post hoc comparison will be made using a Tukey adjustment. 
 
 
6.0 Setting 
The data pertaining to Aim 1 for this study will be recorded in the operating room at MUSC Main Hospital. Data 
collected during Aims 2 and 3 will be recorded in the Locomotor Rehabilitation Laboratory and the Locomotor 
Energetics and Assessment Laboratory respectively, which are both located in the College of Health 
Professions Building C at MUSC. Coded and identifiable data will be stored electronically on a secure server in 
separate folders. Signed consent forms will be located in a locked cabinet in a locked laboratory in the Clinical 
Sciences Building at MUSC. In all, we expect total duration of the study to be approximately 30 days for each 
subject. 
 
7.0 Recruitment Methods 

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During the subject’s preoperative clinic visit, the PI will ask the potential participant if they would like to learn 
more about the study. If so, the PI will introduce the study and ask if he can answer any further questions 
about the study before inviting in the PI’s physician assistant (listed as a study team member). The PI will then 
leave the room and the PI’s physician assistant will review a prescreening checklist to determine whether 
subjects may be eligible for the study (no information obtained during the prescreening will be documented as 
research data). For the screening, potential participants will be asked to confirm that they are between the 
ages of 18 and 80, that they have been previously diagnosed with CLBLP by a pain specialist, and whether 
they have any prior history of spinal neoplasm, infection, arteriovenous malformation and/or radiation to the 
spine. If potential participants answer no to either of the first two questions or yes to either of the remaining 
questions, they will be considered ineligible for the study. Otherwise, the PI’s physician assistant will review the 
informed consent form (ICF) with the potential participant and then leave the room in order to give the potential 
participant sufficient time to read the ICF. 
 
Next, the PI’s physician assistant will conduct a brief medical chart review using Epic to confirm that the 
patient’s age is between 18 and 80 and that the patient has a documented referral from a pain specialist to 
undergo evaluation by the PI to undergo SCS surgery. The Epic ‘Medical History’ tab will also be checked to 
rule out prior history of spinal neoplasm, infection, arteriovenous malformation and/or radiation to the spine. 
 
Careful attention will be placed on good communication. It will be emphasized that participation in the study is 
not necessary for standard of care medical treatment for their condition. It will also be emphasized that the 
subject can withdraw from the study at any time. 
8.0 Consent Process 
Once the potential participant has been given an opportunity to review the consent form in detail, the PI’s 
physician assistant will re-enter the room and go over the sections of the consent with the participant. She will 
answer any questions the potential participant may have. The voluntary nature of the study will again be 
emphasized. It will also be emphasized that the potential participant may exercise their right to take the 
consent form home to discuss with family and friends prior to signing. For potential subjects that provide 
consent to the research study during their clinic visit, a copy of the signed and dated ICF/HIPAA authorization 
form will be provided to them before leaving the clinic. Original forms will be placed in a locked cabinet in a 
locked laboratory in the Clinical Sciences Building at MUSC. On the morning of surgery, IRB-approved study 
personnel will once again review the study procedures and study consent documents – emphasizing the 
voluntary nature of the study and the ability of the subject to withdraw at any time. Subjects who did not sign 
the ICF/HIPAA authorization form during their clinic visit and who still wish to participate in the study will be 
able to sign the forms on the morning of surgery, at which time a copy of the signed and dated forms will be 
provided to them. 
 
9.0 Study Design / Methods 
 
Step 1: Recording and stimulation of spinal potentials during insertion of epidural spinal stimulator 
paddle  
 
On the day of the surgery, subjects will first be placed under general anesthesia for the procedure. Next, after 
positioning the subject on the operating room table, subdermal MEP, SSEP and EMG needle electrodes will be 
placed throughout the body by the neurophysiology team as determined by standard of care guidelines. Once 
the epidural paddle is placed by the surgeon, study procedures will begin by (#1) connecting the terminals of 
the paddle to the LR10 (Tucker Davis Technologies, Alachua, FL) for amplification, filtering and recording of 
electrophysiological signals. Using this recording setup, (#2) MEP and SSEP protocols will be performed to 
determine motor and sensory thresholds, respectively. Next, the surgical procedure will resume and after the 
IPG has been placed, study procedures will begin again and include (#3) activation of both low-frequency tonic 
stimulation (LFTS) and high-frequency burst stimulation (HFBS) patterns from the inserted paddle while 
recording EMG signals.12-13 The surgical procedure being performed (SCS paddle and IPG implantation) for 

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clinical purposes will not deviate in any way from standard of care. The recording and stimulation study 
procedures will occur using equipment already present in the operating room used to test the SCS system as 
per standard of care in addition to the LR10 (Tucker Davis Technologies, Alachua, FL) signal recording 
machine. All devices will be used for their FDA-approved intended use. Our study procedures are expected to 
add approximately 15 minutes to the SCS procedure and will be paid for by internal funds. The standard of 
care versus the research procedures are diagramed below:  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Step 2: Proprioception testing before, during and after SCS stimulation 
All of the following are for research purposes and not considered standard of care for SCS surgery. Following 
an approximately 30-day recovery period from surgical placement of the paddle and IPG, subjects will undergo 
Subject is placed under general 
anesthesia 
and 
positioned 
face 
down. The neurophysiology team 
places subdermal needles for MEP, 
SSEP and EMG measurements and 
connects the wires to the IOMAX 
intraoperative 
neuromonitoring 
system (owned and paid for by 
MUSC). Skin incision is made. The 
SCS paddle is placed into initial 
position. 
The 
neurophysiology 
team 
then 
performs 
MEP 
and 
SSEP 
measurements. The surgeon makes 
small adjustments to the position of 
the paddle based on this information. 
Once the SCS paddle is in initial 
position, 
the 
research 
team 
connects the SCS paddle terminals 
to the LR10 machine (owned and 
paid for by the Rowland lab, takes 
less than 1 minute).  
The research team saves data from 
the SCS paddle as the MEP and 
SSEP 
measurements 
are 
performed (takes 0 minutes). 
Once the SCS paddle is in its final 
position, the SCS paddle terminals 
are disconnected from the LR10 
machine 
and reconnected to 
a 
Boston 
Scientific 
external 
stimulator (owned and paid for by 
Boston Scientific – leaves the OR 
with Boston Scientific representative). 
The stimulator tests the impedance of 
each contact. 
Once 
the 
impedances 
are 
confirmed, the external stimulator is 
used to test each contact on the 
paddle and compare low- and high-
frequency stimulation patterns as 
prescribed by the study protocol 
(takes approximately 15 minutes). 
Standard of care procedures 
Research procedures 

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stimulation configuration mapping (SCM)3,9,11 in the Locomotor Rehabilitation Laboratory at the College of 
Health Professions Building C at MUSC in order to determine electrode and parameter configurations that elicit 
activation of lower extremity musculature. For this testing, we will place surface EMG pads on subjects’ skin 
overlying muscles of interest. Using the Boston Scientific external stimulator interface, we will wirelessly 
activate the implanted spinal paddle and compare muscle activation using LFTS and HFBS patterns by 
systematically testing each individual contact. Subjects will comfortably lie supine on a large, low-rise 
rehabilitation mat common to any physical rehabilitation clinic during SCM. 
 
Next, we will investigate the perceived change in knee joint angle and direction of 
movement reported by the subject in a Threshold to Detect Passive Movement 
(TTDPM) task.3,14 The TTDPM protocol will begin with the subject sitting in the 
Biodex testing seat, with the non-tested leg hanging freely and the tested leg 
strapped to the rotating arm of the dynamometer at the lower shank. The subject 
will be blinded as to the mode and intensity of stimulation: HFBS, LFTS, or no 
stimulation. Furthermore, in order to shield the subject from witnessing initiation, 
direction and approximate distance traveled of the shank, the subject will be asked 
to wear a blindfold and headphones playing a soft background noise (Figure 3). 
The TTDPM will consist of at least 10 trials for each stimulation condition. The 
subject has control of a switch that immediately halts movement of the rotating arm, 
which is to be activated once the subject perceives movement OR if the subject 
begins to feel any pain or discomfort throughout the task. Our research team 
anticipates data collection to last approximately 3 hours per subject for this step (1 
hour for supine SCM, 1 hour for TTDPM and 1 hour for set up and breakdown). 
Proprioception testing will take place before, during and after SCS stimulation. 
 
Step 3: Body weight support and treadmill (BWST) testing before, during and after SCS stimulation 
 
 
All of the following are for research purposes and not considered standard of care for SCS 
surgery. The following methods for gait and EMG module analysis have been developed 
and extensively tested by MUSC researchers at the College of Health Professions.15-18 
Similar to step 2, LFTS and HFBS patterns will be compared by systematically testing 
each individual contact on the paddle while investigating for changes in stepping speed, 
pattern and EMG moduling complexity. Regarding EMG module analysis, muscle activity 
will be recorded bilaterally via surface EMG from the medial gastrocnemius, soleus, tibialis 
anterior, rectus femoris, vastus medialis, biceps femoris, semimembranosus and gluteus 
medius. Furthermore, subjects will also have active LED markers placed over their clothes 
in order to track whole body kinematics throughout this portion of the study. 
 
First, subjects will walk across a GAITRite mat (CIR Systems, Franklin, NJ) to measure 
self-selected overground walking speed and other spatiotemporal gait parameters. 
Subjects will then be permitted to practice walking on the Instrumental Treadmill until they 
feel comfortable. To optimize capture of steady state data on the treadmill, each subject 
will walk for approximately 10 sec prior to the 30 sec of data collection (40 sec per trial). 
This will allow capture of at least 10 consecutive steady state gait cycles (depending on 
cadence) per each amplitude selection for each stimulation delivery technique, which will 
be defined by parameters found during walking SCM. We will allow as much rest as 
needed between trials. For all trials, subjects will wear their own low-heeled shoes. A 
safety harness (Robertson Mountaineering, Fort Collins, CO) mounted to the laboratory ceiling will be worn by 
the participant to protect them in the event of loss of balance. Our research team anticipates data collection to 
last approximately 2 hours per subject for this step (1 hour for walking SCM and gait analysis and 1 hour for 
set up and breakdown). For their participation in step 2 and step 3 of the study, participants will be 
Figure 4: 
Demonstration of 
treadmill walking 
while undergoing 3-
D kinematic tracking 
and EMG capture. 
Figure 3: TTDPM test using a 
Biodex  

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remunerated $50.00 in the form of a check ($10.00 for lunch reimbursement and $40.00 for completion of 
steps 2 and 3). 
 
Through EMG capture and high/low bandpass filtering to extinguish biologic artifact and equipment artifact 
respectively, segments of EMG that were recorded through functional task can be analyzed with an algorithm 
that yields hierarchical complexities representative of muscle synergies.5-6,19  The research team will use 
previously outlined methodology to define modules through non-negative matrix factorization, where analysis 
will be applied to consecutive gait cycles.20  
 
The Instrumental Treadmill (Bertec, Scotland, U.K), GAITRite mat (CIR Systems, Franklin, NJ), motion capture 
system (PhaseSpace, San Leandro, CA), and MA300 EMG system (Motion Labs, Baton Rouge, LA) have 
been used in the same manner described above in the following MUSC IRB approved protocols: 
Pro00028941, Assessment of contributions to impaired walking after neurologic injury; Pro00088728, Fatigue 
and mobility in stroke: a biomechanical and neurophysiological investigation; Pro00048394, The effects of 
impaired post-stroke coordination and motor pathway integrity on mobility performance; Pro00059390, A novel 
mechanics-based intervention to improve post-stroke gait stability. 
 
10.0 
Data Management 
Once a potential participant is asked if they would like to learn more about the study, they will be assigned a 
participant ID. Participant IDs will be assigned consecutively. We will maintain a database that accurately 
reflects all potential subjects that were approached about the study and the results of eligibility evaluation. For 
eligible subjects, the specific types of data that will be collected include: 1) analog local field potentials from the 
SCS, MEP, SSEP and EMG electrodes, 2) digital and analog output signals from the IOMAX intraoperative 
neuromonitoring device, 3) digital, time-stamped, physical displacement data captured from the Biodex 
machine, 3) digital, time-stamped, positioning data produced by the PhaseSpace software, 5) videography 
data, and 6) any available imaging data (dicom files). Raw data will remain on our lab-owned data acquisition 
machines with encrypted hard drives and stored behind a locked door when not directly supervised. Data will 
be copied from all lab-owned data acquisition machines and/or hospital-owned data servers to a password 
protected network server accessible from our lab under the IRB protocol number and participant ID. This will 
constitute the master copy of all data for the lab and will consist of separately stored coded and identifiable 
folders. The purpose of keeping a copy of the raw data is in case the server is interrupted, and it is necessary 
to reconstruct the data. Portions of data will be copied to end-user devices (e.g., desktop, laptop, etc) for data 
analysis, however only the portion needed for analysis will be copied. Any end-user device such as a laptop 
that physically leaves the lab will be encrypted with MUSC-approved software (BitLocker, Microsoft Corp., 
Redmond, WA) which uses the AES encryption algorithm in cipher block chaining or XTS mode with a 256-bit 
key. Desktop machines used for analysis that do not leave the lab and are stored in a locked laboratory will not 
be encrypted. All data on data acquisition and end-user devices will be deleted at the conclusion of the study. 
No PHI will be stored on any data acquisition machine or end-user device. A linking database associating the 
participant ID and subject identifiers will be maintained on MUSC Box, separately from the research data. 
Subject identifiers to be collected include first and last name, gender, date of birth, social security number, 
medical record number, mailing address and telephone numbers. Telephone and medical record numbers are 
required for an approximate 7-day phone call made to subjects following SCS implantation. Additionally, we will 
collect information pertaining to disease severity for each subject, including Visual Analog Scale (VAS) scores, 
a common pain scale, and any other available rating scale scores. These measures will assist in correlating 
our physiological data with severity of disease for each subject. Videography data will be stored in the 
identifiable folder on the password protected network server. The purpose of this data is to correlate movement 
dynamics with physiology data. Finally, we will save imaging data on a password protected network server in 
order to analyze and correlate with our physiological data. Only IRB-approved personnel will have access to 
the linking database. Consent forms will be stored in a locked cabinet in a locked laboratory in the Clinical 
Sciences Building at MUSC.  
 
11.0 
Provisions to Monitor the Data to Ensure the Safety of Subjects 

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Data and Safety Monitoring Plan 
The proposed research involves use of a neural stimulation device and warrants oversight by a Data Safety 
Monitoring Board (DSMB). The primary purpose of the DSMB is to ensure the safety of participants and the 
validity and integrity of data collected during the study. The overall framework involves biannual review of the 
enrollment, safety and adverse event data, and quality control data by the DSMB throughout the period of the 
proposed research. 
 
DSMB composition 
The DSMB will be appointed by the PI and will be composed of individuals who are not on the study team and 
have the following qualifications: (1) a clinical electrophysiologist with expertise in electrical neuromodulation 
and intraoperative monitoring, (2) a board-certified neuropsychologist who specializes in treatment of pain 
syndromes, and (3) a biostatistician with expertise in design and analysis of clinical trials. These three 
individuals bring substantial expertise adequate to monitor data and safety for the proposed research. 
 
DSMB responsibilities 
The responsibilities of the DSMB are as follows. Prior to any enrollment, the DSMB will review the study 
design, protocol, recruitment/enrollment plan, statistical analysis plan, and data and safety monitoring plan. 
Once enrollment begins, the DSMB will convene every 6 months to review the enrollment data, the safety and 
adverse event data and quality control data (see below for detailed data description). The DSMB will review the 
aggregated summary data as well as the individual participants’ data (de-identified). The DSMB may provide 
recommendations for any safety concerns. The DSMB may recommend stopping the study early if the protocol 
has significant safety concerns. The DSMB will review the results and document their reviews in writing. In 
summary, the stopping rules are if the study has unanticipated safety concerns. The DSMB will also be able to 
make recommendations for appropriate action to maintain a reasonable safety profile for the study. The PI will 
provide a report for the IRB to review that summarizes oversight activities, DSMB recommendations and any 
concerns regarding participant safety. 
 
Safety reporting to the DSMB 
Subjects may report safety issues with the study directly to the PI, any member of the PI’s clinical and/or 
research teams, the MUSC Family Care Liaison, the IRB and/or ORI Director. In the absence of any such 
reports, the PI will systematically attempt to uncover any safety issues experienced by a subject during the 
approximate one week follow-up phone call. Any of the following will be reported to the DSMB if noted by the 
subject during the approximate one week follow-up phone call following SCS surgery (Aim 1): severe lower 
back or leg pain unresponsive to pain medication, repeated falls/imbalance, excessive bleeding from wounds, 
lower back irritation or bleeding around the site of paddle or IPG implant and/or return to the hospital. Any of 
the following will be reported to the DSMB if noted during the approximate 30-day return appointment (Aims 2 
and 3): return to hospital, evaluation by another provider for findings related to spinal cord stimulation surgery, 
imaging, lab values and/or other reports indicating complications from spinal cord stimulation surgery. All the 
above-mentioned issues are outside of what would be reasonably expected for a normal postoperative course 
following spinal cord stimulation surgery. In accordance with HRPP Section 4.7, all the above-mentioned 
issues constitute adverse events and will be submitted to the DSMB for review (at 6 month intervals) in 
addition to being recorded in an adverse event log. In addition to serious adverse events, events that are 
unexpected, related or possibly related to a subject’s participation in the research and suggests that the 
research places subjects or others at greater risk of harm than was previously known or recognized constitute 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs) and must be reported directly to the 
IRB (in addition to the DSMB). Finally, all deaths will be reported to the IRB within 24 hours of learning of the 
death, unless the death is expected (e.g., due to disease progression).  
 
12.0 
Withdrawal of Subjects 
Subjects may be withdrawn from the study without their consent, including stopping participation for safety 
reasons. For example, if at any point during the protocol it becomes evident that continuing with the study 

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would present risk in excess of that outlined in this document, data collection for that subject may be 
terminated. However, any data collected before the incident may still be used in analysis. At any time, subjects 
may also express desire to withdraw from the study. We will instruct the subjects that, to withdraw from the 
study, all they need to do is to contact one of the members of the study team and express the desire to be 
excluded from the study. 
 
13.0 
Risks to Subjects 
All procedures will follow standard of care guidelines. Research staff will follow up with each participant by 
phone approximately one week after the surgical procedure, and during the approximate 30-day return, to 
make sure the participants are not having any problems. Nevertheless, this study still poses certain risks as 
outlined in the following sections: 
 
Surgical complication – Due to the 15 extra minutes added to the surgery, connection of the paddle terminals 
outside the surgical field, and extra personnel in the room, there is a slightly increased risk of surgical infection. 
The extra risk of infection due to the research protocol does not increase this risk beyond the 1-5% overall 
historical risk of complications from the SCS surgical procedure. 
 
TTDPM 
While testing for proprioception retention of the lower extremities, subjects may encounter discomfort due to 
non-volitional muscle activation that hinders passive movement. To mitigate this risk, the Biodex system has a 
subject-controlled trigger that immediately stops the dynamometer’s passive motion and may be activated at 
any time a subject experiences discomfort of pain during the test.  
 
Overground and Treadmill Walking  
Subjects will be asked to walk on a pressure sensitive mat at self-selected walking speeds and on a treadmill 
at self-selected walking speeds with each scenario having the subject in an upper thoracic safety harness 
which is tethered to the ceiling for fall protection. Despite the aforementioned safety measures, there still exists 
a risk of loss of balance, fall and potential injury. The risk to subjects through these tasks do not exceed risks 
involved with general physical therapy settings and may result in mild muscle fatigue or discomfort that 
generally subsides within a few days. Subjects will be given ample rest time and may have additional rest time 
at any point throughout data collection periods. Furthermore, subjects will be assisted during large movements 
or during potential transfers across different surfaces by an IRB-approved study member.  
Photography and videography 
Subjects will be videotaped during performance of supine / walking SCM and EMG moduling protocols. We will 
also photograph and/or videotape any other aspect of the subject’s research participation that will help us 
correlate the subject’s condition with the EMG and kinematic data. The videos and photos we record can 
include the full face, upper body, arms, and legs. Photography and videography carry a risk of loss of privacy. 
Photos and videos will be stored on a secure server. Only approved study personnel will have access to these 
files. 
Loss of Confidentiality 
Additional risks include loss of confidentiality. To mitigate this risk, a linking database associating the 
participant ID and subject identifiers will be maintained separately from the research data on a password 
protected server and only IRB-approved personnel will have access to the linking database. 
 
 
14.0 
Potential Benefit to Subjects or Others 
This research is not expected to provide direct benefit to individual subjects, though it may lead to 
improvements in care for patients suffering from chronic pain in the future. A successful study outcome may 
contribute to this improvement and may be used in future subjects undergoing similar procedures. 

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15.0 
Sharing of Results with Subjects 
Due to the extensive amount of time needed for data processing, it will not be possible to disclose individual 
study results to subjects or their healthcare providers. Incidental findings and other results of diagnostic tests 
associated with routine care of subjects will be shared with the subject and their physician by phone, writing 
and/or electronic medical record communication by the PI. 
 
16.0 
Drugs or Devices 
 
All of the following medical devices are to be used as they are FDA approved and marketed. 
 
The LR10 (Tucker Davis Technologies, Alachua, FL), used for signal recording from SCS paddle during 
MEP and SSEP procedures is a non-diagnostic physiological signal amplification device. The device is 
exempt from Investigational device exemptions (IDE) regulation per 21 CFR 812.2 paragraph C 
(exempted investigations) subparagraph 3. (please see 21_CFR_812.2_Exempt_Devices.pdf) 
 
The Biodex Pro System 4 (Biodex Medical Systems, Shirley, NY), used during the TTDPM testing, is an 
upgraded version of a previous Isokinetic dynamometer (Biodex System 3) that was also classified as a 
510K/Pre-market notification device (K951770). Due to the similar nature and intent of use for the upgraded 
model, the Biodex Pro System 4 is exempt from 510K classification as per 21 CFR 890 Subpart A and 21 CFR 
890 Subpart B 890.1925 Isokinetic testing and evaluation system classification. (please see 510(k)_Biodex 
System 3_Biodex Medical.pdf , 510(k)_PremarketExemption.pdf) 
 
The MA300 EMG system (Motion Labs, Baton Rouge, LA), used during EMG module analysis, is a 510K/Pre-
market notification device (K974385) as described in 21 CFR 807 Subpart E (please see 
510(k)_MotionLabs_EMG.pdf) 
 
 
17.0 
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