CRCNS: Model-based Characterization of Spinal Cord Stimulation for Pain
Phase: NA
Conditions: Chronic Pain, Failed Back Surgery Syndrome, Complex Regional Pain Syndromes, Neuropathic Pain
Sponsor: University of Michigan

 
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24 May 2024 
 
 
 
 
 
 
 
 
 
 
 
CRCNS: Model-based Characterization of Spinal Cord Stimulation for 
Pain 
 
NCT04732325 
 
 
 
 

 
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24 May 2024 
CRCNS: Model-based characterization of spinal cord stimulation for 
pain 
A randomized, double-blind, placebo-controlled, crossover, mechanistic study 
investigating the pain-relieving effects of multiple forms of spinal cord stimulation (SCS) 
(i.e., tonic 50 Hz, burst, tonic 1 kHz, sham) in 25 patients undergoing SCS as part of 
their standard of care for chronic pain management. 
 
 
Study Chairman or Principal Investigator:  
Scott F. Lempka, PhD 
Assistant Professor, Biomedical Engineering 
Assistant Professor, Anesthesiology 
University of Michigan 
 
Supported by:  
 
The National Center for Complementary and Integrative Health  
Grant number: 1R01AT010817-01 
 
Study Intervention Provided by:  
N/A 
 
Sponsor of IND (IDE):   
N/A. This study is post-approval mechanistic study using FDA-approved devices that 
will be used in accordance with approved labeling. 
 

 
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Tool Revision History 
Version Number: 0.1  
Version Date: July 13, 2020 
Summary of Revisions Made: Initial draft. 
Version Number: 0.2 
Version Date: November 16, 2020 
Summary of Revisions Made: Updated consent language to include an optional electronic 
consent. 
Version Number: 1.0 
Version Date: December 22, 2020 
Summary of Revisions Made: First approved version. 
Version Number: 1.1 
Version Date: August 17, 2021 
Summary of Revisions Made: Updated study personnel.  
Version Number: 1.2 
Version Date: February 23, 2022 
Summary of Revisions Made: Minor grammatical and formatting corrections. Removal of the 
Treatment Assignment Tool – University of Michigan (TATUM) from the text because the 
Michigan Institute for Clinical & Health Research (MICHR) has discontinued use of this tool (see 
Sections 4.3, 6.2.2, and 9.2). Update to the intra-burst frequency range used in Burst-SCS (see 
Section 5.1). Update to allow participants to retain the patient programmer for participant safety 
(see Sections 6.2.3 and 9.2). Update to the sham stimulation condition to help maintain the 
study blind (see Sections 5.1, 6.2.2, 6.2.3, and 9.2). 
 
Version Number: 1.3 
Version Date: May 24, 2024 
Summary of Revisions Made: Updated study personnel (see STUDY TEAM ROSTER). Added 
clarifying details regarding the target population size of 25 randomized participants (see 
PRÉCIS and Section 4).

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TABLE OF CONTENTS 
Page 
Tool Revision History .................................................................................................... 3 
TABLE OF CONTENTS ............................................................................................................... 4 
STUDY TEAM ROSTER .............................................................................................. 7 
PARTICIPATING STUDY SITES ................................................................................. 8 
PRÉCIS ........................................................................................................................ 8 
Study Title ..................................................................................................................... 8 
1. 
STUDY OBJECTIVES .......................................................................................................... 9 
1.1 
Primary Objective .............................................................................................. 9 
1.2 
Secondary Objectives ...................................................................................... 10 
1.3  
Specific Aims ................................................................................................... 11 
2.  
BACKGROUND AND RATIONALE ............................................................................... 12 
2.1 
Background on Condition, Disease, or Other Primary Study Focus ................ 12 
2.2 
Study Rationale ............................................................................................... 14 
3.  
STUDY DESIGN ............................................................................................................. 17 
4. 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................... 18 
4.1 
Inclusion Criteria .............................................................................................. 19 
4.2 
Exclusion Criteria ............................................................................................. 19 
4.3 
Study Enrollment Procedures .......................................................................... 19 
5.  
STUDY INTERVENTIONS ............................................................................................. 21 
5.1 
Interventions, Administration, and Duration ..................................................... 21 
5.2 
Handling of Study Interventions ....................................................................... 21 
5.3 
Concomitant Interventions ............................................................................... 22 
5.3.1 
Allowed Interventions ............................................................................... 22 
5.3.2 
Required Interventions ............................................................................. 22 
5.3.3 
 Prohibited Interventions ........................................................................... 22 
5.4 
Adherence Assessment ................................................................................... 22 
6.  
STUDY PROCEDURES ................................................................................................. 22 
6.1 
Schedule of Evaluations .................................................................................. 23 
6.2 
Description of Evaluations ............................................................................... 25 
6.2.1 
Screening Evaluation ................................................................................ 29 

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6.2.2 
Enrollment, Baseline, and/or Randomization ........................................... 31 
6.2.3 
Blinding ..................................................................................................... 32 
6.2.4 
Followup Visits .......................................................................................... 33 
6.2.5 
Completion/Final Evaluation ..................................................................... 33 
7.  
SAFETY ASSESSMENTS ............................................................................................. 34 
7.1 
Specification of Safety Parameters .................................................................. 34 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters ................................................................................................................. 35 
7.3 
Adverse Events and Serious Adverse Events ................................................. 36 
7.4 
Reporting Procedures ...................................................................................... 36 
7.5 
Followup for Adverse Events ........................................................................... 38 
7.6 
Safety Monitoring ............................................................................................. 38 
8.  
INTERVENTION DISCONTINUATION .......................................................................... 38 
9.  
STATISTICAL CONSIDERATIONS ............................................................................... 39 
9.1 
General Design Issues .................................................................................... 39 
9.2 
Sample Size and Randomization ..................................................................... 39 
Treatment Assignment Procedures ........................................................................ 40 
9.3  
Definition of Populations .................................................................................. 41 
9.4 
Interim Analyses and Stopping Rules .............................................................. 41 
9.5 
Outcomes ........................................................................................................ 41 
9.5.1 
Primary Outcome ...................................................................................... 41 
9.5.2 
Exploratory Outcomes .............................................................................. 42 
9.6 
Data Analyses .................................................................................................. 51 
10. DATA COLLECTION AND QUALITY ASSURANCE .......................................................... 53 
10.1 Data Collection Forms ..................................................................................... 53 
10.2 Data Management ........................................................................................... 54 
10.3 Quality Assurance ............................................................................................ 54 
10.3.1 
Training ..................................................................................................... 54 
10.3.2 
Quality Control Committee ....................................................................... 54 
10.3.3 
Metrics ...................................................................................................... 55 
10.3.4 
Protocol Deviations ................................................................................... 55 
10.3.5 
Monitoring ................................................................................................. 55 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY ............................................................. 56 
11.1 Institutional Review Board (IRB) Review ......................................................... 56 
11.2 Informed Consent Forms ................................................................................. 56 

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11.3 Participant Confidentiality ................................................................................ 56 
11.4 Study Discontinuation ...................................................................................... 56 
12. COMMITTEES ...................................................................................................................... 57 
13. PUBLICATION OF RESEARCH FINDINGS ........................................................................ 57 
14. REFERENCES ..................................................................................................................... 57 
 

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STUDY TEAM ROSTER  
Scott F. Lempka, PhD 
 
 
 
 
 
          Principal Investigator 
Biomedical Engineering 
University of Michigan 
2800 Plymouth Rd, NCRC 014-184 
Ann Arbor, MI 48109 
Phone: (734) 764-2401 
Email: lempka@umich.edu 
 
 
Steven Harte, PhD 
 
 
 
 
 
 
 
        Co-Investigator 
Domino's Farms/Lobby M 
Ann Arbor MI 48106 
Phone: (734) 998-6939 
Email: seharte@med.umich.edu 
 
Parag Patil, MD, PhD 
 
 
 
 
 
 
        Co-Investigator 
UH South F2306 
Michigan Medicine 
1500 East Medical Center Drive, SPC 5338 
Ann Arbor, MI 48109-5338 
Phone: (734) 615-1520 
Email: pgpatil@med.umich.edu 
 
Chad Brummett, MD  
 
 
 
 
 
 
       Co-Investigator 
Burlington Building Floor 1 
325 E Eisenhower Pkwy 
Ann Arbor, MI 48108-3364 
Phone: (734) 615-7246 
Email: cbrummet@med.umich.edu 
 
Srinivas Chiravuri, MD 
 
 
 
 
 
 
        Co-Investigator 
Burlington Building Floor 1 
325 E Eisenhower Pkwy 
Ann Arbor, MI 48108-3364 
Phone: (734) 615-7246 
Email: chiravun@umich.edu 
 
Daniel J. Clauw, MD  
 
 
 
 
 
 
        Co-Investigator 
Domino's Farm, 24 Frank Lloyd Wright Dr. 
Lobby M, Ste 3100 
Ann Arbor MI 48105-5737 
Phone: (734) 615-7246 
Email: dclauw@med.umich.edu 
 
Katherine A. Scott, BSN, RN  
 
 
 
 
 
 Administrative Staff 
Domino's Farm, 24 Frank Lloyd Wright Dr. 
Lobby M, Ste 3100 
Ann Arbor MI 48105-5737 
Phone: 734-998-7022 
Email: jrsj@umich.edu 

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Michael Gantos, BS   
 
 
 
 
 
    
Study Coordinator 
325 E Eisenhower PKWY Ste #100 
Burlington Building 
Ann Arbor, MI 48108 
Phone: (734) 763-5226 
Email: gantosmi@med.umich.edu 
PARTICIPATING STUDY SITES 
University of Michigan 
Scott Lempka, PhD   
 
 
 
 
 
          Principal Investigator 
NCRC 014-184 
2800 Plymouth Rd 
Ann Arbor, MI 48109 
Phone: (734) 764-2401 
Email: lempka@umich.edu 
 
 
PRÉCIS  
Study Title 
CRCNS: Model-based characterization of spinal cord stimulation for pain 
 
Objectives  
Primary Objective: The primary objective of this study is to compare the ability of multiple 
forms of SCS to modulate pain processing. We will assess pain and sensory processing 
using quantitative sensory testing (QST). Our primary outcome is the effect of multiple 
forms of SCS on dynamic central pain-processing mechanisms measured by the 
perception of pain in response to sequential stimuli (temporal summation). 
 
Exploratory Objectives: We will assess SCS-induced endogenous pain inhibition by 
measuring dynamic pain sensitivity concurrent with the application of a conditioning 
stimulus (conditioned pain modulation). We will also evaluate the effects of SCS using 
static QST measures of sensory detection threshold, pain threshold, and/or tolerance to 
various somatosensory stimuli (e.g., vibration, pressure-pain). We will also assess the 
efficacy of multiple forms of SCS on relevant clinical measures including pain intensity, 
pain quality, pain spread, and quality of life. Finally, we will combine these clinical 
measurements with patient-specific computational models that will include: 1) electric-
field models to estimate the direct neural response to SCS, and 2) circuit models to 
estimate the effects of SCS on pain processing in the spinal cord. 
 
Design and Outcomes   
In a single-center, randomized, double-blind, placebo-controlled, crossover pilot study, 
we will investigate the physiological effects and mechanisms of action of multiple forms 
of SCS (i.e., tonic 50 Hz, burst, tonic 1 kHz, sham) in 25 patients undergoing SCS. In 
this exploratory mechanistic study, we will evaluate the effects of somatosensory stimuli 
(e.g., vibration and pressure-pain stimuli) using static QST measures of sensory 
detection threshold, pain threshold, and/or tolerance to stimuli. We will assess dynamic 
central pain-processing mechanisms by measuring the perception of pain in response to 
sequential stimuli (temporal summation), and endogeneous pain inhibition by measuring 

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pain sensitivity concurrent with the application of a conditioning stimulus (conditioned 
pain modulation). We will also obtain outcome measures to assess changes in pain 
intensity, pain quality, pain spread, and quality of life. We hypothesize that clinically 
effective forms of SCS will decrease temporal summation, reduce pain sensitivity, and 
improve conditioned pain modulation. 
 
Interventions and Duration  
Spinal cord stimulation (SCS) is a neuromodulation therapy used to treat medically 
refractory chronic pain. SCS systems are typically completely internalized systems that 
consist of two main components. The first component is an implanted pulse generator 
(IPG) that typically has a titanium casing and is most commonly implanted in the 
posterior hip area. The second component is electrode arrays consisting of 8-32 metal 
electrodes that are typically made out of platinum-iridium and implanted in the epidural 
space near the dorsal aspect of the spinal cord. There are two main types of SCS 
electrode arrays. The first type is cylindrical electrode arrays that can be implanted on an 
outpatient basis under local anesthesia using a Touhy needle. The second type of arrays 
is a paddle- or plate-style electrode array in which a surgeon performs a laminotomy for 
implantation. In SCS, the IPG generates short duration electrical pulses that are then 
applied to the tissues through the implanted electrode arrays. Subjects will be receiving 
SCS as part of their clinical care and study participation will be approximately 1-3 
months in duration for each participant. 
 
Sample Size and Population  
For this study, we will randomize 25 subjects receiving SCS as part of their clinical care 
for chronic pain management. Subjects will have chronic pain of the trunk and/or limbs 
that is refractory to other conventional forms of treatment.8,9 Patients will be recruited 
without regard to racial or ethnic background. Patients will be enrolled without regard to 
gender. Male and female patients of any ethnic background will be eligible for 
enrollment. The research will not involve children (patients < 18 years of age), pregnant 
women, fetuses, or prisoners. Because these patients will be recruited at the University 
of Michigan, we expect them to primarily reside in Michigan and surrounding states. 
1. STUDY OBJECTIVES 
1.1 Primary Objective 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
Primary 
 
 
The primary objective of this 
study is to assess how multiple 
forms of SCS alter sensory 
processing. 
The primary endpoint will be SCS-
induced changes in temporal 
summation (TS).  
TS refers to an 
increased perception 
of pain in response to 
sequential stimuli of 
equal physical 
strength and it is a 
QST model of neural 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
plasticity and central 
hyper-excitability. 
 
1.2 Secondary Objectives 
OBJECTIVES 
 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
Tertiary/Exploratory  
 
 
The exploratory objectives of 
this study are to assess SCS-
induced changes in static and 
dynamic sensory processing 
and the efficacy of SCS on pain 
quality, pain spread, and quality 
of life. The exploratory 
objectives of this study are also 
to use computational models to 
investigate the physiological 
effects and corresponding 
analgesic mechanisms of SCS. 
 
We will assess the effects of SCS 
on endogenous pain inhibition by 
measuring pain sensitivity 
concurrent with the application of 
a conditioning stimulus (i.e., 
conditioned pain modulation 
(CPM)). We will evaluate the 
effects of SCS using static QST 
measures of sensory detection 
threshold, pain threshold, and/or 
tolerance to various 
somatosensory stimuli (e.g., 
vibration, pressure-pain). We will 
assess the effects of SCS on pain 
intensity using patient-reported 
VAS pain ratings for back pain, leg 
pain, and general pain.1,2 
Additional outcomes will include 
several self-reported patient 
questionnaires, such as the McGill 
Pain Questionnaire to assess 
quality of pain,3 Michigan Body 
Map to quantify the degree of 
widespread body pain,4 EuroQol 
questionnaire to characterize 
quality of life,5 and questionnaires 
from the Patient Reported 
Outcomes Measurements 
Information (PROMIS).6 Finally, 
we will combine these clinical 
measurements with patient-
specific computational models that 
will include: 1) electric-field 
models to estimate the direct 
neural response to SCS, and 2) 
circuit models to estimate the 
These outcome 
measures will 
describe the 
physiological effects 
of SCS on the 
processing of 
different types of 
sensory stimuli. 
These measures will 
also provide insight 
regarding the efficacy 
of multiple forms of 
SCS on spinal and 
supraspinal pain 
processing. VAS 
ratings are the most 
common outcome 
measure in SCS and 
thus we will be able 
to compare our 
outcomes to other 
clinical studies.1,2,7–10 
The patient-reported 
questionnaires are 
validated measures 
that are widely used 
in the field of pain 
research and clinical 
care. With regards to 
the computer 
modeling, our 
previous results with 
computer models,11–
13 support the 
concept that patient-
specific computer 
models can advance 

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effects of SCS on pain processing 
in the spinal cord. 
our scientific 
understanding and 
directly improve 
clinical outcomes 
with SCS and other 
neurostimulation 
therapies. Therefore, 
the outcome 
measures and 
computer modeling 
will help improve our 
scientific 
understanding of the 
pain-relieving effects 
of SCS and guide the 
development of new 
hypotheses and the 
design of future 
clinical studies. 
 
1.3  Specific Aims 
Aim 1: To characterize the anti-nociceptive effects of SCS. 
In a randomized, double-blind, placebo-controlled, crossover study, we will investigate 
the physiological effects and corresponding mechanisms of action of multiple forms of SCS (i.e., 
tonic 50 Hz, burst, tonic 1 kHz, sham) in 25 patients undergoing SCS. We will assess dynamic 
central pain-processing mechanisms by measuring the perception of pain in response to 
sequential stimuli (temporal summation),14 and endogenous pain inhibition by measuring pain 
sensitivity concurrent with the application of a conditioning stimulus (conditioned pain 
modulation).15 We will also evaluate the effects of somatosensory stimuli (e.g., vibration and 
pressure-pain stimuli) using static QST measures of sensory detection threshold, pain 
threshold, and/or tolerance to stimuli. Furthermore, we will obtain outcome measures to assess 
changes in pain intensity, pain quality, pain spread, and quality of life. We hypothesize that 
clinically effective SCS will decrease temporal summation, improve conditioned pain 
modulation, and reduce pain sensitivity. 
 
Aim 2: To define the direct neural response to SCS. 
We hypothesize that patient-specific models capture the details necessary to 
quantitatively describe the neural response to SCS and to correlate model-based predictions 
with experimental measurements of pain modulation. Therefore, we will develop patient-specific 
electric-field models that account for sources of interpatient variability (e.g. anatomy, electrode 
locations, stimulation parameters) for the 25 patients from Aim 1. We will define finite element 
models from the patient-specific preoperative and postoperative medical imaging. To estimate 
the direct neural response to SCS, we will then place multi-compartment neuron models within 
the patient-specific spinal cord anatomy. 
 
Aim 3: To identify the effects of SCS on pain processing in the spinal cord. 
The basic hypothesis of this study is that the physiological effects of SCS can be 
correlated with modulation of specific fiber pathways that help regulate pain processing within 
the spinal cord. However, the specific analgesic mechanisms of clinically effective SCS remain 

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unknown. Therefore, we will develop a population firing-rate circuit model of pain processing in 
the spinal cord. We will use the direct neural response to SCS from Aim 2 as the inputs to our 
circuit model. We will determine what types of spinal cord modulation best correlate with 
experimental measurements of pain modulation during SCS. 
 
Exploratory Aim: Model-based optimization of SCS 
 
Due to our poor scientific understanding of how SCS works and the limited 
individualization of this therapy, we hypothesize that current clinical implementation of SCS is 
suboptimal. Therefore, in this exploratory analysis, we will use our computational models to 
identify stimulation protocols (e.g., alternative waveform parameters) that may improve the 
desired physiological effects and corresponding pain relief. 
2.  BACKGROUND AND RATIONALE 
2.1 Background on Condition, Disease, or Other Primary Study Focus 
SCS was first tested in patients in 1967, two years after Melzack and Wall published the 
gate control theory of pain.16,17 Conventional SCS involves tonic electrical stimulation at a 
moderate frequency (e.g., 40-60 Hz) with the goal of exciting large-diameter (Aβ) sensory 
afferents in the dorsal columns to create paresthesias (e.g., tingling, buzzing, pin and needles, 
pressure) over the painful areas (Fig. 2.1A).18 According to the gate-control theory, some of the 
Aβ fibers have collaterals that project to the affected spinal levels. SCS results in antidromic 
activation of the Aβ fibers that in turn (via their collaterals) lead to inhibition of nociceptive-
specific or wide dynamic range projection neurons in the dorsal horn (Fig. 2.1). In neuropathic 
pain conditions, excessive nociceptive inputs are believed to produce hyperexcitability in these 
projection neurons (i.e., central sensitization). Antidromic activation of Aβ fibers from SCS is 
hypothesized to inhibit output from these projection neurons largely through the activation of 
inhibitory interneurons that help close the “gate” and prevent the transmission of pain signals to 
the brain.19 There is additional experimental evidence that orthodromic Ab axonal activation may 
also help reduce pain via supraspinal mechanisms, such as descending inhibition.20 
 
Stimulator programming involves assessing a variety of parameter combinations (e.g., 
amplitude, pulse width, frequency, stimulation configuration) with the goal of maximizing the 
overlap of SCS-induced paresthesias with a patient’s painful areas. Clinical experience 
suggests that sufficient pain-paresthesia overlap increases the likelihood for pain relief.21 It is 
important to note, that SCS-induced pain relief occurs over a time course of seconds to several 
hours. However, SCS-induced paresthesias occur rapidly (~1 s) and serve as a surrogate for 
pain relief that make it practical to test several sets of stimulation parameters within a standard 
clinical visit. Although widely used for decades, the success rate of SCS, defined as the 
proportion of patients receiving ³ 50% pain relief, is approximately 58%.22 
In an attempt to improve the clinical efficacy of SCS, several novel waveform paradigms 
have emerged on the clinical market within the last several years. Burst-SCS is one of these 
new approaches that delivers intermittent bursts of electrical pulses (five pulses at 500 Hz, 
delivered 40 times per second) to mimic thalamic bursting within the nervous system (Fig. 
2.1B).2 Burst-SCS demonstrates two potential advantages over conventional low-frequency 
SCS: 1) improved pain relief, and 2) pain relief without concomitant paresthesias. Paresthesia-
free pain relief can be extremely beneficial because SCS-induced paresthesias may disturb 
sleep, be experienced as excessive or uncomfortable, and vary with body position.23  
 
Burst-SCS was approved by the FDA in 2016 based on the results of a large multi-
center clinical trial that reported Burst-SCS to be significantly more effective than conventional 
SCS (60% vs. 51% success rate).24 Preliminary evidence suggests that Burst-SCS modulates 
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processing and may function through different mechanisms than conventional SCS.20,25 
However, these potential mechanisms of action require validation with additional studies.  
 
KHFSCS is another novel form of SCS that applies tonic stimulation pulses at a rate ≥ 1 
kHz. In 2015, the FDA approved a KHFSCS system that applies stimulation at a rate of 10 kHz 
and provided dramatic pain relief (~80%) without generating paresthesias (Fig. 2.1B).26 The 
pain-relief mechanisms of KHFSCS are currently unknown. Kilohertz stimulation frequencies 
have shown the ability to generate rapid and reversible conduction block in peripheral nerve 
models.27 This idea of conduction block was a driving force behind the development of KHFSCS 
with the idea that it could block the propagation of painful signals to the brain. However, 
theoretical and experimental data suggest that conduction block is unlikely at the low stimulation 
amplitudes used clinically (i.e. 0.5-5.0 mA).12,28–30 These studies also suggest that the direct 
activation of dorsal column axons is also unlikely with clinical KHFSCS. A recent study 
examined the paresthesias generated by low-frequency stimulation in a group of patients that 
had been receiving KHFSCS as part of their standard clinical care.31 In these KHFSCS patients, 
the paresthesias generated by low-frequency stimulation (utilizing the same electrodes as with 
KHFSCS) did not overlap with the patients’ painful areas. This data suggested that pain-
paresthesia overlap is not necessary and that KHFSCS may be functioning through different 
mechanisms of action relative to low-frequency SCS. Several additional mechanisms of action 
of KHFSCS have also been presented, such as asynchronous activation, desynchronization of 
clusters of neurons firing in synchrony, reduced “wind-up” and suppression of spontaneous 
activity in dorsal horn cells, and excitability changes from possible tissue heating due to the 
increased power deposited in tissue during KHFSCS.20,32,33 
 
While KHFSCS is an exciting new approach, there are several unanswered questions 
and limitations with current clinical implementation of this technology. For example, it is not clear 
what stimulation rate in the kilohertz frequency range provides the optimal pain relief. A recent 
clinical study demonstrated equal pain relief at several frequencies in the kilohertz range (i.e. 1, 
4, 7, and 10 kHz) and stimulation at a lower frequency (e.g. 1 kHz) may provide equivalent pain 
relief at lower energy demands.34 Additionally, although it can be advantageous to provide pain 
relief without concomitant paresthesias, these rapid-onset paresthesias serve as a surrogate to 
select clinically effective stimulation parameters with paresthesia-based low-frequency SCS. 
With paresthesia-free KHFSCS, parameter efficacy can only be determined by patient-reported 
pain relief after several hours of stimulation. 
 
It is an exciting time in the field of SCS and neurostimulation for pain. Over the last 
several years, there have been dramatic technological advancements to develop novel 
approaches that may improve the clinical efficacy of these neurostimulation therapies. These 
advancements include novel waveform paradigms, such as Burst-SCS and KHFSCS, 
innovations in lead design to increase the number of electrode contacts and improve the lead 
mechanical properties, improvements in IPG capabilities to increase battery lifetime, reduce 
invasiveness, and provide closed-loop stimulation. These innovations along with decades of 
clinical experience, have produced potentially powerful therapies to improve the lives of patients 
suffering from chronic pain. However, these advancements have outpaced our scientific 
understanding of these technologies. Remaining unanswered questions may limit the impact, 
optimization, and long-term reliability of these SCS therapies. 
 
From the clinical side, we do not understand why SCS works well in some patients, but 
fails in others. We do not have clear indicators to reveal which patient may initially respond to 
SCS but will fail in the long term. The subjective nature of pain and corresponding pain ratings 
make it difficult to assess the true efficacy of these approaches. Along similar lines, we do not 
have objective biomarkers or surrogates of pain and pain relief to help optimize the clinical 
programming procedures, especially with regards to novel SCS waveform paradigms. Finally, 
how early should we intervene with SCS? SCS is typically only considered after several other 

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treatment options have failed. However, evidence suggests that outcomes may be improved 
with earlier intervention with SCS.35,36 
 
From a scientific perspective, what are the mechanisms of action behind SCS-induced 
analgesia? What are the specific mechanisms of action for tonic SCS, Burst-SCS, and 
KHFSCS? To answer these questions, we need to improve our knowledge of spinal cord 
anatomy and physiology, anatomical factors that affect the electric fields generated in the tissue, 
and how these electric fields translate into physiological and perceptual effects.37 We also don’t 
have a clear understanding of how SCS modulates central pain processing or the degree to 
which placebo effects confound the results of scientific studies.38–40 
 
To better understand the mechanisms of action of SCS, it is critical to perform 
systematic, well-powered, randomized, double-blind, placebo-controlled, preclinical and clinical 
studies. While it is difficult (but possible) to perform placebo-controlled studies with paresthesia-
based approaches, new paresthesia-free paradigms are well suited for placebo-controlled 
trials.34,38,39,41 To further clarify the mechanisms of action of SCS and which patients might 
respond in the long term, objective measures characterizing the physiological effects of SCS 
(e.g., quantitative sensory testing, functional neuroimaging) could be combined with 
conventional patient-reported subjective outcome measures.40 It is also important to establish a 
relationship between the mechanisms of action of SCS and the pathological mechanisms of a 
specific pain condition. This relationship is essential to predict the therapeutic efficacy of SCS 
and to improve patient selection. 
Future research should also move towards developing patient-specific approaches to 
understand mechanisms of SCS. Due to limitations in animal models of chronic pain (e.g., 
inability of animals to report their pain, and unclear translation of animal results to humans),42,43 
it is important that we develop methods to systematically study SCS in human subjects. For 
example, patient-specific computational models that account for interpatient variability in 
anatomy and electrode locations are commonly used in other neurostimulation therapies, such 
as deep brain and transcranial electric stimulation, to investigate mechanisms of action and 
provide clinical decision support.44,45 However, this type of patient-specific modeling approach is 
uncommon in SCS.46 We believe that patient-specific approaches in SCS may be critical to 
understand the mixed clinical outcomes of SCS and will help optimize the clinical effectiveness 
of current and novel SCS technologies. 
2.2 Study Rationale 
More than 1.5 billion people worldwide and ~100 million American adults suffer from chronic 
pain.47,48 Chronic pain is debilitating as it impacts most aspects of a person’s life, including 
physical inability, emotional distress, and/or psychological impairment.49 Unfortunately, 
conventional medical management is often insufficient in relieving chronic pain.50 Opioid 
analgesics are frequently prescribed despite the lack of clinical evidence supporting their long-
term use to treat chronic pain and the associated epidemic of opioid abuse, addiction, and death 
from overdose in the United States.51,52 Less conventional forms of therapy, such as SCS and 
other forms of neurostimulation, may offer a better alternative. However, despite advances in 
technology, the success rates of these neurostimulation approaches have plateaued and 
significant opportunities remain to improve clinical efficacy. Limited outcomes of both 
conventional medical management and neurostimulation procedures can largely be attributed to 
our poor scientific understanding of how these therapies relieve chronic pain. 
Spinal cord stimulation (SCS) is a neurostimulation therapy that can be considered for 
patients who are refractory to other treatment options (e.g., pharmaceuticals).53,54 In SCS, 
electrical pulses modulate neural activity in the spinal cord in an attempt to prevent pain signals 
from reaching the brain. SCS is widely used all over the world and exceeds USD 1.8 billion in 
annual sales, with as many as 50,000 spinal cord stimulators implanted annually.55,56 While SCS 

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can provide dramatic pain relief in some patients, a large number of patients fail to respond to 
this therapy. Success rates also vary widely across studies and efficacy declines over treatment 
time.22 This limited success can largely be attributed to the fact that we don’t know how it works. 
Therefore, the goal of this project is to investigate the pain-relief mechanisms of SCS by 
combining clinical measurements of pain modulation with detailed computational models of 
SCS. 
In this study, we will adopt a systematic, well-controlled, patient-specific approach to 
characterize SCS. We believe this type of approach is necessary to improve our scientific 
understanding of chronic pain and how to treat it. This study will also help develop the 
experience and technology necessary to characterize neurostimulation approaches for other 
neurological disorders. To investigate the anti-nociceptive effects of SCS, we will conduct a 
placebo-controlled study in 25 patients undergoing SCS for chronic pain. We will obtain 
outcome measures and use quantitative sensory testing (QST) to assess spinal and supraspinal 
pain processing. Because these mechanistic questions are difficult to answer experimentally, 
we will combine these clinical measurements with patient-specific computational models that will 
include: 1) electric-field models to estimate the direct neural response to SCS and 2) circuit 
models to estimate the effects of SCS on pain processing in the spinal cord. 
 
 
Figure 2.1. Spinal cord stimulation (SCS). (A) An electrode array is implanted in the epidural 
space dorsal to the spinal cord to stimulate Ab axons and create analgesia. (B) Conventional 
SCS applies short-duration pulses at 40-60 Hz. Burst SCS is a new type of paresthesia-free 
stimulation that applies bursts of stimulation at 40 Hz. Kilohertz-frequency SCS is another novel 
form of paresthesia-free stimulation that applies pulses at ³ 1 kHz. 
 
 
Patients to be enrolled in this study will be undergoing SCS to manage their chronic pain 
as part of their clinical care and will be subject to the standard risks associated with this therapy. 
These risks are not part of this research. However, the participants will also be subject to 
potential risks associated with the experimental procedures described in this study. The risks 
associated with this research study can be best understood if separated in the following 
categories: risk related to electrical stimulation by the implanted spinal cord stimulator, risk of 
the medical imaging procedures, risk of outcome measures, risk related to quantitative sensory 
testing, and risk of loss of confidentiality. 
 
Risk related to electrical stimulation 

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During the stimulator programming session, electrical stimulation delivered to the spinal 
cord is titrated over a range of amplitudes. Side effects related to higher stimulation, such as 
muscle contractions, may occur, but are known to be reversible by either reducing the amplitude 
of stimulation or by stopping the stimulation entirely. Whenever using electricity to stimulate 
tissue, there is also the possibility of a shock hazard, including an electrical burn. However, only 
electrical stimulators approved by the US Food and Drug Administration for SCS will be used in 
this study. Therefore, the risk of tissue damage or electrical shock during the electrical 
stimulation is minimal.  
 
When determining the amplitude at which the stimulation first becomes uncomfortable 
(i.e., discomfort threshold), the participant will experience some discomfort due to uncomfortable 
paresthesias or muscle contractions. It is also possible that the participant will experience 
similar discomfort during the remainder of the parameter selection or programming process. In 
either case, the stimulation amplitude will be decreased immediately or the stimulation turned off 
completely. To avoid or minimize participant discomfort, the stimulation amplitude will first be set 
to a low amplitude and increased in small increments. 
 
Risk of medical imaging procedures 
 
Each participant will receive a thoracic or cervical X-ray computed tomography (CT) scan 
to determine the locations of the implanted electrodes. This CT is not part of the participant’s 
standard clinical care and requires the participant to undergo additional exposure to radiation. 
One of the major risks associated with radiation exposure is an increased risk of cancer. The 
patient consent form will identify the cumulative risks of radiation exposure from both potential 
standard of care imaging procedures and the additional research-related tests. 
 
Risk related to quantitative sensory testing (QST) 
 
Overall, the QST procedures may cause minor but temporary physical discomfort. 
However, the QST experiments will follow strict safety standards and will be as brief as 
possible. The intensity of each stimulus will be limited to levels that are deemed safe and 
acceptable. Additionally, study personnel are trained by the investigators to be sensitive to 
participant discomfort and concerns. The participant can inform the person to stop the QST at 
any time that the pain or unpleasantness of the task becomes intolerable.  
 
The Multimodal Automated Sensory Testing (MAST) may cause some temporary physical 
discomfort on the thumbnail. The MAST system includes multiple software, electrical, and 
mechanical safeguards to ensure that the amount of pressure applied does not exceed safe 
limits, including a safety release pin that the subject can turn to immediately release the 
pressure actuator from his or her thumb. The test is terminated at or before 10 kg/cm2 of 
pressure, which is a commonly used maximum pressure level in human sensory testing and 
does not result in physical injury. Subjects will always have personal control over the stimulus 
and can stop it at any time or express instructions to stop the stimuli. The subjects can also 
withdraw their thumb from the device. 
 
The vibrometer, pressure algometer, and the pointed skin probe are commonly used in 
QST studies and should not cause any tissue injury at the maximum forces applied in this study. 
However, these instruments may cause minor physical discomfort in the areas of testing that is 
expected to resolve within minutes of test completion. These instruments may also cause small 
skin indentations and/or skin reddening that is expected to resolve within a few hours. These 
tests will be halted if the participant reports a pain rating of 100 out of 100. 
 
Risk of outcome measures 
 
The outcome measures will include standardized self-reported pain ratings and symptom 
questionnaires. Other measures will include electronic drawings of the anatomical location(s) of 

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each participant’s pain over his/her body. We consider the outcomes measures to be used in 
this study to be of minimal risk. There is still a possibility of discomfort associated with being 
asked personal questions about medical history, symptoms, or feelings. The subject may refuse 
to answer any question on the questionnaires or surveys that may be uncomfortable. 
 
Risk of loss of confidentiality 
 
This research involves initially obtaining identifiable patient-subject private information 
(e.g., name, contact information) or biospecimens (e.g., urine samples) due to collecting 
standard of care data in addition to the research data for the project. Therefore, loss of 
participant confidentiality is a potential risk in this research. However, we will follow necessary 
steps to minimize this risk. 
3.  STUDY DESIGN 
In a single-center, randomized, double-blind, placebo-controlled, crossover pilot study, 
we will investigate the physiological effects and mechanisms of action of multiple forms of SCS 
(i.e., tonic 50 Hz, burst, tonic 1 kHz, sham) in 25 patients undergoing SCS. In this exploratory 
mechanistic study, we will assess dynamic central pain-processing mechanisms by measuring 
the perception of pain in response to sequential stimuli (temporal summation), and endogenous 
pain inhibition by measuring pain sensitivity concurrent with the application of a conditioning 
stimulus (conditioned pain modulation). We will evaluate the effects of somatosensory stimuli 
(e.g., vibration and pressure-pain stimuli) using static QST measures of sensory detection 
threshold, pain threshold, and/or tolerance to stimuli. We will also obtain outcome measures to 
assess changes in pain intensity, pain quality, pain spread, and quality of life. We hypothesize 
that clinically effective forms of SCS will decrease temporal summation, reduce pain sensitivity, 
and improve conditioned pain modulation. 
 
In this study, we will perform a post-approval mechanistic study. We will perform a 
mechanistic study using FDA-approved devices that will be used in accordance with approved 
labeling. We will implement a randomized, double-blind, placebo-controlled, crossover study. 
This study design will allow us to test the physiological effects of multiple forms of SCS within 
individual participants. It will also allow us to quantify the effects of sham stimulation. We believe 
variability in SCS are largely due to “placebo” effects and/or lack of understanding of their 
mechanisms of action. A majority of previous clinical studies were performed in an unblinded 
manner whose results may have been confounded by a “placebo” effect.1,7–9,57 One major 
criticism of previous SCS studies is the absence of blinding due to the presence of stimulation-
induced paresthesia(s). With the advent of paresthesia-free SCS waveforms, such as Burst-
SCS and KHFSCS, the paradigm is shifting. Clinical studies using Burst-SCS and KHFSCS 
have reported success in stimulating without producing paresthesias. However, a majority of 
these studies were performed in an unblinded manner. Therefore, the effect of “placebo” 
remains to be quantified. Comparing the physiological effects of Burst-SCS and KHFSCS to 
sham (no) stimulation will help systematically control for placebo effects and will help identify the 
true pain-relieving effects of SCS. For the fourth and final treatment allocation, all participants 
will receive seven days of tonic 50 Hz SCS that will generate paresthesias over their painful 
areas. This treatment is performed last because participants will likely know that they are 
receiving active stimulation due to the paresthesias and this design will minimize the chance of 
breaking the blind during the previous treatments. During the study, subjects will be instructed to 
maintain a stable level of medications for control of chronic pain symptoms. 
As described in Section 9.5, the primary outcome will be SCS-induced changes in 
temporal summation (TS). TS refers to an increased perception of pain in response to 
sequential stimuli of equal physical strength (Fig. 9.1A). It is a quantitative sensory testing 
(QST) model of neural plasticity and central hyper-excitability that is thought to reflect the 

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progressive increase in neuronal firing of dorsal horn neurons in response to repetitive 
nociceptive C-fiber stimulation (i.e., windup).58 We will also evaluate several exploratory 
outcome measures. We will assess SCS-induced endogenous pain inhibition by measuring 
dynamic pain sensitivity concurrent with the application of a conditioning stimulus (conditioned 
pain modulation). We will also evaluate the effects of SCS using static QST measures of 
sensory detection threshold, pain threshold, and/or tolerance to various somatosensory stimuli 
(e.g., vibration, pressure-pain). We will also assess the efficacy of multiple forms of SCS on 
relevant clinical measures including pain intensity, pain quality, pain spread, and quality of life. 
Finally, we will combine these clinical measurements with patient-specific computational models 
that will include: 1) electric-field models to estimate the direct neural response to SCS, and 2) 
circuit models to estimate the effects of SCS on pain processing in the spinal cord. 
As described in Section 4.3, this study will occur at a single site, the University of 
Michigan. Subjects will be receiving SCS as part of their clinical care and study participation will 
be approximately 1-3 months in duration for each participant. We expect the total study duration 
to be approximately 3 years. 
 
Figure 3.1. Clinical study design. 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS  
 
For this study, we will recruit subjects receiving SCS as part of their clinical care for 
chronic pain management. We will recruit subjects until we are able to randomize 25 
participants. Patients will be elected without regard to racial or ethnic background. Patients will 
be enrolled without regard to gender. Male and female patients of any ethnic background will be 
eligible for enrollment. The research will not involve children (patients < 18 years of age), 
pregnant women, fetuses, or prisoners. We expect participants to primarily reside in Michigan 
and surrounding states. According to the results of a recent multicenter clinical trial of SCS,26 
with regard to gender, we expect the enrolled population to consist of 10/25 males and 15/25 
females. With regard to ethnicity, we expect the patient enrollment to consist of 24/25 Non-
Hispanic/Latino and 1/25 Hispanic/Latino. With regard to race, we expect the patient enrollment 
to consist of 23/25 White, 1/25 Black or African American, 0-1/25 American Indian/Alaska 
Native, 0-1/Asian, 0-1/25 Native Hawaiian or Other Pacific Islander, and 0-1/25 More than One 

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Race. This is only a targeted distribution and the final enrollment will ultimately depend on 
candidates presenting to the study who fulfill the inclusion and exclusion criteria and choose to 
consent to the study. 
4.1 Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria: 
• 
Chronic intractable pain of the trunk and/or limbs. 
• 
Undergoing SCS as part of standard clinical care for chronic pain management. 
• 
Candidate will have been implanted with a commercial SCS device that can apply 
the necessary treatments (i.e., tonic 50 Hz, burst, tonic 1 kHz, sham). 
• 
Candidates who are 18 years or older and can speak, read, and understand English. 
• 
Ability to understand study procedures and to comply with them for the entire length 
of the study. 
• 
Must be willing to participate in COVID-19 symptom screening and answer questions 
about COVID-19 diagnosis 1-3 days before a scheduled visit. 
• 
Must be willing to wear a face covering during study visits. 
4.2 Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in 
this study: 
• 
Subjects who are pregnant or nursing. 
o For both chronic pain subjects and healthy subjects of childbearing potential, and 
having no intrauterine device (IUD) or hysterectomy, and who are able to 
become pregnant, we will perform a urine pregnancy test to confirm pregnancy. 
• 
Subjects with current, habitual, or previous use within the last 12 months of artificial 
nails, nail enhancements, or nail extensions that cover any portion of either thumbnail. 
Exceptions, including brief and/or occasional use, may be permissible at the discretion of 
the study personnel. 
• 
Subjects who are unable or unwilling to cooperate with clinical testing. 
• 
Subjects having any impairment, activity or situation that in the judgment of study 
personnel would prevent satisfactory completion of the study protocol  
• 
Inability or unwillingness of individual or legal guardian/representative to give written 
informed consent. 
• 
Subjects who currently have or tested positive in the last 14 days for COVID-19, or are 
symptomatic for COVID-19. 
Note:  The research will not involve children (patients < 18 years of age), pregnant women, 
fetuses, or prisoners. 
4.3 Study Enrollment Procedures  
This study will occur at a single site, the University of Michigan. We will actively and 
passively recruit participants. We will actively recruit patients from clinics at the University of 
Michigan (UM), such as clinics in the Department of Anesthesiology and the Department of 
Neurosurgery. These departments will have access to the purpose of the study, intended patient 
population, and inclusion/exclusion criteria. For this study, we will consider chronic pain patients 
who are being treated with SCS from their own doctors as part of their standard clinical care. 
For active recruitment, our team of pain specialists (e.g., anesthesiologists and/or 

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neurosurgeons) and other study personnel at UM will identify potential candidates and inform 
them about the study. The study coordinator or a person from the study team will contact the 
candidates (e.g., via telephone) to discuss details about the study (e.g., eligibility determination) 
and/or to verify interest. The necessary contact information (e.g., telephone number) of the 
candidates will be obtained by searching appointment logs and/or medical records. 
For passive recruitment, we will post publicly accessible flyers and brochures throughout UM 
Clinics, and also in various locations around Michigan Medicine (e.g., University Hospital). We 
will also post flyers and brochures across various other Pain Clinics and Hospitals in Livingston, 
Washtenaw, and/or Wayne County. IRB-approved flyers and brochures will be hung in several 
locations (e.g., waiting areas) in these clinics and hospitals. These flyers will have contact 
information of the study team (e.g., email, phone) and will also have a description of the study 
(resource included in section 8-1.8 of the IRB application). Interested candidates may initiate 
contact with the study team.  
As detailed in Section 6.2, potential subjects who are interested in participating in the study 
will be contacted by a member of the study team responsible for enrollment to assess interest 
and eligibility. Interested candidates will have the study and the eligibility criteria explained to 
them. If at this point they wish to continue with enrollment, the candidate will be invited to 
participate in a study screening visit. Screening will be done over phone to verify eligibility. The 
research team will adopt an optional electronic informed consent procedure using SignNow. 
This option will be our preferred method for obtaining consent. For eligible and interested 
candidates, a study team member will discuss the study with the patient and obtain consent 
over the phone. The consent form will be read to the participant and time will be allowed for 
questions or if the patient would like to read/review the consent form on their own before 
electronically signing.  
For eligible candidates, we will schedule an enrollment visit and/or other subsequent visits. 
We may also email candidates the consent forms to study and think about participation. For 
interested and eligible candidates, we will schedule the enrollment visit and/or other subsequent 
visits. All potential subjects will be assigned a unique screening ID. Those volunteers who do 
not meet the eligibility criteria or who choose not to participate in the study at either the 
telephone Pre-Screen or the Screening Visit will be logged. Personal identifiers will be kept until 
the study has been closed to recruitment, at which time they will be destroyed. This will prevent 
repeat screenings of potential participants.  
Screen failures will be defined as participants who consent to participate in the clinical trial 
but are not subsequently entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants, to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this trial (screen failure) because 
of issues, such as pregnancy, or recent use of artificial nails may be rescreened. Rescreening 
will be limited to one occurrence per individual. Rescreened participants should be assigned the 
same participant number as for the initial screening. 
Candidates who do not have access to the internet will sign the consent form during the 
screening visit. The screening visit will begin with the informed consent interview. During the 
consent interview we will explain the study verbally and in writing. If interested, candidates will 
sign an informed consent, and will be given a copy. We will conduct the consent interview in a 
private setting (e.g., examination room, office), allowing sufficient time for prospective subjects 
to make an informed decision. Furthermore, we will also offer candidates the option of taking the 
informed consent form home to study and think about participation, with a follow up with one of 
the investigators or study personnel. Once the subject has formally consented to participate 
they will undergo a screening examination by a member of the study team. After the screening 

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visit, study personnel will follow up with the patient after consent and screening to schedule all 
research visits. 
Each visit will take approximately 1-4 hours to perform all of the desired assessments. The 
screening visit will take approximately 2 hours, the behavioral sessions will take approximately 2 
hours, the imaging session will last approximately 1 hour, and each programming session will 
last approximately 1 hour. 
As described in Section 6.2.2, we will randomize each participant to one of the six treatment 
arms. 
5.  STUDY INTERVENTIONS  
5.1 Interventions, Administration, and Duration  
Spinal cord stimulation (SCS) is an FDA-approved neurostimulation therapy for patients 
suffering from refractory chronic pain. SCS systems are typically completely internalized 
systems and consist of two main components. The first component is an implanted pulse 
generator (IPG) that typically has a titanium casing and is most commonly implanted in this 
posterior hip area. The second component is electrode arrays consisting of 8-32 metal 
electrodes that are typically made out of platinum-iridium and implanted in the epidural space 
near the dorsal aspect of the spinal cord. There are two main types of SCS electrode arrays.59 
The first type is cylindrical electrode arrays that can be implanted on an outpatient basis under 
local anesthesia using a Touhy needle. The second type of arrays is a paddle- or plate-style 
electrode arrays in which a surgeon performs a laminotomy for implantation. The IPG generates 
electrical pulses that are applied to the tissues through the implanted electrode arrays. 
Dosing and Administration: Subjects will receive burst, tonic 1 kHz, tonic 50 Hz. and sham 
SCS. Each treatment will be applied for a duration of seven days. Participants will be blinded 
during programming. Burst-SCS will be applied at a burst-rate of ~40-60 Hz, intra-burst 
frequency of ~200-500 Hz, and ~2-5 pulses per burst. KHFSCS will be applied at a rate of ~1 
kHz. To ensure proper blinding, we will set the amplitude of stimulation so that participants do 
not feel any stimulation-induced paresthesias.2 We will perform sham SCS by setting the 
amplitude to 0 mA.2 For some systems, if the stimulation amplitude is decreased to 0 mA, the 
system will report that the stimulation is OFF and the participants will know that they are not 
receiving stimulation. Therefore, for these systems, we will perform sham SCS by setting the 
stimulation parameters to their minimal values: pulse width (~20 µs), frequency (~2 Hz), and 
amplitude (~0.1 mA). These settings will correspond to a small fraction (<0.05%) of the amount 
of current normally applied during active SCS and will provide a sham condition that helps 
maintain the study blinding. After the third treatment allocation, each participant will receive 
seven days of tonic 50 Hz SCS that will generate paresthesias over their painful areas. After 
testing is completed, we will interrogate the stimulator to ensure that the stimulation settings 
were not altered during any treatment allocation. 
5.2 Handling of Study Interventions  
The spinal cord stimulation (SCS) systems to be used in this study are commercially 
available and will be used in accordance with approved labelling. No modifications will be made 
for this study. For this study we will consider commercial SCS devices from companies, such as 
Boston Scientific Corporation (Valencia, CA), Abbott Laboratories (Chicago, IL), or Nuvectra 
(Plano, TX). These commercial systems have the capabilities to apply the types of SCS that will 
be considered in this study: tonic 50 Hz, burst, and tonic 1 kHz. 
Commercial SCS systems will have been prescribed by the participant’s physician as part of 
their standard clinical care for chronic pain management. In this study, we will only consider 

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subjects who are implanted with commercial systems that can apply all of the desired 
treatments (i.e., tonic 50 Hz, burst, tonic 1 kHz, sham). However, there are differences in how 
each commercial system applies the different treatments. Therefore, we will track the device 
type for each participant and examine potential device-related differences in our outcome 
analyses. 
5.3 Concomitant Interventions  
For this protocol, a prescription medication is defined as a medication that can be 
prescribed only by a properly authorized/licensed clinician. Medications to be reported in the 
Case Report Form (CRF) are concomitant prescription medications, over-the-counter 
medications and supplements. The patient population that will be considered in this study will 
typically be on concomitant medications to manage their chronic pain. Fluctuations in these pain 
medications could affect the study endpoints. Therefore, during this study, we will instruct 
subjects to maintain a stable level of medications for control of chronic pain symptoms. We will 
also track medication use by having each participant report their prescription and over-the- 
counter medication and supplement use at each visit. At screening and at all study visits, we will 
have patients complete a concomitant medications survey that has the participants report the 
following information for each medication and supplement: drug name, total daily dosage 
(quantity), total daily usage (units), frequency taken, indication, start date, and end date (will 
leave blank if still taking). 
5.3.1 Allowed Interventions 
Participants may remain on current medications used to manage and treat chronic pain 
symptoms. All treatments, whether prescription or over-the-counter, will be tracked and 
recorded on the concomitant medication form. Participants will be asked to refrain from 
changing their existing ongoing treatments during the course of the study.  
5.3.2 Required Interventions 
There are no required interventions, however, participants will be asked and assessed 
for willingness to limit the introduction for any new medications or treatment modalities for 
control of chronic pain symptoms during the study.                            
5.3.3  Prohibited Interventions 
Participants will be excluded from the study if they are participating in other therapeutic 
trials, or have completed a trial within the last 30 days from their enrollment date. 
5.4 Adherence Assessment  
All necessary outcome measures and documents will be completed during the study visits. 
However, we will check for adherence to the specific type of stimulation (i.e., tonic 50 Hz, burst, 
tonic 1 kHz, sham). At the end of each treatment allocation and after the testing is completed, 
we will interrogate the participant’s implanted stimulator to ensure that the stimulation settings 
were not altered during the specific treatment phase. For this study, we will only consider 
randomized participants who successfully completed the Sham SCS treatment along with at 
least one other active (i.e., burst, tonic 1 kHz, tonic 50 Hz) SCS treatment along with the 
associated outcome measures for each treatment. 
6.  STUDY PROCEDURES  

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6.1 Schedule of Evaluations 
  
Screening/ 
enrollment visit 
Randomizationa 
Treatment 
Treatment  
Treatment  
(50 Hz SCS) 
Final visit 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Day -62 to Day 0 
Day 0 ±  2 days 
Day 7 ±  2 days 
Day 14 ±  2 days 
Day 21 ±  2 days 
Day 28 ±  2 days 
Informed Consent 
X 
 
 
 
 
 
Hospital Anxiety and Depression 
Scale (HADS)  
X 
X 
X 
X 
X 
X 
EQ-5D Health Questionnaire  
X 
X 
X 
X 
X 
X 
Demographics 
X 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
Socio-demographics 
X 
 
 
 
 
 
Urine Pregnancy Test 
X 
 
 
 
 
 
Brief Pain Inventory (BPI)  
X 
X 
X 
X 
X 
X 
Coping Strategies Questionnaire 
(CSQ)  
X 
X 
X 
X 
X 
X 
Michigan Body Map (MBM)  
X 
X 
X 
X 
X 
X 
PainDETECT  
X 
X 
X 
X 
X 
X 
Pain Disability Index (PDI)  
X 
X 
X 
X 
X 
X 
Fibromyalgia Survey Questionnaire 
(FSQ)  
X 
X 
X 
X 
X 
X 
Patient-Reported Outcomes 
Measurement Information System 
Sleep Disturbance Short Form 
Questionnaire (PROMIS-SD) 
X 
X 
X 
X 
X 
X 
Short Form McGill Pain 
Questionnaire (SFMPQ) 
X 
X 
X 
X 
X 
X 
Visual Analog Scale (VAS) – 
included in SFMPQ  
X 
X 
X 
X 
X 
X 
Vitals (heart rate, blood pressure, 
respiration rate, blood temperature), 
height and weight  
X 
X 
X 
X 
X 
X 
Multimodal Automated Sensory 
Test (MAST)  
b 
X 
X 
X 
X 
X 
Vibrometer Test 
b 
X 
X 
X 
X 
X 
Algometer Test 
b 
X 
X 
X 
X 
X 
Temporal summation (TS) – 
PinPrick Test 
b 
X 
X 
X 
X 
X 
Conditioned Pain Modulation (CPM) 
Test 
b 
X 
X 
X 
X 
X 
Computed tomography (CT) 
 
X 
 
 
 
 
Randomization 
 
c 
 
 
 
 
Treatment (Burst, 1kHz, 50Hz, 
Sham SCS) 
 
d 
X 
X 
X 
X 

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Stimulator programming 
 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
Study debriefing 
 
 
 
 
 
X 
a The randomization visit (Visit 2) may also occur on the same day as the screening/enrollment visit (Visit 1) 
b Familiarization only 
c Randomization will occur at the end of Visit 2 
d Treatment will begin at the end of Visit 2

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6.2 Description of Evaluations  
The schedule of study procedures and assessments is 6.1 Schedule of Evaluations. The 
descriptions of the procedures to be performed at each visit are provided below. 
 
Screening/enrollment (Visit 1) 
• 
Review study procedures and requirements with participant 
• 
Review informed consent, only for candidates that do not consent electronically via 
SignNow.  
• 
Collect demographic and sociodemographic information 
• 
Conduct psychological screening assessment (HADS) 
• 
Collect vital signs (heart rate, blood pressure, respiration rate, body temperature, height 
and weight) 
• 
Obtain medical history (EQ-5D Health Questionnaire) and FM Survey Questionnaire 
[FSQ]  
• 
Collect symptoms of chronic pain  
o Pain disability Index (PDI) 
o Short Form McGill Pain Questionnaire (SFMPQ) 
o Michigan Body Map (MBM) 
o PainDETECT 
o Brief Pain Inventory (BPI) 
o Visual Analog Scale (VAS) and SFMPQ  
• 
Determine impact of chronic pain on daily life (CSQ) 
• 
Administering a urine pregnancy test to women of childbearing potential 
• 
Document current concomitant medications 
• 
Familiarize participant to the sensory testing procedure 
o Multimodal Automated Sensory Test (MAST) 
o Vibrometer Test 
o Algometer Test 
o PinPrick Test 
o Conditioned Pain Modulation (CPM) Test 
• 
Documentation of any adverse events 
 
Randomization (Visit 2) 
After a participant has been deemed a candidate for the study, this visit can occur on the same 
day as Visit 1 (screening/enrollment).  
• 
Collect vital signs (heart rate, blood pressure, respiration rate, body temperature, height 
and weight) 
• 
Review and record any changes in concomitant medications  
• 
Rate participants current pain on a scale Visual Analog Scale (VAS) and SFMPQ  
• 
Collect  
o Pain disability Index (PDI) 
o Short Form McGill Pain Questionnaire (SFMPQ) 
o Michigan Body Map (MBM) 
o PainDETECT 
o Brief Pain Inventory [BPI] 
o Visual Analog Scale (VAS) and SFMPQ  
o Coping Strategies Questionnaire (CSQ) 
o Hospital Anxiety and Depression Scale (HADS) 

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o EQ-5D Health Questionnaire 
o Fibromyalgia Survey Questionnaire (FSQ) 
• 
Conditioned Pain Modulation (CPM) Test – Assessment to examine how the body 
naturally controls pain 
• 
Measure participant’s sensitivity to different stimuli 
o Vibrometer Test 
o Algometer Test 
o PinPrick Test (Temporal summation) 
o Multimodal Automated Sensory Test (MAST) 
• 
Randomization* 
• 
Deliver treatment (Burst, 1kHz, or Sham SCS) 
• 
Stimulator programming 
o Perception threshold 
o Discomfort threshold 
o Paresthesia mapping 
• 
Documentation of any adverse events 
• 
Computed tomography (CT) scan 
 
*At the end of the Visit 2, randomization will occur. We will randomize participants to one of six 
randomly allocated sequences that each contain four treatments: burst, 1 kHz, sham, and 50 Hz 
SCS. Participants will receive each treatment for seven days. 
 
Treatment (Visit 3) 
After participants have received approximately seven days of the first treatment, we will perform 
the study procedures listed below. After performing these study procedures, the stimulation 
parameters will be adjusted to apply the second treatment allocation in the respective treatment 
arm. Participants will be blinded during programming. 
• 
Collect vital signs (heart rate, blood pressure, respiration rate, body temperature, height 
and weight) 
• 
Review and record any changes in concomitant medications  
• 
Rate participants current pain on a scale Visual Analog Scale (VAS) and SFMPQ  
• 
Collect  
o Pain disability Index (PDI) 
o Short Form McGill Pain Questionnaire (SFMPQ) 
o Michigan Body Map (MBM) 
o PainDETECT 
o Brief Pain Inventory [BPI] 
o Visual Analog Scale (VAS) and SFMPQ  
o Coping Strategies Questionnaire (CSQ) 
o Hospital Anxiety and Depression Scale (HADS) 
o EQ-5D Health Questionnaire 
o Fibromyalgia Survey Questionnaire (FSQ) 
• 
Conditioned Pain Modulation (CPM) Test – Assessment to examine how the body 
naturally controls pain 
• 
Measure participant’s sensitivity to different stimuli 
o Vibrometer Test 
o Algometer Test 
o PinPrick Test (Temporal summation) 
o Multimodal Automated Sensory Test (MAST) 
• 
Deliver treatment (Burst, 1kHz, or Sham SCS) 

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• 
Stimulator programming 
o Perception threshold 
o Discomfort threshold 
o Paresthesia mapping 
• 
Documentation of any adverse events 
 
Treatment (Visit 4) 
After participants have received approximately seven days of the second treatment, we will 
perform the study procedures listed below. After performing these study procedures, the 
stimulation parameters will be adjusted to apply the third treatment allocation in the respective 
treatment arm. Participants will be blinded during programming. 
• 
Collect vital signs (heart rate, blood pressure, respiration rate, body temperature, height 
and weight) 
• 
Review and record any changes in concomitant medications  
• 
Rate participants current pain on a scale Visual Analog Scale (VAS) and SFMPQ  
• 
Collect  
o Pain disability Index (PDI) 
o Short Form McGill Pain Questionnaire (SFMPQ) 
o Michigan Body Map (MBM) 
o PainDETECT 
o Brief Pain Inventory (BPI) 
o Visual Analog Scale (VAS) and SFMPQ  
o Coping Strategies Questionnaire (CSQ) 
o Fibromyalgia Survey Questionnaire (FSQ) 
• 
Conditioned Pain Modulation (CPM) Test – Assessment to examine how the body 
naturally controls pain 
• 
Measure participant’s sensitivity to different stimuli 
o Vibrometer Test 
o Algometer Test 
o PinPrick Test (Temporal summation) 
o Multimodal Automated Sensory Test (MAST) 
• 
Deliver treatment (Burst, 1kHz, or Sham SCS) 
• 
Stimulator programming 
o Perception threshold 
o Discomfort threshold 
o Paresthesia mapping 
• 
Documentation of any adverse events 
 
Treatment (50 Hz SCS) (Visit 5) 
After participants have received approximately 7 days of the third treatment, we will perform the 
study procedures listed below. After performing these study procedures, the stimulation 
parameters will be adjusted to apply the final treatment allocation (tonic 50 Hz SCS). Although 
participants will be blinded during programming, 50 Hz SCS generates paresthesias and so 
participants will likely be aware that they are receiving active stimulation. 
• 
Collect vital signs (heart rate, blood pressure, respiration rate, body temperature, height 
and weight) 
• 
Review and record any changes in concomitant medications  
• 
Rate participants current pain on a scale Visual Analog Scale (VAS) and SFMPQ  
• 
Collect  
o Pain disability Index (PDI) 

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o Short Form McGill Pain Questionnaire (SFMPQ) 
o Michigan Body Map (MBM) 
o PainDETECT 
o Brief Pain Inventory (BPI) 
o Visual Analog Scale (VAS) and SFMPQ  
o Coping Strategies Questionnaire (CSQ) 
o Fibromyalgia Survey Questionnaire (FSQ) 
• 
Conditioned Pain Modulation (CPM) Test – Assessment to examine how the body 
naturally controls pain 
• 
Measure participant’s sensitivity to different stimuli 
o Vibrometer Test 
o Algometer Test 
o PinPrick Test (Temporal summation) 
o Multimodal Automated Sensory Test (MAST) 
• 
Deliver treatment (50 Hz SCS) 
• 
Stimulator programming 
o Perception threshold 
o Discomfort threshold 
o Paresthesia mapping 
• 
Documentation of any adverse events 
 
Final study visit (Visit 6) 
After participants have received approximately 7 days of 50 Hz SCS, we will perform the study 
procedures listed below. After performing these study procedures, the participant’s SCS system 
will be returned to the clinically-effective stimulation settings that were previously determined 
through standard-of-care procedures. 
• 
Collect vital signs (heart rate, blood pressure, respiration rate, body temperature, height 
and weight) 
• 
Review and record any changes in concomitant medications  
• 
Rate participants current pain on a scale Visual Analog Scale (VAS) and SFMPQ  
• 
Collect  
o Pain disability Index (PDI) 
o Short Form McGill Pain Questionnaire (SFMPQ) 
o Michigan Body Map (MBM) 
o PainDETECT 
o Brief Pain Inventory (BPI) 
o Visual Analog Scale (VAS) and SFMPQ  
o Coping Strategies Questionnaire (CSQ) 
o Fibromyalgia Survey Questionnaire (FSQ) 
• 
Conditioned Pain Modulation (CPM) Test – Assessment to examine how the body 
naturally controls pain 
• 
Measure participant’s sensitivity to different stimuli 
o Vibrometer Test 
o Algometer Test 
o PinPrick Test (Temporal summation) 
o Multimodal Automated Sensory Test (MAST) 
• 
Stimulator programming 
o Perception threshold 
o Discomfort threshold 
o Paresthesia mapping 

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• 
Documentation of any adverse events 
• 
Study debriefing 
 
6.2.1 Screening Evaluation 
This study will occur at a single site, the University of Michigan. We will actively and 
passively recruit participants. We will actively recruit patients from clinics at the University of 
Michigan (UM), such as clinics in the Department of Anesthesiology and the Department of 
Neurosurgery. These departments will have access to the purpose of the study, intended patient 
population, and inclusion/exclusion criteria. For this study, we will consider chronic pain patients 
who are being treated with SCS from their own doctors as part of their standard clinical care. 
For active recruitment, our team of pain specialists (e.g., anesthesiologists and/or 
neurosurgeons) and other study personnel at UM will identify potential candidates and inform 
them about the study. The study coordinator or a person from the study team will contact the 
candidates (e.g., via telephone) to discuss details about the study (e.g., eligibility determination) 
and/or to verify interest. The necessary contact information (e.g., telephone number) of the 
candidates will be obtained by searching appointment logs and/or medical records. 
For passive recruitment, we will post publicly accessible flyers and brochures throughout UM 
Clinics, and also in various locations around Michigan Medicine (e.g., University Hospital). We 
will also post flyers and brochures across various other Pain Clinics and Hospitals in Livingston, 
Washtenaw, and/or Wayne County. IRB-approved flyers and brochures will be hung in several 
locations (e.g., waiting areas) in these clinics and hospitals. These flyers will have contact 
information of the study team (e.g., email, phone) and will also have a description of the study 
(resource included in Section 8-1.8 of the IRB application). Interested candidates may initiate 
contact with the study team.  
Potential subjects who are interested in participating in the study will be contacted by a 
member of the study team responsible for enrollment to assess interest and eligibility. Interested 
candidates will have the study and the eligibility criteria explained to them. If, at this point, they 
wish to continue with enrollment the candidate will be invited to participate in a study screening 
visit. Screening will be done over phone to verify eligibility. For eligible candidates, we will 
schedule an enrollment visit and/or other subsequent visits. We may also email candidates the 
consent forms to study and think about participation. For interested and eligible candidates, we 
will schedule the enrollment visit and/or other subsequent visits. All potential subjects will be 
assigned a unique screening ID. Those volunteers who do not meet the eligibility criteria or who 
choose not to participate in the study at either the telephone Pre-Screen or the Screening Visit 
will be logged. Personal identifiers will be kept until the study has been closed to recruitment, at 
which time they will be destroyed. This will prevent repeat screenings of potential participants. 
Consenting Procedure 
The research team will adopt an optional electronic informed consent procedure using 
SignNow. This option will be the preferred method for obtaining consent. A study team member 
will reach out to a candidate over the telephone to discuss the study and obtain consent with the 
patient over the phone using SignNow. The consent form will be read to the participant and time 
will be allowed for questions or if the patient would like to read/review the consent form on their 
own. All candidates will receive an electronic copy of the consent form after signing. If a 
candidate does not have access to the internet the following steps will be taken.  
 
The screening visit will begin with the informed consent interview. During the consent 
interview we will explain the study verbally and in writing. If interested, candidates will sign an 
informed consent, and will be given a copy. The other signed consent form will be placed within 
the study binder. We will conduct the consent interview in a private setting (e.g., examination 

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room, office), allowing sufficient time for prospective subjects to make an informed decision. 
Furthermore, we will also offer candidates the option of taking the informed consent form home 
to study and think about participation, with a follow up with one of the investigators or study 
personnel. Once the subject has formally consented to participate they will undergo a screening 
examination by a member of the study team. After the screening visit, study personnel will follow 
up with the patient after consent and screening to schedule all research visits. 
It is important to note that we will withhold information regarding the type of treatment (i.e., 
different forms of active stimulation vs. sham), and the order of treatment the subjects will 
receive during the study (concealment). Instead, we will inform subjects that we are adjusting 
the settings on their SCS device. We will inform candidates that the purpose of this study is to 
investigate the physiological effects and potential mechanisms of action of different types of 
SCS. We will also explain to each candidate that there will be no expected benefit to him/her by 
participating in this research study. However, it is possible (although not anticipated) that during 
this research new stimulator settings may be found that could be beneficial. We will also explain 
that the knowledge gained from this research may be beneficial for others, society, and/or 
science.  
Note: We will debrief subjects at the conclusion of their last research visit (i.e., Visit 6). 
Concealment is necessary to conduct this research study to avoid potential for altering subject 
behavior such that study results are biased.  
We will request for waiver of consent as part of the project to obtain the necessary contact 
information (e.g., telephone number) of candidates for recruitment prior to them signing a 
consent. We believe that this research could not practicably be carried out without the waiver or 
alteration. This is because we will need to obtain the contact information (e.g., telephone 
number) of candidates for recruitment prior to them signing a consent. This is essential to 
discuss details about the study (e.g., eligibility determination) and/or to verify interest. 
We will request alterations to the informed consent process to include incorporating specific 
elements of concealment as part of this research. We will withhold information regarding the 
type of treatment (Burst-SCS, KHFSCS, Sham SCS, 50 Hz SCS) and the order of treatment 
that the subjects will receive during the study (concealment). To reliably compare the effects of 
active vs. sham SCS in subjects receiving SCS therapy as part of their standard of care, it is 
essential that we withhold information regarding the type of treatment and the order of treatment 
the subjects receive during the study. This blinding could potentially avoid altering subject 
behavior during the blinded phase of the study thereby justifying its use in achieving the goals of 
this research. 
We do not believe that the waiver or alteration would cause harm, insults, injury to 
relationships, loss of job or insurance, injury to their health or well-being, etc. Potential risks 
might be related to loss of patient confidentiality. However, we will minimize this risk through 
several procedures. For example, we will make sure that the patient-subject information (e.g., 
contact information) obtained from appointment logs or medical records is stored only on secure 
(UM) computers, and that this information is maintained in a password-protected computer 
program at all times. Furthermore, we will make sure that only study team members listed on 
the IRB application will have access to this information. Therefore, this criterion affirms the 
request for a waiver or alteration of the informed consent. 
Screening 
Potential subjects who are interested in participating in the study will be contacted by a 
member of the study team responsible for enrollment. Interested candidates will have the study 
and the eligibility criteria explained to them. If, at this point, they wish to continue with enrollment 
the candidate will be invited to participate in a study screening visit. 
 

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The screening visit begins with the informed consent interview. Once the subject has 
formally consented to participate (by either signing the consent electronically or in person) they 
will undergo a screening examination by a member of the study team. This includes: 
• 
Completing demographic, sociodemographic, and medical history questionnaires 
• 
Collecting and reviewing patient’s pain rating and self-reported questionnaires and 
surveys 
• 
Assessing fibromyalgia status by completing Fibromyalgia Symptom Questionnaire 
(FSQ)  
• 
Conducting a physical assessment (height and weight) and collecting vital signs 
• 
Completing and reviewing Psychological Screening questionnaires (HADS) 
• 
Administering a urine pregnancy test to women of childbearing potential 
• 
Documenting and reviewing current concomitant medications 
 
Completion of these screening procedures will allow the study personnel to verify that the 
subject meets the full inclusion/exclusion criteria. For this study utilizing a single consent form, 
randomization should occur within two months of completing the screening procedures. 
 
6.2.2 Enrollment, Baseline, and/or Randomization 
Enrollment 
This study will occur at a single site, the University of Michigan. If a subject expresses 
interest in the study and completes the informed consent process, their eligibility based on the 
full inclusion/exclusion criteria will be verified during the screening visit. Study personnel will 
follow up with the subject after consent to schedule all research visits. The subject will be 
deemed enrolled upon meeting the study eligibility criteria. 
Baseline Assessments 
If patients meet eligibility criteria, we will ask them (during the screening visit) if they 
would like to enroll in the study. If they enroll, we will ask them to sign an informed consent 
form/document, and invite them to be part of various study visits. During the baseline at Visit 1, 
the following assessments will be performed: 
• 
Assess patients’ psychological status (e.g., anxiety, depression) using self-reported 
patient questionnaires/surveys (e.g., EuroQol questionnaire, EQ-5D5 and Hospital 
Anxiety and Depression Scale, HADS).60  
o If patients meet criteria for extreme anxiousness or depression (as indicated in 
the EQ-5D questionnaire or an equivalent score of 11-21 on HADS) we will 
offer/provide them with a “Depression Resource Handout”. However, patients 
can still continue their participation in the study. 
• 
Collect patients’ vital signs (heart rate, blood pressure, respiration rate, and body 
temperature), height, and weight.  
• 
Collect demographics, sociodemographics, and concomitant medications from the 
patients. 
Randomization 
Within two months of enrollment, we will randomize subjects to one of six randomly 
allocated sequences consisting of the following treatments: burst, 1 kHz, sham, and 50Hz SCS. 
Subjects will receive each treatment for seven days following one of the six randomly allocated 

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sequences (crossover design) (Fig. 3.1). We will perform testing before the start of the 
randomization and at the end of each seven-day treatment period. Subjects will be blinded 
during programming. To ensure proper blinding, we will set the amplitude of stimulation so that 
patients do not feel any stimulation-induced paresthesias (except for 50 Hz SCS which requires 
paresthesias).2 Sham SCS will be performed by setting the amplitude to 0 mA.2 For some 
systems, if the stimulation amplitude is decreased to 0 mA, the system will report that the 
stimulation is OFF and the participants will know that they are not receiving stimulation. 
Therefore, for these systems, we will perform sham SCS by setting the stimulation parameters 
to their minimal values: pulse width (~20 µs), frequency (~2 Hz), and amplitude (~0.1 mA). 
 
6.2.3 Blinding 
We will have two research teams. One team will be unblinded and will perform stimulator 
programming/adjustment, and the other team will be blinded and will perform clinical testing and 
collect study outcome measures. 
Participants will be blinded during programming. During the stimulator programming 
session, we will adjust the settings on the subjects' SCS device. We will adjust the settings such 
that subjects will receive seven days of a specific treatment allocation. To ensure proper 
blinding during the first three treatment allocations, we will set the stimulation amplitude so that 
the participants do not feel any stimulation-induced paresthesias. Sham SCS will be performed 
by setting the amplitude to 0 mA. For some systems, if the stimulation amplitude is decreased to 
0 mA, the system will report that the stimulation is OFF and the participants will know that they 
are not receiving stimulation. For these systems, we will perform sham SCS by setting the 
stimulation parameters to their minimal values: pulse width (~20 µs), frequency (~2 Hz), and 
amplitude (~0.1 mA). Therefore, participants will not experience stimulation-induced 
paresthesias during Sham SCS. However, during an active treatment allocation, stimulation-
induced paresthesias may sometimes occur (usually as a tingling sensation) due to positional 
changes (e.g., bending, lifting) and/or extreme movement. To minimize the occurrence of these 
stimulation-induced paresthesias, we will have the participants assume multiple positions (e.g., 
sitting, standing, supine, prone) during the programming session and ensure that the stimulation 
amplitude is low enough to avoid stimulation-induced paresthesias in any of these bodily 
positions. Therefore, the participant experience should be similar for the first three treatments. 
After completion of the first three treatment allocations, each participant will receive seven days 
of tonic 50 Hz SCS that will generate paresthesias over their painful areas. While having 50 Hz 
SCS as the last treatment in all participants may introduce a potential order effect, this treatment 
is performed last because patients will likely know that they are receiving active stimulation due 
to the paresthesias and this design will minimize the chance of breaking the blind during the first 
three treatment allocations. 
During this study, it is possible that participants may experience insufficient pain relief 
and/or discomfort during some of the treatments. Therefore, to reduce patient risk we will allow 
patients to keep the patient programmer. The participants will be instructed not to adjust the 
stimulation settings during each treatment. At the end of each treatment allocation, we will 
interrogate the participant’s implanted stimulator to ensure that the stimulation settings were not 
altered during the specific treatment phase. For some systems, patients are given a magnet that 
can be used to turn the stimulation off in the case of an emergency. For participants with these 
systems, we will instruct the participants to use the magnet, if needed, in the case of 
emergency. The magnet can be used to turn the stimulation on or off, in the absence of the 
programmer. 
It is possible that during some treatment allocations, such as during Sham SCS, 
participants may experience insufficient pain relief. If participants complain of significant 
discomfort and they are considering exiting the study, we will have the unblinded study 

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personnel examine the current treatment allocation to determine if the participant is receiving 
stimulation settings that vary substantially from their clinical parameters. If necessary, the 
participant can decide to have the stimulation settings returned to those determined to be 
effective through standard-of-care programming procedures. 
 
6.2.4 Followup Visits 
• 
Visit 3 (Day 7 ±  2 days): 
§ 
Vital signs 
§ 
Concomitant medications  
§ 
Surveys and questionnaires  
§ 
Quantitative sensory testing 
§ 
Administer treatment 
§ 
Stimulator programming 
§ 
Adverse events 
• 
Visit 4 (Day 14 ±  2 days): 
§ 
Vital Signs 
§ 
Concomitant medications 
§ 
Surveys and questionnaires 
§ 
Quantitative sensory testing 
§ 
Administer treatment 
§ 
Stimulator programming 
§ 
Adverse Events 
• 
Visit 5 (Day 21 ±  2 days): 
§ 
Vital Signs 
§ 
Concomitant medications 
§ 
Surveys and questionnaires 
§ 
Quantitative sensory testing 
§ 
Administer treatment 
§ 
Stimulator programming 
§ 
Adverse Events 
6.2.5 Completion/Final Evaluation 
The following procedures will be performed during the final visit (Visit 6 –  Day 28 ±  2 
days):  
§ 
Vital Signs 
§ 
Concomitant medications 

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§ 
Surveys and questionnaires 
§ 
Quantitative sensory testing 
§ 
Stimulator programming 
§ 
Adverse Events 
§ 
Study debriefing 
After the completion of all study procedures, the participants stimulation parameters will be 
returned to the settings selected through standard-of-care programming procedures. 
As detailed in Section 8, there are many reasons for participants to discontinue the study 
early. Subject participation is strictly voluntary and the research strictly knowledge driven; 
therefore, a subject may withdraw from further participation in the study without penalty or harm. 
Any reason(s) the subject may give for terminating his or her participation will be kept 
confidential. We will store the study documents according to the procedures outlined in the 
Section 11.3 of this protocol. Study personnel will be authorized to release a subject from further 
study participation according to the following guidelines: 
o The researcher believes that it is not in the subject’s best interest to stay in the study. 
o Subject becomes ineligible to participate. 
o Subject’s condition changes such that they need treatment that is not allowed while 
taking part in the study. 
o Subject does not follow instructions from the researchers. 
o The study is suspended or canceled. 
Upon termination of a subject, the investigators will ensure the subject is dismissed with any 
study documents to which they are entitled. Subjects will be compensated for their completed 
study visits prior to termination. Investigators will require no further obligation or participation 
from a terminated subject. The reason for participant discontinuation or withdrawal from the 
study will be recorded on the appropriate Case Report Form (CRF). 
Discontinuation from SCS will require discontinuation from the study, and remaining 
study procedures will not be completed. If a clinically significant finding is identified (including, 
but not limited to changes from baseline) after enrollment, the investigator or qualified designee 
will determine if any change in participant management is needed. Any new clinically relevant 
finding will be reported as an adverse event (AE). 
7.  SAFETY ASSESSMENTS  
7.1 Specification of Safety Parameters 
Participant safety will be monitored while individuals are enrolled in the study. The table 
below lists expected risks by study intervention/procedure, as well as criteria for management 
and modification of the study intervention regimen or participant assessments if an adverse 
event occurs. 
Known Potential Risks 
Criteria for Management 
Intervention Modification 
(if any) 
Electrical stimulation 
• Muscle contractions 
• Shock hazard (i.e., 
electrical burn) 
• Participant complains of 
• Stimulation amplitude will 
first be set to a low 
amplitude. 
• We will only use stimulators 
approved by the U.S. Food 

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discomfort 
and Drug Administration. 
Medical Imaging 
procedures (CT) 
• Exposure to radiation and 
increased risk of cancer 
• Participant may experience 
discomfort or anxiety from 
being in the confined space 
• Claustrophobia 
• Participant consent form will 
identify the cumulative risks 
of radiation and exposure. 
• Pads and blankets will be 
provided to reduce 
discomfort. 
Quantitative Sensory 
Testing (QST) 
 
• May cause minor but 
temporary physical 
discomfort 
• Study personnel are trained 
by the investigator to be 
sensitive to participant 
discomfort and concerns. 
• Participants are able to stop 
the QST at any time. 
Multimodal Automated 
Sensory Testing (MAST) 
• Participant complains of 
physical discomfort on the 
thumbnail 
• Participants will always 
have personal control over 
the stimulus and can top it 
at any time or express 
instructions to stop. 
• Participants can withdraw 
their thumb from the device 
or turn a safety release pin 
to immediately release the 
pressure actuator. 
The Vibrometer, Pressure 
Algometer, Pointed Skin 
Probe, and Conditioned 
Pain Modulation (CPM) 
Test 
• Participant complains of 
discomfort in the areas of 
testing 
• Skin irritation/redness 
• The test can be halted if the 
participant reports a pain 
rating of 100. 
• The participant can inform 
study personnel to stop the 
test at any time that the pain 
or unpleasantness of the 
task becomes intolerable. 
7.2 Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters  
Study progress and safety will be reviewed monthly (and more frequently if needed). 
Progress reports, including patient recruitment, retention/attrition, and adverse events (AEs) will 
be provided to the Independent Monitoring Committee (IMC) semi-annually. An Annual Report 
will be compiled and will include a list and summary of AEs. In addition, the Annual Report will 
address (1) whether AE rates are consistent with pre-study assumptions; (2) reasons for 
dropouts from the study; (3) whether all participants met entry criteria; (4) whether continuation 
of the study is justified on the basis that additional data are needed to accomplish the stated 
aims of the study; and (5) conditions whereby the study might be terminated prematurely. The 
Annual Report will be sent to the IMC and will be forwarded to the Institutional Review Board 

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(IRB) and National Center for Complementary and Integrative Health (NCCIH). The IRB and 
other applicable recipients will review progress of this study on an annual basis. 
7.3 Adverse Events and Serious Adverse Events  
Adverse event (AE) means any untoward medical occurrence associated with the use of 
an intervention in humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
An AE or suspected adverse reaction will be considered "serious" if, in the view of either the 
investigator or sponsor, it is any AE that: 
o Is fatal; 
o Is life threatening, meaning the patient was at immediate risk of death from the reaction 
as it occurred, i.e., it does not include a reaction that, had it occurred in a more serious 
form or progressed, might have caused death; 
o Causes a persistent or significant disability or incapacity; 
o Requires or prolongs inpatient hospitalization. Inpatient hospitalization will be considered 
a hospitalization if it is longer than 24 hours or requires an intervention to treat emergent 
symptomatology (non-diagnostic); 
Other important medical events may be considered SAEs when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes as listed in this definition. We will report SAEs to the 
IRBMED per the IRBMED Standard AE Reporting Plan at 
https://az.research.umich.edu/file/864. If the SAEs are not related to the study, we will report 
them at Continuing Review. If the SAEs are related to the study, we will report them within 
seven days or sooner to the IRB. We will also report AEs and SAE’s to the Principal Investigator 
(PI). If there is any evidence of a pattern of unanticipated AEs (regardless of causality), or 
SAEs, we will immediately have an independent third party review these data. Based on the 
conclusions of this third party, the PI will either terminate the study or convene the Data Safety 
and Monitoring Board (DSMB) to make recommendations.   
7.4 Reporting Procedures 
Severity of event: We will grade the signs and symptoms as mild, moderate, severe, or 
life threatening according to the following definitions: 
Grade 
Definition 
Mild 
Causing no limitation of usual activity 
Moderate 
Causing some limitations of usual activities 
Severe 
Causing inability to carry out usual activities 
Life 
Threatening 
Patient was at immediate risk of death from the event  
 
Relationship to study intervention: All adverse events (AEs) must have their relationship 
to study intervention assessed by the clinician who examines and evaluates the participant 
based on temporal relationship and his/her clinical judgment. The degree of certainty about 
causality will be graded using the categories below. 
• 
Related – The AE is known to occur with the study intervention, there is a reasonable 
possibility that the study intervention caused the AE, or there is a temporal relationship 

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between the study intervention and event. Reasonable possibility means that there is 
evidence to suggest a causal relationship between the study intervention and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study 
intervention and event onset, or an alternate etiology has been established. 
 
Expectedness: The study Principal Investigator (PI) will be responsible for determining 
whether an adverse event (AE) is expected or unexpected.  An AE will be considered 
unexpected if the nature, severity, or frequency of the event is not consistent with the risk 
information previously described for the study intervention. 
 
 
Time period and frequency for event assessment and follow-up: The occurrence of an 
adverse event (AE) or serious adverse event (SAE) may come to the attention of study 
personnel during study visits and interviews of a study participant presenting for medical care, 
or upon review by a study monitor. 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be 
captured on the appropriate case report form (CRF). Information to be collected includes event 
description, time of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis), and time of 
resolution/stabilization of the event. All AEs occurring while on study will be documented 
appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE.  
Changes in the severity of an AE will be documented to allow an assessment of the duration 
of the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
 
Reporting adverse events: We will report SAEs to the IRBMED per the IRBMED 
Standard AE Reporting Plan at https://az.research.umich.edu/file/864. If the SAEs are not 
related to the study, we will report them at the study continuing review. If the SAEs are related 
to the study, we will report them within seven days or sooner to the IRB. We will also report AEs 
and SAEs to the Principal Investigator (PI). If there is any evidence of a pattern of unanticipated 
AEs (regardless of causality), or SAE, we will immediately have an independent third party 
review these data. Based on the conclusions of this third party, the PI will either terminate the 
study or convene a Data Safety and Monitoring Board (DSMB) to make recommendations.  
 
Reporting events to participants: We will inform both the subject and the subject's 
physician in the event that a potentially significant, unexpected disease or condition is identified 
incidental to a study treatment or procedure. 
 
Reporting of pregnancy: As part of this research, participants may undergo specific 
medical imaging procedures, such as X-ray computed tomography (CT). For this research, we 
will consider pregnancy a contraindication for these medical imaging procedures. Therefore, 
before performing any medical imaging procedure as part of this research, we will perform a 
urine pregnancy tests for participants of child bearing potential, and having no intrauterine 
device (IUD) or hysterectomy, and who are able to become pregnant. If a participant becomes 
pregnant or nursing after enrollment and/or does not wish to take the pregnancy test at the 
screening visit, the participant will be excluded from the imaging procedures but will be allowed 
to remain in the study and participate in the remaining study procedures. This information will be 

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reported to the IRB as an Other Reportable Information or Occurrences (ORIO) within seven 
calendar days of becoming aware of the event or information. 
7.5 Followup for Adverse Events 
 
Study personnel will record all reportable events with start dates occurring any time after 
informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last 
day of study participation. At each study visit, the investigator will inquire about the occurrence 
of AE/SAEs since the last visit. Events will be followed for outcome information until resolution 
or stabilization. 
7.6 Safety Monitoring  
All research personnel involved in any way in this project will have completed training in 
the protection of human research participants per guidelines issued by the United States 
Department of Health and Human Services, Office for Human Research Protection. The 
protocol will undergo review and approval by the University of Michigan IRBMED and other 
necessary regulatory and oversight entities prior to implementation.  
 
We do not expect serious side effects or AEs from this research. AEs that do occur will 
be reported according to FDA guidelines, and reports will be sent to the University of Michigan 
IRBMED as required. The Principal Investigator (PI) will be notified when an AE occurs and will 
determine the attribution and relatedness of each adverse event. 
 
We will also create and work with an independent Data Safety Monitoring Board (DSMB) 
to monitor safety issues. The DSMB will meet periodically throughout the duration of the study. 
The DSMB will also report its findings of any adverse events or decisions regarding modification 
of the protocol to the University of Michigan IRBMED committee. 
 
The study coordinator and project leads will meet monthly with the PI to assess overall 
study progress, including regulatory matters, recruitment, adverse events, data quality, and to 
review any interim analyses. Outcomes of these meetings will be reported to the University of 
Michigan IRBMED on a quarterly basis. All protocols and consent forms are approved by the 
University of Michigan IRB and reviewed yearly. 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial 
participants are protected, that the reported trial data are accurate, complete, and verifiable, and 
that the conduct of the trial is in compliance with the currently approved protocol/amendment(s), 
with International Conference on Harmonisation Good Clinical Practice (ICH GCP), and with 
applicable regulatory requirement(s). The sponsor clinical monitoring service may conduct 
periodic on-site reviews of the study, including study initiation visit, periodic site visit and a study 
closeout visit. 
8.  INTERVENTION DISCONTINUATION  
Discontinuation from SCS will require discontinuation from the study, and remaining 
study procedures will not be completed. If a clinically significant finding is identified (including, 
but not limited to changes from baseline) after enrollment, the investigator or qualified designee 
will determine if any change in participant management is needed. Any new clinically relevant 
finding will be reported as an adverse event (AE). 
Subject participation is strictly voluntary and the research strictly knowledge driven; 
therefore, a subject may withdraw from further participation in the study without penalty or harm. 
Any reason(s) the subject may give for terminating his or her participation will be kept 
confidential. We will store the study documents according to the procedures outlined in Section 
11.3 of this protocol. We will require no further information of the subject and the subject will be 
compensated for his/her completed study visits prior to termination. 

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Study personnel will be authorized to release a subject from further study participation 
according to the following guidelines: 
o The researcher believes that it is not in the subject’s best interest to stay in the study. 
o Subject becomes ineligible to participate. 
o Subject’s condition changes such that he/she needs treatment that is not allowed 
while taking part in the study. 
o Subject does not follow instructions from the researchers. 
o The study is suspended or canceled. 
Upon termination of a subject, the investigators will ensure the subject is dismissed with any 
study documents to which he/she is entitled. Subjects will be compensated for their completed 
study visits prior to termination. Investigators will require no further obligation or participation 
from a terminated subject. 
The reason for participant discontinuation or withdrawal from the study will be recorded on 
the appropriate Case Report Form (CRF). Subjects who sign the informed consent form and are 
randomized but do not receive the study intervention may be replaced. Subjects who sign the 
informed consent form, and are randomized and receive the study intervention, and 
subsequently withdraw, or are withdrawn or discontinued from the study, will not be replaced. 
9.  STATISTICAL CONSIDERATIONS  
9.1 General Design Issues  
We will use descriptive statistics to present participants’ demographics and various 
outcome measures. Categorical data will be presented as frequencies and percentages. 
Normally distributed continuous data will be presented with means and standard deviations. 
Non-normal continuous data will be presented with medians and interquartile ranges.  
Because this study will employ the crossover design, for inferential tests, we will use 
linear mixed-effects models to analyze continuous outcomes (e.g., temporal summation, pain 
intensity on the visual analog scale (VAS)). These models will include a participant-level random 
intercept to account for correlations of measurements from the same participant. For binary 
outcomes (e.g., ≥50% improvement in VAS scores), we will use mixed effects logistic models. 
We will obtain the least-squares estimates (e.g., mean temporal summation, mean VAS score, 
or probability of have a ≥50% improvement in VAS) for the treatments and perform group 
comparisons with the appropriate contrasts. We will establish statistical significance with two-
sided p<0.05. 
9.2 Sample Size and Randomization 
The primary endpoint will be spinal cord stimulation (SCS)-induced changes in temporal 
summation (TS). We will calculate TS scores by subtracting the average pain rating of the 
single-stimulus trials from the average pain rating of the ten-stimuli trials (see Section 9.5.1). If 
the difference is a positive number, we will conclude that there was pain summation, where 
larger numbers will indicate increased pain summation or TS. If the difference is zero or a 
negative number, we will conclude that there was no pain summation or TS. As described in 
Section 3, we will consider four types or factor levels of SCS: Burst-SCS, KHFSCS, 50 Hz SCS, 
and Sham SCS. We will consider a repeated-measures design in which all four levels are tested 
in each participant. We will employ linear mixed-effects models in our analysis. Therefore, our 
null hypothesis will be that the group means with regards to TS are all equal. Our alternate 
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hypothesis, we will perform the appropriate post-hoc analyses to determine specific differences. 
To determine specific treatment effects, we will perform the following pairwise tests: Burst vs. 
Sham, 1 kHz vs. Sham, and 50 Hz vs. Sham. These tests do not require an adjustment for 
multiplicity because they are hierarchical. 
We will perform statistical analysis on SCS-induced changes in TS measured by 
differences in the corresponding TS. For our study, we assumed a sample size of 20 (25 
recruited with an attrition rate of 20% that was estimated from prior SCS studies that employed 
a similar crossover study design39,41), 80% power, and 5% level of significance with two-tailed 
tests. Using a paired t test, this will allow us to detect a within-subject effect size (i.e., 
standardized difference score, dz) of 0.68, reflecting the difference between active and sham 
SCS. While this study is exploratory, in the most comparable study conducted to date, eight 
subjects with neuropathic pain underwent SCS.61 Assuming a correlation value of 0.5 between 
TS measured in the same subject, the dz for the effects of “ON” versus “OFF” stimulation was 
0.89. A similar effect size in our study will achieve a statistical power greater than 95% with a 
sample size of 20. 
Treatment Assignment Procedures 
We will have two research teams. One team will be unblinded and will perform stimulator 
programming/adjustment, and the other team will be blinded and will perform clinical testing and 
collect study outcome measures. 
Within two months of enrollment, we will randomize subjects to one of six randomly-
allocated sequences consisting of the following treatments: burst, 1 kHz, sham, and 50Hz SCS. 
Subjects will receive each treatment for seven days following one of the six randomly allocated 
sequences (crossover design) (Fig. 3.1). We will perform testing before randomization and at 
the end of each seven-day treatment period. 
Participants will be blinded during programming. During the stimulator programming 
session, we will adjust the settings on the subjects' SCS device. We will adjust the settings such 
that subjects will receive seven days of a specific treatment allocation. To ensure proper 
blinding during the first three treatment allocations, we will set the stimulation amplitude so that 
the participants do not feel any stimulation-induced paresthesias. Sham SCS will be performed 
by setting the amplitude to 0 mA. For some systems, if the stimulation amplitude is decreased to 
0 mA, the system will report that the stimulation is OFF and the participants will know that they 
are not receiving stimulation. For these systems, we will perform sham SCS by setting the 
stimulation parameters to their minimal values: pulse width (~20 µs), frequency (~2 Hz), and 
amplitude (~0.1 mA). Therefore, participants will not experience stimulation-induced 
paresthesias during Sham SCS. However, during an active treatment allocation, stimulation-
induced paresthesias may sometimes occur (usually as a tingling sensation) due to positional 
changes (e.g., bending, lifting) and/or extreme movement. To minimize the occurrence of these 
stimulation-induced paresthesias, we will have the participants assume multiple positions (e.g., 
sitting, standing, supine, prone) during the programming session and ensure that the stimulation 
amplitude is low enough to avoid stimulation-induced paresthesias in any of these bodily 
positions. Therefore, the participant experience should be similar for the first three treatments. 
After completion of the first three treatment allocations, each participant will receive seven days 
of tonic 50 Hz SCS that will generate paresthesias over their painful areas. While having 50 Hz 
SCS as the last treatment in all participants may introduce a potential order effect, this treatment 
will be performed last because patients will likely know that they are receiving active stimulation 
due to the paresthesias and this design will minimize the chance of breaking the blind during the 
first three treatment allocations. 
Participants will be instructed not to adjust the stimulation settings during each 
treatment. At the end of each treatment allocation, we will interrogate the participant’s implanted 
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phase. For some systems, patients are given a magnet that can be used to turn the stimulation 
off in the case of an emergency. For participants with these systems, we will instruct patients to 
use the magnet, if needed, in the case of emergency. The magnet can be used to turn the 
stimulation on or off, in the absence of the programmer. 
 
It is possible that during some treatment allocations, such as during Sham SCS, 
participants may experience insufficient pain relief. If participants complain of significant 
discomfort and they are considering exiting the study, we will have the unblinded study 
personnel examine the current treatment allocation to determine if the participant is receiving 
stimulation settings that vary substantially from their clinical parameters. If necessary, the 
participant can decide to have to the stimulation settings returned to those determined to be 
effective through standard-of-care programming procedures. 
9.3  Definition of Populations 
For this study, we will utilize a per-protocol analysis dataset. We will only consider 
randomized participants who completed the Sham SCS treatment along with at least one other 
active (i.e., burst, tonic 1 kHz, tonic 50 Hz) SCS treatment along with the associated outcome 
measures for each treatment. 
9.4 Interim Analyses and Stopping Rules 
Planned interim analyses: There are no planned interim analyses. 
Safety analyses: In this post-approval mechanistic study, we will not evaluate a formal 
safety endpoint. We will code adverse events (AEs) according to the Medical Dictionary for 
Regulatory Activities (MedDRA) preferred terms. We will calculate AEs once for a given 
participant. We will present AEs with regards to severity, frequency, relationship, and 
expectedness. We will present serious AEs leading to premature discontinuation from the study 
in a table. We will collect and summarize adverse events, including the proportion of participants 
who experience at least one AE and the number of AEs per participant. We will also determine if 
the AE rates for this study were consistent with pre-study assumptions derived from AE rates in 
previously published studies. Potential differences in the AE rates between this study and prior 
studies could have significant implications for interpreting the results of this study. 
This study will be stopped prior to its completion if: (1) the intervention is associated with 
adverse effects that call into question the safety of the intervention; (2) difficulty in study 
recruitment or retention; (3) any new information becomes available during the trial that 
necessitates stopping the trial; or (4) other situations occur that might warrant stopping the trial. 
9.5 Outcomes  
9.5.1 Primary Outcome   
Temporal Summation (TS). The primary endpoint will be SCS-induced changes in 
temporal summation (TS). TS refers to an increased perception of pain in response to 
sequential stimuli of equal physical strength (Fig. 9.1A). It is a quantitative sensory testing 
(QST) model of neural plasticity and central hyper-excitability that is thought to reflect the 
progressive increase in neuronal firing of dorsal horn neurons in response to repetitive 
nociceptive C-fiber stimulation (i.e., windup).58 In this assessment, we will use a handheld 
pointed skin probe to apply fixed-intensity stimuli of 256 mN or 512 mN. The weight of the 
pointed skin probe (i.e., 256 mN or 512 mN) will be selected based on the sensitivity of the 
patient’s painful and control testing sites. In this paradigm, we will apply a single fixed intensity 
stimulus (256 mN or 512 mN) using a handheld pointed skin probe perpendicular to the 
subject’s skin for approximately 0.5 seconds. Following a 5-second pause, we will apply a train 
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Immediately following the single stimulus and the train of 10 stimuli, we will ask the subjects to 
report the pain intensity of the stimulus using a 0-100 NRS. We will conduct this testing 
paradigm (a single stimulus followed by a train of 10 stimuli) three times with the same 256 mN 
or 512 mN stimulator, and each cycle will be separated by at least 10 seconds. We will calculate 
TS scores by subtracting the average pain rating of the single-stimulus trials from the average 
pain rating of the ten-stimuli trials. If the difference is a positive number, we will conclude that 
there was pain summation, where larger numbers will indicate increased pain summation or TS. 
If the difference is zero or a negative number, we will conclude that there was no pain 
summation or TS. The primary endpoint will be the continuous TS values calculated at the end 
of each seven-day treatment period. Furthermore, at 15- and 30-seconds following the last train 
of 10 stimuli, we will ask subjects to rate any residual pain sensation in the testing area using 
the 0-100 NRS. 
 
 
Figure 9.1. Quantitative sensory testing (QST). (A) Temporal summation (TS), (B) Conditioned 
pain modulation (CPM), and (C) Vibrometry. 
 
9.5.2 Exploratory Outcomes   
We will consider all other outcome measures in our study as exploratory outcomes. We 
will perform a battery of psychophysical pain tests in the participants. The overall objective of 
these tests is to evaluate pain processing at different levels of the neuraxis. We will assess 
generalized mechanical sensitivity using a Multimodal Automated Sensory Testing (MAST) 
device (Fig. 9.2). We will assess spinal segmental sensitivity using a vibrometer and a pressure 
algometer. We will assess descending pain inhibition using the test of conditioned pain 
modulation (CPM). We will conduct all tests, including patient familiarization and training. For 
each test, we will read scripted instructions to the patients, and we will advise them that they 
can stop testing at any time without penalty if the sensations become intolerable. 
 
Generalized Mechanical Sensitivity. We will assess generalized mechanical sensitivity 
using the MAST device.62 The device consists of: 1) a wireless, hand-held thumbnail pressure 
stimulator with a circular 10 mm2 rubber tip, 2) client interface displaying a pain-rating scale, and 
3) a clinician interface used to design and control testing paradigms and generate data reports 
(Fig. 9.2). In this study, we will use the MAST device to deliver mechanical stimuli in the form of 
a series of automated (ascending) pressures onto the thumbnail bed (Fig. 9.2B). 
 

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Figure 9.2. Generalized mechanical sensitivity assessed using the MAST system. (A) MAST 
system components: thumbnail pressure stimulator, patient interface displaying a pain-rating 
scale, and clinician interface used to design and control testing paradigms and generate data 
reports. (B) Close-up view of the thumbnail pressure stimulator. 
 
First, we will apply 1-2 light “sample” pressures to the participant’s thumbnail to ensure 
proper thumb positioning. Once the subject’s thumbnail is in the proper position, we will conduct 
the familiarization procedure. We will apply a series of discrete pressure-pain stimuli to the 
subject’s left or right thumbnail. After each pressure is released, we will ask the subjects to rate 
their pain on a VAS or a 0-100 numerical rating scale (NRS), with 0 representing “no pain” and 
100 representing “worst possible pain”. If any pressure is intolerable, subjects are allowed to let 
us know and the pressure will be released immediately. Subjects can also release the pressure 
themselves by pressing the ‘STOP’ button on their screen. Following familiarization, we will 
conduct the MAST ascending test, where we will apply an ascending series of discrete pressure 
stimuli with a duration of 2.5-5 s beginning at 0.25 kg/cm2 and increasing in 0.25-0.50 kg/cm2 
steps to the subject’s opposite thumbnail. We will ask the subjects to rate their pain using a VAS 
or a 0-100 NRS. Testing is completed when a pain rating >80 using a VAS or a 0-100 NRS is 
received or after 10 kg/cm2 of pressure has been applied. The MAST system will calculate, in 
kilograms of force, the patient’s pain detection threshold, tolerance, and moderate and high 
supra-threshold pain values. Following this test, a second series of tolerable pressures (as 
determined from the MAST ascending test) may be delivered in a random order. Note: This 
paradigm may require minor modifications during the execution of this protocol. These 
modifications will not exceed the parameters described above, i.e., maximum pressure intensity 
will never exceed 10 kg/cm2. 
 
Spinal Segmental Sensitivity. We will assess spinal segmental sensitivity using a manual 
vibrometer63 and a pressure algometer64,65 at the primary pain site (Fig. 9.3). The primary pain 
site is defined as the area of maximum pain intensity (i.e., the area of worst possible pain) as 
reported by the patient. If severe hyperalgesia or allodynia prevents testing of the primary pain 
site, we will select an adjacent, less sensitive pain area. We will also perform testing at mirror 
sites (site directly opposite to the tested pain site) and/or bilaterally at several control sites (e.g., 
trapezius, lateral epicondyle, forearm). We will perform testing with the subject resting in a 
stationary position (e.g., sitting, supine, prone) to reduce the possibility of postural compression 
of the nerves being tested. 
We will use a handheld vibrometer (VSA-3000, Medoc Inc., Ramat Yishai, Israel) with a 
1 cm2 circular probe (Fig. 9.3A) to deliver vibratory, non-painful stimuli to determine sensitivity to 
vibration. We will apply an ascending series of vibratory stimuli. Subjects will report the first 

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sensation of vibration (denoted as vibratory threshold). We will average the vibratory thresholds 
across two or three consecutive trials at each site separated by intervals of approximately 20 to 
60 seconds. We may also apply a random sequence of fixed intensity vibratory stimuli, 1-3 
times each, to the individual sites. 
 
 
Figure 9.3. Spinal segmental sensitivity assessed using a (A) Vibrometer and a (B) Algometer. 
TS is assessed using a (C) PinPrick stimulator. 
 
We will use a handheld, analog pressure algometer (FPK Algometer, Wagner 
Instruments, Greenwich, CT) with a 1 cm2 flat rubber probe (Fig. 9.3B) to deliver pressure-pain 
stimuli. We will increase the pressure at a rate of approximately 0.30 kg/cm2 or 30-50 kPa/s 
(100 kPa/s maximum rate), to a maximum of 10 kg/cm2. Subjects will report their first sensation 
of pain (pressure-pain detection threshold) and pressure-pain tolerance. We will average the 
pressure-pain thresholds and pressure-pain tolerance across two or three consecutive trials at 
each site separated by intervals of approximately 20 to 60 seconds. We may also apply a 
random sequence of fixed intensity pressures, 1-3 times each, to the individual sites. We will 
ask the subjects to report the pain intensity of the pressure stimuli using a VAS or a 0-100 NRS. 
Conditioned Pain Modulation (CPM). We will use CPM to test the effect of a noxious 
“conditioning” stimulus on a “test” stimulus to determine the efficiency of (supraspinal) 
descending pain inhibition (Fig. 9.1B). We will use pressure delivered by the algometer as the 
test stimulus, and a contralateral thumbnail pressure (using MAST) as the conditioning stimulus. 
We will determine pressure-pain thresholds before and after application of a conditioning 
stimulus. The conditioning stimulus is a 60-second continuous pressure to the contralateral 
thumbnail at the exact or similar pain intensity as the test stimulus. During the first 30-s, 
subjects will rate the intensity of the thumbnail pressure alone on a VAS or a 0-100 NRS. 
Parallel to the last 30-seconds of CPM conditioning while the subjects’ thumb is still in the 
MAST device, we will reapply the test stimulus and determine pressure-pain thresholds. We will 
conduct the CPM test separately on the pain site and the control site. We will evaluate CPM as 
the mean difference in pressure-pain thresholds before and after application of a conditioning 
stimulus. If the difference in pressure-pain threshold is found to be negative, the subject is 
considered to have achieved an inhibitory CPM response; if the difference in pressure-pain 
threshold is found to be zero or positive, it is concluded that the subject did not exhibit a CPM 
response. 
 
 
Other important considerations. If the participant has been diagnosed with peripheral 
neuropathy in the upper extremity that could potentially interfere with the MAST results, we will 
skip the MAST and thumb-based CPM procedures. However, the participant will complete the 
other tests. If the participant has a missing, severely malformed, or injured thumb on which 
testing is to be performed, we will conduct MAST testing on the opposite thumb, provided it is 
not missing nor injured. For example, we would conduct both familiarization and testing on the 
dominant thumb if the non-dominant thumb was abnormal, or vice-versa. To permit sufficient 
tissue recovery, we will provide a rest interval of 5-10 minutes between the MAST familiarization 

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protocol and the MAST test, if we conduct testing on the same thumb. We will record the thumb 
on which familiarization and testing occurred. If both thumbs are missing and/or injured, we will 
skip the MAST and the thumb-based CPM tests. However, the participant will complete the 
other tests. 
 
Visual analog scale (VAS). We will measure intensity of back pain, leg pain, and general 
pain using patient-reported ratings on the VAS. VAS ratings are the most commonly-used 
clinical outcome measure in SCS. Operationally, a VAS is usually a horizontal line, 100 mm in 
length, anchored by word descriptors at each end, such as “no pain” and “worst possible pain”. 
The patient marks on the line the point that they feel represents their perception of their current 
state. The VAS score is determined by measuring in millimeters from the left hand end of the 
line to the point that the patient marks. The main advantage of using VAS ratings is that it will 
allow us to compare our outcomes to other clinical results available in the literature.1,2,7–9,41,66 
Self-reported patient questionnaires. We will measure additional exploratory outcomes 
using several self-reported patient questionnaires. We will measure secondary outcomes using 
several self-reported patient questionnaires. We will use the Short-Form McGill Pain 
Questionnaire (SFMPQ)67 and the Pain Disability Index (PDI)68 to assess the patient’s 
description of the quality of pain. The main component of the SFMPQ consists of 15 descriptors 
(11 sensory and 4 affective) rated on a 4-point intensity scale (0=none to 3=severe). Three pain 
scores are derived from the intensity rank values of the words chosen for sensory, affective and 
total descriptors. The SFMPQ also includes the present pain intensity index (i.e., the VAS), and 
an evaluative overall intensity of total pain experience. The PDI is a six-question survey 
regarding daily living activity. Range is 0 (completely able to function) to 10 (totally unable to 
function), with higher number indicating greater disability. We will use the Brief Pain Inventory 
(BPI) to assess the severity of pain and its impact on daily functioning.69 The BPI is a nine-
question survey with scores ranging from 0 to 10, with higher scores indicating more severe 
pain and greater interference with functioning. We will use the Michigan Body Map (MBM) to 
assess body areas where chronic pain is experienced, and specifically quantify the degree of 
widespread body pain in the patient (i.e., pain centralization).4 We will also use the Fibromyalgia 
Survey Questionnaire (FSQ) in combination with the MBM to assess pain centralization.70 We 
will use the PainDETECT to detect neuropathic pain components in patients.71 We will use the 
Hospital Anxiety and Depression Scale (HADS) to assess anxiety and depression,60 Patient 
Reported Outcomes Information System Sleep Disturbance Short Form questionnaire (PROMIS 
SD) to assess sleep interference, and Coping Strategies Questionnaire (CSQ) to assess 
catastrophizing in patients.72 We will use the EQ-5D Health Questionnaire to characterize the 
patient’s quality of life.5 We will administer these questionnaires on paper and/or using the 
Qualtrics survey platform. 
 
Patient-specific computer modeling. The goal of this computational modeling is to develop 
patient-specific computer models that correctly simulate the neural response to SCS. Existing 
computer models of SCS largely ignore inter-patient variability. We hypothesize that patient-
specific models capture the details necessary to quantitatively describe the axonal response to 
SCS and to correlate model-based predictions with clinical outcomes. Therefore, we will 
develop patient-specific computer models of SCS for the 25 participants. These computer 
models will consist of two components: 1) a patient-specific electrical volume conductor model, 
and 2) a spinal cord model. We will develop these patient-specific models in three steps: 
1) 
Calculate the patient-specific extracellular voltages generated by SCS. 
2) 
Define axon models in the spinal cord. 
3) 
Assess the axonal response to SCS by coupling the electric fields to the axon 
models. 
Prior to electrode implantation, participants will have received an MRI or CT myelogram of the 
spine as part of their standard of care. We will use this imaging to provide detailed localization 
of the spinal cord and relevant anatomy. If we do not have access to the appropriate 

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preoperative imaging, the participant will be excluded from the CT imaging procedures in this 
study and we will not perform modeling analyses for this participant. However, the participant 
will be allowed to remain in the study and participate in the remaining study procedures. This 
information will be reported to the IRB as an Other Reportable Information or Occurrences 
(ORIO) within seven calendar days of becoming aware of the event or information. 
 
Postoperatively, we will determine the electrode locations with a 3D CT scan. We will use 
the commercial software package, Mimics Innovation Suite (Materialise, Belgium), to co-register 
the MRI and CT. Once the imaging data has been co-registered, we will segment the implanted 
electrodes, spinal cord, CSF, dura, epidural space, and bone to generate a patient-specific finite 
element model (FEM) (Fig. 9.4). We will discretize the FEM with tetrahedral elements and 
employ higher node densities near the electrodes to ensure model accuracy. To achieve a 
model solution, we will specify the current at the electrode(s) (Dirichlet boundary conditions) and 
specify insulating and ground surfaces (Neumann boundary conditions) and solve the Poisson 
equation. We will parameterize each patient-specific FEM with established conductivity 
values.73–77  
 

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Figure 9.4. Patient-specific finite element model (FEM). (A) In this example, we used 
preoperative MRI scans to define the participant’s anatomy (e.g., spinal cord, cerebrospinal fluid 
(CSF), spine) and a postoperative X-ray computed tomography (CT) scan to define the 3D 
electrode locations. (B) We coregistered the 3D objects segmented from the preoperative and 
postoperative images to define a patient-specific FEM. The figure on the top right shows 
outlines of the 3D FEM objects in the preoperative MRI. The figure on the bottom right shows 
the voltages generated on the surface of the spinal cord for a -1 V bipolar stimulus (Note: In this 
figure, the electrode array and spinal cord are not drawn on the same scale). 
 
 
After we have calculated the electric fields during SCS, we will populate the model with 
multi-compartmental models of myelinated Aβ somatosensory axons in the dorsal column (DC) 
and their collaterals within the dorsal horn.78 We will incorporate physiological fiber size 
distributions, axon collaterals, and the 3D orientations of dorsal root (DR) fibers as they enter 
the spinal cord.79–81 Each of these factors has been shown to affect activation thresholds.76,82,83 

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For each patient, we will determine 3D axon trajectories based on the patient's spinal cord 
anatomy segmented from his/her MRI scan. We will construct electrically-equivalent models by 
importing an axon's 3D geometrical data into the software package, NEURON.84 We will 
generate multi-compartment cable models by segmenting each neural process into 
compartments and joining neighboring compartments via axial resistances determined by the 
compartment length and diameter.85 Each compartment will also contain a representative set of 
linear and non-linear transmembrane conductances. We will base these nonlinear membrane 
currents on the traditional Hodgkin-Huxley formalism.86 We will use a repertoire of three active 
sodium channel conductances (Nav1.7, Nav1.8, Nav1.9) along with two potassium channel 
conductances (KDR (delayed rectifier) and KA (A-type)) to represent the membrane biophysics of 
the sensory axons. The mathematical details of these conductances have been previously 
described in the literature.87,88 This numerical multi-compartment approach represents a method 
to incorporate the necessary 3D neuron geometries and the ion channel kinetics at the nodes of 
Ranvier. 
 
The third step in our model analysis will be to assess the direct axonal response to each 
type of SCS. For each patient, we will perform this step by applying the patient-specific 
extracellular voltages (step 1) to the 3D patient-specific axon models (step 2) (Fig. 9.5). We will 
then calculate the axonal responses and activation thresholds for individual axons. 
 
 
Figure 9.5. Axonal response to SCS. (A) Axial and sagittal views of isopotential lines of the 
extracellular voltages generated by SCS. The voltage distributions were calculated from the 
patient-specific finite element model. (B) To estimate the direct axonal response to SCS, we 
interpolated the SCS-induced extracellular voltages onto the axon models. With sufficient 
depolarization, action potentials were initiated in an axon and propagated in both orthodromic 
and antidromic directions. The figure shows the time-dependent transmembrane voltages at 
several nodes in a dorsal column (DC) axon and illustrates action potential generation with a 50 
Hz SCS waveform. 
 
 
We will validate the design and parameters of our patient-specific computer models with 
detailed clinical measurements in each patient. We will determine two stimulation thresholds 
that are standard measurements with clinical SCS programming89: 
Perception threshold (PT) =  amplitude at which the participant first detects the stimulation, 
usually felt as a tingling sensation (i.e., paresthesia), related to 

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DC fiber activation 
Discomfort threshold (DT) =  amplitude at which the stimulation becomes uncomfortable due 
to motor effects or other discomfort, related to DR fiber 
activation 
While we do not know the neuromodulatory effects of various forms of clinically effective SCS, 
such as burst and kilohertz-frequency SCS, it is well accepted that stimulation at PT and DT 
correspond to dorsal column and dorsal root fiber activation, respectively.76 Therefore, in each 
participant, we will measure the PT and DT for tonic 50 Hz, burst, and 1 kHz SCS. At PT, we will 
also have each patient indicate the areas of stimulation-induced paresthesias by drawing on a 
human figure on a tablet.90 These drawings will help ensure that the models predict the correct 
activation in the spinal cord somatotopy corresponding to the paresthetic regions. If necessary, 
we will adjust the model parameters (e.g., tissue conductivities) until the models predict the 
appropriate activations at PT and DT for 50 Hz, burst, and 1 kHz SCS. 
 
Spinal circuit model. We will implement a circuit model of pain processing in the dorsal 
horn based on the gate-control theory of pain.17 This circuit model will include populations of 
inhibitory interneurons (I), excitatory interneurons (E), wide-dynamic range (i.e., neurons that 
respond to both nociceptive and non-nociceptive inputs) projection neurons (W), and a mid-
brain neuronal population (T) (Fig. 9.6). It will also include inputs from three types of afferent 
fibers: large-diameter myelinated somatosensory Ab, thinly myelinated nociceptive Ad, and 
unmyelinated nociceptive C fibers. 
 
 
Figure 9.6. Circuit model of pain processing in the spinal cord. a) The model includes 
connections to/from the mid-brain and the following populations: inhibitory interneurons (I), 
excitatory interneurons (E), WDR projection neurons (W), and a mid-brain neuronal population 
(T). The model also includes three afferent fiber populations: Ab, Ad, and C fibers. b) Average 
firing rates for the three afferent fiber populations. SCS is applied at time = 0 ms. Tonic and 
burst SCS each increase the firing rates of the Ab fibers. 
 
 
We will use a population-level firing-rate formalism to describe the average firing rates of 
the I, E, W, and T populations in the dorsal horn circuit. We will assume that the rate of change 
of the average firing rate in Hz (i.e., the average number of spikes per unit time) of the W, I, E, 
and T neuron populations, fW, fI, fE, and fT, respectively, will be determined by nonlinear 
response functions.91 We will represent the monotonically-increasing firing-rate response 
functions using hyperbolic tangent functions and assuming a sigmoidal shape. The shape of the 
hyperbolic tangent functions will be defined by the average and maximum firing rates of the 
respective populations so that the input-output curve of each population qualitatively agrees with 
experimental observations.92 The firing rate of the W population will be the primary output of the 
model. The firing rate of wide-dynamic range projection neurons is correlated with the 

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magnitude of pain93 and has been used in animal studies as a proxy for SCS efficacy.19,94–96 
 
The input to our circuit model will be the activity of the Ab, Ad, and C afferent fibers with 
relative densities based on the literature (9% Ab; 9% Ad; 82% C).97,98 The three fibers types 
have different diameters and myelination properties that result in different conduction velocities. 
Because the temporal aspects of the inputs are critical to pain processing and the response to 
SCS, we will use published conduction velocities for each fiber type (Ab: 14-30 m/s; Ad: 2.2-8 
m/s; C: 0.6-1.5 m/s).99 For peripherally generated afferent stimulation (e.g., painful stimulus), we 
will generate recurring events at the Ab, Ad, and C fiber inputs with arrival latencies assuming 
~1 m between the site of stimulation and the dorsal horn network. To represent baseline 
afferent input activity during chronic pain conditions, we will apply Poisson spike trains with 
means and variances consistent with those of spike trains recorded in animal models of 
neuropathic pain (Ab mean = 2.2 spikes/s, Ad mean = 2.2 spikes/s, C mean = 1.5 spikes/s)100,101 
and we will set 30% of the Ab and Ad fiber inputs to exhibit bursting behavior.96,100,102 To 
represent afferent input activity in response to a painful stimulus, we will apply primary afferent 
spike trains with individual interspike intervals with mean frequencies representative of 
peripheral afferent activity during steady-state natural “pinch” stimulation (Ab mean – 9 spikes/s, 
Ad mean – 9 spikes/s, C mean = 2.5 spikes/s).103 To input this spiking activity into our 
population-level model, we will compute the average firing rate in each group of fibers by a 
moving average over a time window of 10 ms. These baseline population firing rates for the 
three types of afferents will be the inputs into the model, in addition to the Aβ activity induced by 
electrical stimulation as described below. 
 
To determine the effects of tonic 50 Hz, burst, and 1 kHz SCS on pain processing in the 
spinal cord, we will couple the axonal responses predicted by the patient-specific electric-field 
models (Fig. 9.5) to this population firing-rate model of pain processing in the dorsal horn (Fig. 
9.6). It is well accepted that SCS leads to modulation of the large-diameter Ab fibers.76 
Therefore, we will use the patient-specific electric-field models to estimate how the activity of 
individual fibers in the Ab population are modulated by SCS. To do this, as part of our 
quantitative sensory testing procedures, we will first identify a primary pain site corresponding to 
the dermatome at which pain is the most intense for each patient. We will define a circuit model 
of pain processing for the spinal level corresponding to this primary pain site. It is well known 
that Aβ afferents give off collaterals from their ascending and descending branches at levels 
other than those at which they entered the spinal cord and that Aβ collaterals plays a key role in 
the gate theory of pain.17 Thus, we will incorporate data from the literature describing the 
rostral/caudal extent of Aβ fibers entering at all levels of the spinal cord and the distribution of 
their collaterals to determine which spinal segments have collaterals that project and have 
inputs into the primary pain level.81 These specific axons will serve as inputs that connect to the 
I and W populations in the circuit model of pain processing at the primary pain site. We will use 
the patient-specific electric field models to determine how these axons are modulated by the 
different types of SCS. 
 
We will validate the output of our population firing-rate model in multiple steps. We will 
ensure that our model reproduces well-known phenomenon, such as central sensitization or 
“wind-up”. Wind-up is an increased excitability of the neurons in the spinal cord, particularly the 
wide-dynamic range projection neurons, due to repetitive stimulation of C fibers. Therefore, we 
will generate repetitive low-frequency (1 Hz) C-fiber inputs and compare the output of our W 
population to previous experimental data demonstrating wind-up.94,96,104–107 As described in 
Section 9.5.1, temporal summation (TS) of pain is the human analogue of wind-up, and so we 
will also match the output or degree of central sensitization to the experimental measurements 
of TS. In our primary outcome considering SCS-induced changes in TS, we will apply a 
repetitive 1 Hz stimulus and have the patient rate their pain as a function of time. In human 
subjects, each subsequent stimulus becomes more painful and is believed to represent wind-up 

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within the spinal cord. Therefore, we will be able to compare increases in the pain ratings from 
our participants (reflecting wind-up) to increases in the output of the W population in our model. 
 
We will also validate that our circuit model reproduces descending inhibition. We will 
compare our model results to the experimental measurements performed in the CPM paradigm. 
During this CPM paradigm, a patient receives a conditioning stimulus and a painful test stimulus 
and rates the pain of this test stimulus (Fig. 9.1B). In human patients, the conditioning stimulus 
has the effect of reducing the pain levels of the test stimulus and is believed to represent 
descending pain inhibition.108 Therefore, we will compare the reduced pain levels observed 
during CPM in each patient to the changes in W output in our model produced by increased 
inputs from the T population. We will represent the test stimulus as increased inputs from the all 
three afferent populations (Ab = 9 spikes/s, Ad = 9 spikes/s, C = 2.5 spikes/s).96,103 We will 
represent the conditioning stimulus by increasing the weighting parameter between the T and W 
populations that would produce increased inhibition of W.92 
We will use the validated model to investigate the underlying mechanisms of pain relief 
induced by SCS. We will compare the model output (i.e., W population firing rate) on a patient-
by-patient basis. We will also compare the model outputs predicted between the groups of 
responders versus non-responders. For patients who obtained successful pain relief with SCS, 
we will compare the model output for clinically effective stimulation parameters versus clinically 
ineffective stimulation parameters. 
9.6 
Data Analyses  
Analysis of the primary efficacy endpoint(s): The primary endpoint will be SCS-induced 
changes in temporal summation (TS) (see Section 9.5.1). We will use a repeated-measures 
approach in which the continuous TS values will be calculated at the end of each seven-day 
treatment period, i.e., type of SCS. To analyze SCS-induced changes in TS measured at the 
end of each treatment period, we will use linear mixed-effects models that will include a 
participant-level random intercept to account for correlations of measurements from the same 
participant. We will obtain the least-squares estimates of the mean TS for the treatments and 
perform group comparisons with the appropriate contrasts. We will establish statistical 
significance with two-sided p<0.05. We will utilize a per-protocol analysis dataset. We will only 
consider randomized participants who completed the Sham SCS treatment along with at least 
one other active (i.e., burst, tonic 1 kHz, tonic 50 Hz) SCS treatment along with the associated 
outcome measures for each treatment. 
Analysis of the secondary endpoint(s): N/A. 
Baseline descriptive statistics: We will use descriptive statistics to assess data quality 
and characterize relationships between variables. We will list the aggregate data using means 
and standard deviations for normally distributed data and medians and interquartile ranges for 
non-normal data. We will consider several baseline demographics and clinical characteristics, 
such as gender, pain duration, pain diagnosis, previous back surgery, and co-treatments (e.g., 
opioids, antidepressants, anticonvulsants, NSAIDs/simple analgesics, other). We will consider 
the QST outcome measures characterizing baseline static and dynamic pain processing. 
Finally, we will also consider the exploratory outcome measures related to baseline pain 
intensity, pain quality, pain spread, and quality of life. 
Sub-group analyses: This study is an exploratory mechanistic study examining the 
physiological effects of multiple forms of SCS on sensory processing. Due to the small number 
of participants that will be considered in this study (i.e., n=20), we will not analyze primary or 
exploratory endpoints based on age, race/ethnicity, or other demographic characteristic(s). 
However, sex has been shown to be an important variable to consider in chronic pain and 
sensory processing. Therefore, although we may not detect significant differences due to the 

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small sample size in this exploratory study, we will consider sex as a biological variable when 
analyzing the primary and exploratory endpoints. 
Tabulation of individual participant data: We will list individual participant data with 
regards to the primary outcome. For each type of SCS (Burst-SCS, 1kHz SCS, 50Hz SCS, 
Sham SCS), we will list the TS value calculated for each individual participant. We will use the  
mean TS value to quantify SCS-induced changes in TS. For the exploratory endpoints, we will 
list the aggregate data using means and standard deviations for normally distributed data and 
medians and interquartile ranges for non-normal data. 
Exploratory analyses: To investigate the anti-nociceptive effects of SCS, we are 
proposing to conduct an exploratory, mechanistic, placebo-controlled study in 25 patients 
undergoing SCS for chronic pain. We will use quantitative sensory testing (QST) to assess 
spinal and supraspinal pain processing. In addition to the primary outcome described in Section 
9.4.2, we will perform several exploratory analyses. We will evaluate the effects of 
somatosensory stimuli using static QST measures of sensory detection threshold, pain 
threshold, and/or tolerance to stimuli (i.e., vibratory threshold, pressure-pain threshold). We will 
also assess dynamic central pain-processing mechanisms, such as endogenous pain inhibition, 
by measuring pain sensitivity concurrent with the application of a conditioning stimulus (i.e., 
conditioned pain modulation (CPM)).15 Furthermore, we will obtain outcome measures to assess 
changes in pain intensity, pain quality, pain spread, and quality of life. Additional exploratory 
outcomes will include patient-reported VAS ratings for back, leg, and general pain,1,2 and 
several self-reported patient questionnaires, such as the Short-Form McGill Pain Questionnaire 
to assess quality of pain,3 Michigan Body Map to quantify the degree of widespread body pain,4 
EQ-5D to characterize quality of life,5 Pain Disability Index (PDI) to measure pain-related 
disability,68 and questionnaires from the Patient Reported Outcomes Measurements Information 
(PROMIS)6. We will identify responders as patients who demonstrate a ≥ 50% reduction in 
average pain intensity (as measured by the VAS) with active SCS as compared to sham 
stimulation, a standard criterion for success with SCS.22 We hypothesize that patients who 
respond to specific types of SCS will show decreased spinal segmental sensitivity, particularly 
decreased vibration sensitivity and pressure-pain sensitivity. We believe that effective SCS will 
also modulate dynamic central pain-processing mechanisms. We hypothesize that effective 
types of SCS (i.e., patients who show ≥50% reduction in average pain intensity) will reduce TS 
(primary outcome) and improve inhibitor CPM. 
Because these mechanistic questions are difficult to answer experimentally, we will also 
perform exploratory analyses with patient-specific computational models that will include: 1) 
electric-field models to estimate the direct neural response to SCS, and 2) circuit models to 
estimate the effects of SCS on pain processing in the spinal cord. We hypothesize that patient-
specific models capture the details necessary to quantitatively describe the neural response to 
SCS and to correlate model-based predictions with experimental measurements of pain 
modulation. Therefore, we will develop patient-specific electric-field models that account for 
sources of interpatient variability (e.g., anatomy, electrode locations, stimulation parameters) for 
the 25 participants. We will define finite element models from the patient-specific preoperative 
and postoperative medical imaging. To estimate the direct neural response to SCS, we will then 
place multi-compartment neuron models within the patient-specific spinal cord anatomy.  
The basic hypothesis of this study is that the physiological effects of SCS can be 
correlated with modulation of specific fiber pathways that help regulate pain processing within 
the spinal cord. However, the specific analgesic mechanisms of clinically effective SCS remain 
unknown. Therefore, as a second component of our computational modeling approach, we will 
develop a population firing-rate circuit model of pain processing in the spinal cord. We will use 
the direct neural response to SCS estimated from the electric-field models as the inputs to our 
circuit model. We will determine what types of spinal cord modulation best correlate with 
experimental measurements of pain modulation during SCS.  

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Finally, due to our poor scientific understanding of how SCS works and the limited 
individualization of this therapy, we consider current clinical implementation of SCS to be 
suboptimal. Therefore, in this exploratory analysis, we will use our computational models to 
identify stimulation protocols (e.g., alternative waveform parameters) that may improve the 
desired physiological effects and corresponding pain relief. 
10. DATA COLLECTION AND QUALITY ASSURANCE 
10.1 
Data Collection Forms  
All study related information will be collected via self-reported questionnaire as per the table 
below. 
Form Name 
 
 
 
 
 
Data Collection Method 
Screening & Demographics 
 
 
 
 
Informed Consent  
 
 
 
 
Study Coordinator /  
 
 
 
 
 
 
 
 
Team Member 
Demographics 
 
 
 
 
 
Participant 
Socio-demographics 
 
 
 
 
Participant 
Concomitant Medications  
 
 
 
Participant 
Vitals (heartrate, blood pressure, respiration rate,  
Clinical staff 
blood temperature), height and weight 
 
 
 
 
Self-Report Patient Questionnaires 
Short Form McGill Pain Questionnaire (SFMPQ)  
Participant 
Pain Disability Index (PDI) 
 
 
 
Participant 
Brief Pain Inventory (BPI)  
 
 
 
Participant 
Michigan Body Map (MBM)  
 
 
 
Participant 
Fibromyalgia Survey Questionnaire (FSQ)  
 
Participant  
PainDETECT  
 
 
 
 
 
Participant  
Hospital Anxiety and Depression Scale   
 
Participant 
(HADS)  
Patient-Reported Outcomes Measurement  
 
Participant 
Information System Sleep Disturbance 
Short Form Questionnaire (PROMIS-SD) 
Coping Strategies Questionnaire (CSQ)  
 
Participant 
EQ-5D Health Questionnaire 
 
 
 
Participant 
 
Visual Analog Scale (VAS) – included in SFMPQ 
Participant 
 
Generalized Mechanical Sensitivity 
Multimodal Automated Sensory Test (MAST) 
 
Participant /  
 
 
 
 
 
 
 
 
Study Coordinator / 
 
 
 
 
 
 
 
 
Team Member 
 
Spinal Segmental Sensitivity 
Vibrometer Test  
 
 
 
 
Participant / 
 
 
 
 
 
 
 
 
Study Coordinator /  
 
 
 
 
 
 
 
 
Team Member 
Algometer Test 
 
 
 
 
 
Participant /  
 
 
 
 
 
 
 
 
Study Coordinator /  

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Team Member 
      PinPrick Test 
 
 
 
 
 
Participant /  
 
 
 
 
 
 
 
 
Study Coordinator /  
 
 
 
 
 
 
 
 
Team Member 
 
Quantitative Sensory Testing (QST) 
Conditioned Pain Modulation (CPM) Test 
 
Participant /  
 
 
 
 
 
 
 
 
Study Coordinator /  
 
 
 
 
 
 
 
 
Team Member 
 
Stimulator programming 
 
 
 
 
 
Burst, 1kHz, 50Hz, Sham SCS 
 
 
 
Participant /  
 
 
 
 
 
 
 
 
Study Coordinator /  
 
 
 
 
 
 
 
 
Team Member 
 
Safety 
Adverse Events 
 
 
 
 
 
Study Coordinator /  
 
 
 
 
 
 
Team Member 
10.2 
Data Management  
The University of Michigan Division of Pain Research, Chronic Pain and Fatigue Research 
Center, and other study personnel will be responsible for the collection of all source information. 
All Case Report Forms will be approved by the University of Michigan IRB.  
Participants will complete electronic surveys or paper-based questionnaires. Electronic 
questionnaires will be completed via the Qualtrics Research Core at the University of Michigan. 
Data will be verified and checked for completeness and initialed by the study coordinator or 
other team member prior to the completion of the visit. All data will be entered into a research 
database (REDCap) by the study team. 
Study data will be collected and managed using REDCap electronic data capture tools 
hosted at University of Michigan. REDCap (Research Electronic Data Capture) is a secure, 
web-based application designed to support data capture for research studies, providing: 1) an 
intuitive interface for validated data entry; 2) audit trails for tracking data manipulation and 
export procedures; 3) automated export procedures for seamless data downloads to common 
statistical packages; and 4) procedures for importing data from external sources. 
10.3 
Quality Assurance  
10.3.1 Training 
All study team members are required to be certified by the University of Michigan 
Program for Education and Evaluation in Responsible Research and Scholarship (PEERRS). In 
addition, research staff are required to follow study specific operating procedures as 
documented in the Manual of Operations and approved by the study PI. 
10.3.2 Quality Control Committee  
There is no quality control committee for this study, however, the study team will perform 
internal quality management of study conduct, data collection, documentation and completion. 
An individualized quality management plan will be developed to describe quality management. 
Quality control (QC) procedures will be implemented beginning with the data entry 
system and data QC checks that will be run on the database that will be generated. Any missing 
data or data anomalies will be communicated to the study team for clarification/resolution. 

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Following written Standard Operating Procedures (SOPs), the monitors will verify that 
the clinical trial is conducted and data are generated and collected, documented (recorded), and 
physiological effects of spinal cord stimulation for pain reported in compliance with the protocol, 
International Conference on Harmonisation Good Clinical Practice (ICH GCP), and applicable 
regulatory requirements.  
The investigational site will provide direct access to all trial related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and 
inspection by local and regulatory authorities. 
10.3.3 Metrics 
All outcome measures will be assessed for quality. If an outcome’s value is above or 
below the possible range for that outcome, the data will be flagged for review. 
10.3.4 Protocol Deviations 
Protocol deviations will be documented on the visit checklist at each visit by the study 
team member responsible for that visit. The study coordinator will review the deviation and 
report to the study team via the Deviations Tracking Log. Corrective Actions, if required, will be 
noted in the subject file and study documentation. Major protocol deviations that may adversely 
impact safety of participants, or impact integrity/validity of the data and minor protocol deviations 
as part of a pattern and/or suggesting a systemic problem in study conduct that potentially 
places subjects or others at a greater risk of harm than was previously known or recognized will 
be reported as an Other Reportable Information or Occurrences (ORIO) within seven days of 
becoming aware of the event or information. Minor protocol deviations that do not impact safety 
of participants or impact integrity/validity of the data – for example, schedule deviations, minor 
informed consent deviations (wrong version date, wrong expiration date, as long as the content 
is same) will be reported as part of scheduled continuing review.  
10.3.5 Monitoring 
 
The Independent Monitoring Committee (IMC) for this study is comprised of Drs. Emily 
Levin, Daniel Leventhal, and Catherine Spino. Drs. Levin, Leventhal, and Spino are not 
associated with this research project and work independently of the PI, Dr. Scott Lempka. They 
are not part of the key personnel involved in this grant. No member of the Committee has 
collaborated or co-published with the PI within the past three years. They are qualified to review 
the participant safety data generated by this study because of their unique expertise. 
 
Emily Levin, MD is a board-certified neurosurgeon with specialization in neurostimulation 
approaches to treat movement disorders, pain, and other neurological disorders. Dr. Levin is a 
Clinical Assistant Professor in Neurosurgery at the University of Michigan. She is also the Chief 
of Neurosurgery and the Associate Chief of Surgery at the Veterans Administration Health 
Center in Ann Arbor, MI and co-directs the deep brain stimulation program for movement 
disorders. 
 
Daniel Leventhal, MD, PhD is a neurologist and Assistant Professor of Neurology in the 
Movement Disorders division at the University of Michigan. His primary clinical duties are at the 
VA Ann Arbor Healthcare System, where he co-directs the Deep Brain Stimulation program for 
Movement Disorders. Dr. Leventhal also directs a basic science laboratory at the University of 
Michigan that performs experimental studies to investigate the brain circuit abnormalities that 
contribute to the clinical manifestations of Parkinson Disease and related disorders. 
 
Catherine Spino, PhD is a Research Professor of Biostatistics at the University of 
Michigan. Dr. Spino is the Director of the Statistical Analysis of Biomedical and Educational 
Research (SABER) unit, which provides statistical and operational excellence to single- and 
multi-center clinical studies. She has been the director of multiple data coordinating centers for 
single- and multi-center clinical studies. Dr. Spino has more than 25 years of experience in the 

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design, conduct and analysis of data from clinical studies in a variety of therapeutic areas, as 
well as extensive experience and expertise in managing data and coordinating centers. 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY  
11.1 
Institutional Review Board (IRB) Review  
The protocol, informed consent form(s), recruitment materials, and all participant 
materials will be submitted to the Institutional Review Board (IRB) for review and approval. 
Approval of both the protocol and the consent form must be obtained before any participant is 
enrolled. Any amendment to the protocol will require review and approval by the IRB before the 
changes are implemented to the study. In addition, all changes to the consent form will be IRB-
approved; a determination will be made regarding whether a new consent needs to be obtained 
from participants who provided consent, using a previously approved consent form. 
11.2 
Informed Consent Forms 
Informed consent is a process that is initiated prior to the individual agreeing to 
participate in the study and continues throughout study participation. Extensive discussion of 
risks and possible benefits of study participation will be provided to subjects and their families, if 
applicable. A consent form describing in detail the study procedures and risks will be given to 
the subject. Consent forms will be IRB-approved, and the subject is required to read and review 
the document or have the document read to him or her. The investigator or designee will explain 
the research study to the subject and answer any questions that may arise. The subject will sign 
the informed consent document prior to any study-related assessments or procedures. Subjects 
will be given the opportunity to discuss the study with their surrogates or think about it prior to 
agreeing to participate. They may withdraw consent at any time throughout the course of the 
study. A copy of the signed informed consent document will be given to subjects for their 
records. The rights and welfare of the subjects will be protected by emphasizing to them that the 
quality of their clinical care will not be adversely affected if they decline to participate in this 
study. The consent process will be documented in the study record. To complete the informed 
consent process at the end of study participation, study staff will inform the subject when his/her 
participation has come to an end and will document the discussion in the study record. 
11.3 
Participant Confidentiality  
The study requires obtaining direct patient identifiers due to collecting standard of care 
data in addition to the research data for the project. We will assign subject numbers to patients 
and those numbers will be used in the research. We will maintain a password-protected file 
linking subject numbers to identifying information on a UM computer. Research personnel will 
store identified study data in accordance with standard regulations and will not be disclosed or 
shared with any outside third parties. Identifying information will be severed from study data that 
is reported. Only relevant research personnel listed in the institutional review board (IRB) study 
application will have access to study files and folders. We will protect the data on a laptop 
computer or on a removable device by encryption. 
11.4 
Study Discontinuation  
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
investigator, funding agency, and regulatory authorities. If the study is prematurely terminated or 
suspended, the Principal Investigator (PI) and/or other study personnel will promptly inform 

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study participants, the Institutional Review Board (IRB), and sponsor and will provide the 
reason(s) for the termination or suspension. Study participants will be contacted, as applicable, 
and be informed of changes to study the visit schedule. Circumstances that may warrant 
termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants  
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
The study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor and the IRB. 
12. COMMITTEES 
There are no additional committees associated with this study. 
13. PUBLICATION OF RESEARCH FINDINGS  
The clinical trial will be registered and the results information submitted to 
ClincalTrials.gov as outlined in the policy and according to the specific timelines stated in the 
policy. All informed consent documents will include statements that specifically indicate the 
posting of all clinical trial information to ClincalTrials.gov. The University of Michigan has an 
internal policy in place to ensure the clinical trials results reporting occur in compliance with 
policy requirements. This policy is enacted through the University of Michigan Medical School 
Clinical Trials Support Office. 
 
We will also ensure that results are available to the public at large through timely 
publication of data and we will leverage the University of Michigan’s communication liaisons to 
issue press releases on findings to disseminate findings to a lay audience. Additionally, the 
study governance does not include a Steering Committee. 
14. REFERENCES  
1.  
De Ridder D, Vanneste S, Plazier M, van der Loo E, Menovsky T. Burst spinal cord 
stimulation: Toward paresthesia-free pain suppression. Neurosurgery 2010;66(5):986–90.  
2.  
De Ridder D, Plazier M, Kamerling N, Menovsky T, Vanneste S. Burst spinal cord 
stimulation for limb and back pain. World Neurosurg [Internet] 2013;80(5):642-649.e1. 
Available from: http://dx.doi.org/10.1016/j.wneu.2013.01.040 
3.  
Melzack R. The McGill Pain Questionnaire: Major properties and scoring methods. Pain 
1975;1(3):277–99.  
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