Developing Brain Stimulation as a Treatment for Chronic Pain in Opiate Dependent
Phase: EARLY_PHASE1
Conditions: Chronic Pain, Opiate Dependence, Lower Back Pain
Sponsor: Medical University of South Carolina

Version #4; 11/05/2019 
 
Page 1 of 24 
 
Study Title: Developing brain stimulation as a treatment for chronic pain in opiate dependent 
individuals 
NCT: NCT03681769 
Document Date: 11/16/2019 
 
 
 

Version #4; 11/05/2019 
 
Page 2 of 24 
 
NCTPROTOCOL TITLE: 
Developing brain stimulation as a treatment for chronic pain in opiate dependent individuals 
PRINCIPAL INVESTIGATOR: 
 
Jeffrey Borckardt, PhD 
 
 
 

Version #4; 11/05/2019 
 
Page 3 of 24 
 
  
1.0 
Objectives / Specific Aims 
Effective control of chronic pain is a top priority in the United States, as approximately 10% of adults 
have severe chronic pain – most of which is chronic lower back pain (CLBP). However, despite the 
advances in neuroscience over the past 20 years, we still largely treat chronic pain with opiate narcotics, 
much as was done in the Civil War. In addition to their high abuse liability and dependence potential (1), 
only 30–40% of chronic pain patients declare they receive satisfactory (>50%) relief from their pain 
through pharmacological treatment (Attal et al., 2006). In these patients a common clinical practice is to 
escalate the dose of opiates as tolerance develops – which unfortunately has contributed to escalation in  
opiate overdose deaths (2), a resurgence of intravenous heroin use, and $55 billion in societal costs (3). 
Consequently there is a critical need for new, treatments that can treat pain and reduce reliance on 
opiates in individuals with chronic pain. 
 
The goal of this R21 proposal is to evaluate 2 novel non-invasive brain stimulation strategies to 
mitigate pain and the brain’s response to pain in CLBP patients that are currently taking chronic 
opiates, or that are seeking an alternative treatment for pain. Transcranial Magnetic Stimulation 
(TMS), can induce long term potentiation (LTP-like) and long term depression (LTD-like) effects on 
brain activity in a frequency dependent manner.   Our group has previously demonstrated that LTP-like 
TMS to the dorsolateral prefrontal cortex (DLPFC, a node in the Executive Control Network (ECN)) can 
decrease perceived pain and corresponding BOLD signal in the “Pain Network’ (7, 8, 10-12). The Pain 
Network is an expansion of the Salience Network (SN; insula, dorsal anterior cingulate) which includes 
the thalamus and somatosensory cortex(4-6). The analgesic effects of DLPFC TMS can be blocked by 
naloxone – suggesting that the analgesic effects of LTP-like DLPFC TMS are opiate mediated. 
Additionally, DLPFC TMS delivered postoperatively leads to less patient administered morphine use 
(PCA-pump) in the hospital and less opiate use in the outpatient setting (9).  These data all suggest that 
LTP-like DLPFC TMS is a promising candidate for treating pain (Strategy 1, Aim 1).     
 
An alternative strategy is to apply LTD-like stimulation to the medial prefrontal cortex (LTD-like 
mPFC rTMS (Strategy 2, Aim 2). This strategy is based on our understanding of functional neural 
architecture, wherein the SN is modulated by 2 other core networks: the executive control network (ECN) 
and the default mode network (DMN). As stated above, it is possible to attenuate activity in the SN 
through LTP-like TMS to the  DLPFC, a node in the ECN.  It is also possible to attenuate the SN through 
LTD-like TMS to the ventral medial prefrontal cortex (a node in the DMN). The proposed study will be 
the first to employ a randomized, double-blind, sham-controlled design to parametrically evaluate 
the longitudinal effects of 16 days of rTMS to the DLPFC (Aim 1) or the  MPFC (Aim 2) on self-
reported pain and the brain’s response to pain. This will be done in a cohort of patients recruited 
from the community as well as MUSC clinics with chronic lower back pain that have not been able 
to find adequate pain relief, whether or not they are using prescription opiates for 3 or more 
months.  Participants will be randomized to receive rTMS to the DLPFC (iTBS), MPFC (cTBS), or sham 
(50% at each site), using a Latin square randomization. Resting state connectivity will be collected 3 
times: before the 1st day of TMS, after the 12th day of TMS, and before the 16th day of TMS (the last day 
administered). 
  
Aim 1. Evaluate DLPFC rTMS as a tool to dampen pain and the engagement of the Pain Network. 
Hypothesis 1: DLPFC TMS will attenuate the baseline brain response to pain (Pain Network activity) and 
increase activity in the ECN when the patient is given instructions to ‘control’ the pain.  
Aim 2. Evaluate MPFC rTMS as a tool to dampen pain and the engagement of the Pain Network. 
Hypothesis 1: MPFC TMS will also attenuate the baseline brain response to pain (Pain Network activity) 
but will not effect the ECN or SN when the patient is given instructions to ‘control’ the pain.  

Version #4; 11/05/2019 
 
Page 4 of 24 
 
 
(Exploratory Aim): We will evaluate if there are rate-dependent effects between baseline SN connectivity 
with the ECN and DMN and the efficacy of each TMS strategy on subjective pain. Data will be analyzed 
by using multivariate pattern analysis (MVPA) (2014). While the primary outcomes will be MRI V1 vs 
V2, we will also examine the relative ‘durability’ of the effects on pain by comparing the MRI data at the 
end of all TMS visits between and within groups with factor analysis.  
 
The relative efficacy of these strategies will directly translate to development of a large clinical trial 
investigating rTMS as an innovative, new treatment option for pain in patients with CLBP.   
 
2.0 
Background 
BACKGROUND AND SIGNIFICANCE. Effective control of chronic pain is a top priority in the 
United States, as approximately 10% of adults have severe chronic pain – most of which is chronic lower 
back pain (CLBP)(National Institute of Health Statistics, 2006). CLBP is the leading cause of job-related 
disability and missed work. However, despite the advances in neuroscience over the past 20 years, we still 
largely treat CLBP pain with opiate narcotics, much as was done in the Civil War.  In addition to their 
high abuse liability and dependence potential (1), only 30–40% of chronic pain patients declare they 
receive satisfactory (>50%) relief from their pain through pharmacological treatment (59). 96% of chronic 
pain patients using opiates reported insufficient control of pain, and on average opiate-using pain patients 
have experienced CLBP for more than a decade (59). A 2012 study demonstrated that patients with 
chronic pain resort to non-medical use of prescription opiates at high rates.  This abundant use and misuse 
of opiates is a  developing crisis, with 4.3 million users in 2014 (1), over 40% of prescription drug 
overdoses in the United States attributable to opioid analgesics (2), and total societal costs exceeding an 
estimated $55 billion (3). Of individuals who misuse opioids, 80 to 90% initiated after having a legitimate 
prescription (13, 14) and 81% endorse pain as their reason for non-medical prescription opioid use 
(NMPOU) (14). Consequently there is a critical need for new, treatments that can treat pain and 
reduce reliance on opiates in individuals with chronic pain. The goal 
of this R21 proposal is to evaluate 2 novel non-invasive brain 
stimulation strategies to mitigate pain in CLBP patients that are 
currently taking chronic opiates or that are seeking an alternative to 
relieve pain. 
 
Evaluating rTMS as a new, non-pharmacological approach to treating 
pain in opiate using individuals. TMS is a non-invasive brain 
stimulation method that is currently FDA-approved for the treatment of 
major depressive disorder. Repeated trains of stimulation can cause 
long-term potentiating (LTP) or depressing (LTD) effects on cortical 
areas directly under the coil (approximately 2cm depth) as well as 
monosynaptic 
projections 
(15-19). 
Our 
group 
has 
previously 
demonstrated that LTP-like TMS to the dorsolateral prefrontal cortex 
(DLPFC, a node in the Executive Control Network (ECN)) can decrease 
perceived pain as well as corresponding BOLD signal in the “Pain 
Network in healthy controls (7, 8, 30) and clinical populations (31-34). 
The Pain Network is an expansion of the Salience Network (SN; insula, 
dorsal 
anterior 
cingulate) 
which 
includes 
the 
thalamus 
and 
somatosensory cortex (4-6). The SN represents the attentional aspects of 
pain whereas the thalamus and somatosensory cortex represent somatic 
aspects of pain. The analgesic effects of DLPFC TMS can be blocked by 
naloxone, an opiate antagonist, suggesting TMS-induced analgesia is 
 
Figure 1. Dynamic Interaction of Core
functional connectivity networks. Adapted
from Lerman et al 2014 JAMA Psychiatry.
The Salience Network (SN), Executive
Control Network (ECN), and Default Mode
Network (DMN) represent 3 Core neural
networks 
in 
the 
brain 
which 
are
dynamically coupled. During pain, the SN
& DMN are positively correlated (red),
whereas the SN & ECN are anticorrelated
(negatively 
correlated, 
blue). 
The
outcomes of these aims will allow us to
investigate baseline networks dynamic in
CLBP patients treated with opiates (which
has never been done) and test the
hypotheses that increasing activity in the
ECN 
(LTP-like 
TMS; 
Aim 
1), 
and
decreasing activity in the DMN (LTD-like
TMS) will dampen pain in CLBP patients.
The acute effect of 10 days of TMS as well
as 1&2 month durability will be assessed.  
ECN  
(Aim 1 
target) 
DMN 
(Aim 2 
target) 
SN 
(attentional 
aspects of the 
Pain network) 

Version #4; 11/05/2019 
 
Page 5 of 24 
 
Figure 
Default 
Mode 
Network 
Executive 
Control 
Network 
opiate mediated (7, 8). Dr. Borckardt (Co-Investigator) was the first to demonstrate that when LTP-like 
DLPFC rTMS was delivered in the postoperative recovery room, patients used less morphine in the 
hospital and required less morphine long-term (9). These data all suggest that LTP-like DLPFC TMS 
is a promising candidate for treating pain (Strategy 1, Aim 1). This study will be the first to merge 
these findings, aiming to investigate the effects of TMS in both chronic opiate users, and individuals that 
cannot find any alternative to help relieve their pain.     
 
An alternative strategy is to apply LTD-like stimulation to the medial prefrontal cortex (LTD-like 
mPFC rTMS (Strategy 2, Aim 2). This strategy is based on our understanding of functional neural 
architecture, wherein the SN is modulated by 2 other core networks: the executive control network (ECN) 
and the default mode network (DMN) (Figure 1). As stated above, it is possible to attenuate activity in the 
SN through LTP-like TMS to the DLPFC, a node in the ECN.  It is also possible to attenuate the SN 
through LTD-like TMS to the medial prefrontal cortex (a node in the DMN) (Hanlon et al 2017). The 
proposed study will be the first to employ a randomized, double-blind, sham-controlled design to 
parametrically evaluate the longitudinal effects of 12 days of rTMS, followed by 4 maintenance 
rTMS sessions, delivered to the DLPFC (Aim 1) or the MPFC (Aim 2) on self-reported pain and the 
brain’s response to pain. This will be done in a cohort of patients recruited from the community as 
well as MUSC clinics with chronic lower back pain that have not been able to find adequate pain 
relief, whether or not they are using prescription opiates for 3 or more months.   
 
The scientific rationale for rTMS effects on 
pain in CLBP patients using chronic opioids. 
TMS is the only non-invasive tool available to 
directly activate a specific neural circuit in 
humans. Opiate dependent individuals have 
reduced functional connectivity (35) between 
regions of the Pain Network (e.g. dorsal 
anterior cingulate cortex [dACC], insula, and 
thalamus (4-6, 36)) and the ECN (e.g. DLPFC 
(37)). 
Previous 
TMS 
studies 
have 
demonstrated that increasing activity in the 
ECN lowers perceived pain (27-29) and changes activity in nodes of the Salience Network (cingulate, 
insula) (30, 38, 39) which represent the attentional aspects of the pain network. One form of TMS is 
known as theta burst stimulation (TBS). This biologically-relevant pulse sequence, is translationally 
derived from preclinical studies in learning and memory, and has powerful effects on cortical 
excitability in humans (40), wherein the same LTP-like effects of 10hz TMS are achieved much 
faster with TBS.  As with traditional rTMS, TBS can induce LTP-like or LTD-like effects on by 
applying the pulses intermittently (iTBS, LTP-like) or continuously (cTBS, LTD-like) (40). While the 
promise of inducing a lasting neuroplastic change in the Pain Network of opiate dependent individuals is 
enticing, it is not clear that the ‘plasticity potential’ of these circuits is as high in chronic opiate users as in 
healthy controls.  Our preliminary data evaluating TMS to the DLPFC as a tool for dampening pain 
circuitry is promising (Aim 1, Strategy 1). However, given previously observed deficits in executive 
function in chronic pain patients on chronic opiates(44), it may be more efficacious to attenuate activity in 
the MPFC (Aim 2, Strategy 2) which would likely target the affective components of pain. The rationale 
for this alternative hypothesis is that in patients with chronic, ongoing pain, normal regulatory mechanism 
are disrupted, and pain processing is shifted towards more emotionally oriented circuits, such as the 
MPFC (34-36). This alteration in brain function encourages the exploration of alternative treatment 
locations in this population.  
 

Version #4; 11/05/2019 
 
Page 6 of 24 
 
Early Feasibility Data: Quantitative Sensory Testing of pain in opiate using individuals after 10 
sessions of rTMS (Strategy 1 and 2). Our group recently initiated a 10 day clinical trial of these 2 
strategies as tools to decrease behavioral reports of pain.  From June 2017 to October 2017 we were able 
to enroll and successfully acquire Quantitative Sensory Testing data from 10 individuals (5 of whom 
received each strategy for 10 days). 8 of the 10 remained enrolled for the full treatment. The 2 that didn’t 
finish were terminated due to a Hurricane in our area (Sept 2017). This initial feasibility trial is promising 
and individuals appear to be receiving pain relief (as demonstrated by their continued engagement). 
However, without a rigorous sham control group or longitudinal neuroimaging data, the results of this 
pilot study will be limited to Quantitative Sensory Testing.   Through this R21 mechanism we hope to be 
able to build upon the early success of this trial by including a rigorous, randomized, sham-controlled 
design which includes neuroimaging data necessary to understand mechanisms of action of these 
innovative 
new 
treatment 
approaches.   
 
Aims 1 & 2 of this proposal will address the next critical steps in developing DLPFC  or MPFC TMS as a 
new, innovative treatment option for pain: 1) Do multiple sessions of rTMS have a sustainable impact on 
pain in CLBP patients? And 2) Are there consistent patterns of neural activity to pain that serve as a 
predictive biomarker for TMS efficacy in these individuals?    
INNOVATION. The proposed research is innovative in several ways. First, we are developing a 
conceptually innovative, alternative treatment strategy for chronic pain, which involves non-
pharmacologic modulation of the circuits responsible for the perception of pain. This would be a 
significant conceptual advance for the field of chronic pain management. While LTP-like DLPFC rTMS 
has been promising as a tool for pain in non-opiate dependent individuals, the experiments outlined in this 
proposal represent a critical next step in their development for this CLBP population chronically using 
opiates. The knowledge gained from these Aims would be the basis for further examination in a larger 
Clinical Trial of TMS (R01) and would hasten the pipeline through which TMS could be developed as an 
evidence-based neuromodulation strategy for physicians and pain management providers to offer to 
patients with chronic lower back pain. Second, while most TMS investigations focus on the relative 
efficacy of stimulation at a single site (or a single functional network), by evaluating 2 strategies in this 
proposal we will be uniquely positioned to advance the field. Third, we are using a novel stimulation 
profile, theta burst stimulation (TBS) that was supported by our preliminary data, and is built on a 
foundation from learning and memory literature in preclinical research. This stimulation profile will 
significantly reduce the total time of active stimulation relative to 10 Hz rTMS, thus reducing patient 
burden.  
 
3.0 
Intervention to be studied (if applicable) 
See section 2.0 for more information about the interventions being investigated. 
 
4.0 
Study Endpoints (if applicable) 
Through this R21 mechanism we hope to be able to build upon the early success of this trial by including 
a rigorous, randomized, sham-controlled design which includes neuroimaging data necessary to 
understand mechanisms of action of these innovative new treatment approaches.   
 
5.0 
Inclusion and Exclusion Criteria/ Study Population 
Participants. We will enroll 48 men and women 18-75 years old with CLBP. These individuals can also 
have a history of current prescription opioid use (>3 months) for the treatment of pain. Participants will be 
recruited through MUSC clinics as well as the outer community. Patients that have previously agreed to 
be contacted for research will be referred to the study or contacted via telephone.  The risks of MRI and 
TMS to the unborn fetus are not well understood. Therefore, to be included, females must not be pregnant 

Version #4; 11/05/2019 
 
Page 7 of 24 
 
as determined by a urine pregnancy test and must be utilizing reliable birth control during the course of 
the study. 
 
Inclusion Criteria: 
1. Age 18-75 (to maximize participation)  
2. Can currently be using prescription opiates 
3. Able to read and understand questionnaires and informed consent. 
4. Is not at elevated risk of seizure (i.e., does not have a history of seizures, is not currently 
prescribed medications known to lower seizure threshold)  
5. Does not have metal objects in the head/neck.  
6. Does not have a history of traumatic brain injury, including a head injury that resulted in 
hospitalization, loss of consciousness for more than 10 minutes, or having ever been informed that 
they have an epidural, subdural, or subarachnoid hemorrhage.  
7. Does not have a history of claustrophobia leading to significant clinical anxiety symptoms. 
Exclusion Criteria: 
1. Any psychoactive illicit substance use (except marijuana and nicotine) within the last 30 days by 
self-report and urine drug screen. 
2. Meets DSM-V criteria for current axis I disorders of obsessive-compulsive disorder, bipolar 
affective disorder, schizophrenia, dissociate disorders, eating disorders, and any other psychotic 
disorder or organic mental disorder.   
3. Has current suicidal ideation or homicidal ideation. 
4. Has the need for maintenance or acute treatment with any psychoactive medication including anti-
seizure medications and medications for ADHD. 
5. Females of childbearing potential who are pregnant (by urine HCG), nursing, or who are not using 
a reliable form of birth control. 
6. Has current charges pending for a violent crime (not including DUI related offenses). 
7. Does not have a stable living situation. 
8. Suffers from chronic migraines. 
 
Inclusion of Women and Minorities 
In 2016, the ratio of male:female individuals using opiates for pain was approximately 1:1.  We will 
recruit in accordance with this ratio. There will be no exclusion criteria with respect to ethnic background.  
The population of Charleston, SC is 52.2% White, 41.1% African American, and1.6% Asian. 4.4% of the 
population is Hispanic/Latino.  This is a relatively low percentage of Hispanic individuals based on 
national statistics. We will seek to enroll 5 Hispanic or Latino participants to be closer to the national 
average.  Given the high concentration of African-Americans, all  racial minorities will likely be black or 
African-American.  We will strive however, to recruit a diverse population including American Indians, 
Asians, and Pacific Islanders if possible. As necessary, advertisements will be placed in newspapers and 
radio stations with primarily African-American or Hispanic readerships and listenership’s (e.g., 
Charleston Post and Courier, The Charleston Free Press, WQMG FM).  
 
6.0 
Number of Subjects 
48 participants will be enrolled in this research study. 

Version #4; 11/05/2019 
 
Page 8 of 24 
 
 
7.0 
Setting 
General Facilities and Resources  
The Medical University of South Carolina ranks in the upper third of federal research funds received by 
US medical schools and fosters cross-departmental collaborations as a means of integrating the basic and 
clinical sciences through its many research centers. 
 
The Department of Psychiatry & Behavioral Sciences emphasizes excellence in clinical care, teaching, 
and research. MUSC Psychiatry is headquartered in its own building, the Institute of Psychiatry (IOP), 
where the majority of the department’s faculty, residency training programs, research programs, and 
administrative offices are located. The department ranks among the top 15 psychiatry departments in the 
U.S., and the top 3 in the Southeast, in terms of funding from the National Institutes of Health. In FY2008 
departmental faculty received 124 grant and contract awards, totaling $24.2 million in extramural research 
support. Ongoing research projects range from basic neuroscience and brain imaging, to clinical 
pharmacology and treatment studies. The department’s Center for Drug and Alcohol Programs, which 
includes a major NIH-funded Alcohol Research Center, involves extensive collaboration with basic 
science and other clinical departments. The addictions program was ranked 9th in the nation by U.S. 
News & World Report (2009). The main research divisions in the Department are the Brain Stimulation 
Laboratory, Center for Drug and Alcohol Programs, Clinical Neuroscience Division, Family Services 
Research Center, Geropsychiatry Division, National Crime Victims Center, Public Psychiatry Division, 
and Weight Management Center.   
 
The Brain Stimulation Laboratory (BSL) is located in a series of labs and offices (>3000 square feet) 
primarily located on the 5th floor of the Institute of Psychiatry (IOP). BSL studies use electromagnetic 
approaches as either research tools investigating neuroscience questions or as investigational or FDA 
approved treatments for brain diseases. Techniques actively being used by BSL researchers and their 
collaborators include: transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS), 
transcranial direct current stimulation (tDCS), electroconvulsive therapy (ECT), deep brain stimulation 
(DBS) and epidural cortical stimulation (epCS). MUSC’s BSL team has been a world leader in TMS 
research since 1995, performing basic research studies using TMS as well as using TMS in clinical trials 
for depression, pain and addiction. 
 
Facilities and Resources Specific to the PI:  
Dr. Borckardt’s primary office and laboratory is in the Brain Stimulation Division of the 
Department of Psychiatry. She will utilize the resources of the Brain Stimulation Laboratory.   
 
Dr. Borckardt manages the BSL suite located in the Center for Biomedical Imaging along with Dr. 
George.  This suite contains a room (10ft x 10 ft.) dedicated for TMS stimulation. This room currently 
contains 2 computers, a desk for patient interviewing, and a Magstim Bistim TMS system.  
 
8.0 
Recruitment Methods 
Participants with chronic pain will be recruited via flyers placed throughout the MUSC campus, 
community, MUSC clinics, broadcast messages, Craigslist, and via phone calls to individuals that have 
participated in previous studies with our group and have given permission to be contacted if other studies 
become available. Participants will also be recruited at community events using advertising materials. At 
these events, participants will have the opportunity to fill out a card stating that they are interested in 
being contacted about our research studies. These cards will contain their name, email, and phone 
number. They will be placed in a secure, opaque container in order to protect their identity, and will be 
destroyed after an initial contact has been made. 

Version #4; 11/05/2019 
 
Page 9 of 24 
 
 
A chart review will be conducted for research purposes.  Potentially eligible patients will be identified.  
The potentially eligible patients in the PIs practice will be informed about the study as the PI feels is 
appropriate.  Then potential patients who have agreed to be contacted for future research by logging their 
MUSC Research Permissions preferences in MyChart will be contacted by phone and invited to 
participate. All other patients will be contacted through their providers to be informed of the study if the 
provider feels it is appropriate. 
 
Subjects that are currently enrolled in the study will also be invited to participate in the recruitment of 
other subjects. If they choose to participate, they will be given coupons that can be distributed to other 
people (e.g., peers, acquaintances) who they think could be eligible and interested in the study. The 
individuals that are given these coupons can contact the study office themselves if interested in 
participating. If they decide to participate in the study, the currently enrolled subject will be given $10 for 
each coupon received from the enrollment of new participants. This recruitment tool is completely 
voluntary and if subjects elect not to participate, participation in this study will not be affected in any way. 
Participants will be screened and provide written informed consent to participate which will be obtained 
by study personnel. Participants will have an opportunity to ask questions and can discontinue 
participation at any time without penalty. 
 
9.0 
Consent Process 
 Individuals that have previously consented to be contacted about future research studies will be contacted 
and phone screened to determine preliminary eligibility. They will be scheduled for their screening visit, 
which will take place at the Center for Biomedical Imaging in the BSL suite. Informed consent will be 
reviewed with the potential participant by a member of the key personnel on this proposal. The consent 
will be signed by the participant as well as one of the Key Personnel on the proposal. A copy of the 
consent will be given to the subject and the original placed in the research record. All records will be 
stored in locked departmental files. Section 301(d) of the Public Health Service Act of November 4, 1988 
also protects a layer of protection for the privacy of health information for individuals that engage in 
federally funded medical research. 
 
10.0 Study Design / Methods 
Multidisciplinary Team. We have assembled diverse talents to develop translational approaches to TMS 
treatment development for opiate dependence. Our team has extensive experience in: 1) TMS (Borckardt), 
2) NIH trials in chronic lower back pain (Borckardt, Back), 3) pain management (Borckardt), 4) 
neuroimaging (Borckardt), and 5) statistical modeling (Borckardt, Lauer). In addition to providing critical 
effect size data for a planned R01, this grant will provide an opportunity for several MUSC trainees in the 
DART Resident research program (Jennifer Jones, MD), and a NIDA T32 (Tonisha Kearney Ramos, 
PhD) to get hands-on training with neuroimaging, TMS, and opiate dependent individuals. Dr. Brady will 
serve as a scientific advisor and meet regularly with the team to provide insight on outcomes and patient 
recruitment.  
 
Overview. The proposed study will be the first to employ a randomized, double-blind, sham-controlled 
design to parametrically evaluate the longitudinal effects of 16 days of rTMS to the DLPFC (Aim 1) or 
the MPFC (Aim 2) on self-reported pain and the brain’s response to pain. This will be done in a cohort of 
patients recruited from MUSC clinics and the outer community with chronic lower back pain.  
Participants will be randomized to receive TMS to the DLPFC, MPFC, or sham (50% at each site), using 
a Latin square randomization. Resting state connectivity will be collected at each MRI scanning session.. 
Quantitative Pain Testing will be collected 12 times. MRI data will be collected 3 times: before the 1st 
visit of TMS, before the 12th visit of TMS, and before the 16th visit of TMS.  

Version #4; 11/05/2019 
 
Page 10 of 24 
 
Figure 3. TMS stimulation 
sites, derived from EEG 10-
20 landmarks.  
 
 
 
 
 
 
 
 
 
 
 
 
Participants. We will enroll 48 men and women 18-75 years old with CLBP that have a history of 
current prescription opioid use (>3 months) for the treatment of pain. Participants will be recruited 
through the community along with MUSC clinics. Patients that have previously agreed to be contacted for 
research and have current chronic pain will be referred to the study.  Our prior history with targeted 
enrollment (See Significance) indicates this is feasible within 20 months, leading to full completion by 22 
months. Exclusion criteria: Typical MRI and TMS exclusionary criteria, including metal above the neck 
or implanted in the body, use of prescription medications that lower seizure threshold, a history of 
seizures or traumatic brain injury, pregnancy or trying to become pregnant, current substance use or 
dependence (other than opioids and nicotine), history of seizure disorder, and claustrophobia. Participants 
will provide written informed consent following explanation of the study. Sample size estimate: A power 
estimate for Aim 1 and 2 was prepared using an original fMRI dataset previously collected in our 
laboratory (8). In this experiment, 18 healthy controls performed the same fMRI pain paradigm as the 
present study before and after a single session of 10 Hz rTMS. Mean parameter estimates for the “heat 
pain vs. rest” condition were extracted from several a priori regions of interest. These data yielded an 
effect size which ranged from 0.70 (thalamus) to 1.08 (insula) (n=15 yields 80% power using a two-sided 
p<0.05). Allowing for a 10% dropout rate after the screening visit, and up to a 20% dropout rate at the end 
of the Treatment phase (Week 4), as well as a 10% data loss rate for MRI (Aim 2) due to individuals with 
excessive head motion in the MRI scanner, screening 58 individuals should lead to complete data from 48 
individuals (16 real DLPFC, 16 real MPFC, 16 sham (50% at each site).  Randomization will be handled 
by the MUSC data coordination center of the Biostatistical Unit (Abigail Lauer, biostatistician) and a 
Latin Square design with replacement will be used to ensure even enrollment across groups with 
replacement.   
 
General Methods 
Screening Visit – Consent. Participants will receive a series of assessments designed to evaluate opioid 
dependence, psychiatric conditions, chronic pain and mood. These include the MINI International 
Neuropsychiatric Interview (46), Brief Pain Inventory (47), Timeline Followback (48), Becks Depression 
Inventory II (49), State-Trait Anxiety Inventory (50), the Pittsburgh Sleep Quality Index (PSQI), the 
Barratt Impulsiveness Scale (BIS), and Profile of Mood States (51). Data will be collected using 
REDCap™, and entered directly into the online portal to ensure security and prevent data loss.  
 
Intervention –●MRI Visits 1-3. Following enrollment, participants will 
meet the study personnel for Assessment & MRI Scanning (details below). 
The procedures at MRI Visit 1 will be repeated at MRI Visit 2 (after 12 days 
of rTMS), and at MRI Visit 3 (after 16 days of rTMS). ●rTMS Treatment 
sessions: After the Screening visit, patients will be randomized to receive 16 
days of real or sham rTMS treatment. Based on prior studies in our 
laboratory that have applied 10 days of TMS to various clinical populations, 
 Table 1. Study Design. Aim 1&2 will be conducted in parallel.  
^primary goal: evaluate 2 TMS strategies as tools to decrease acute pain and brain reactivity to 
pain. 
^secondary goal: durability 
Aim 1
dlPFC
Real
dlPFC
Sham
Aim 2
mPFC
Real
mPFC
Sham
Group Assignment
Screening 
Week 1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
TMS Sessions
XXX
XXX
XXX
XXX
X
X
X
X
Clinical Assessments
XXX
XXX
XXX
XXX
X
X
X
X
X
X
X
X
Quantitative Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
Quantitative Pain Testing
X
X
X
X
X
X
X
X
X
X
X
X
Neuroimaging
X
X
X
Induction Phase
Maintenance Phase
Follow Up Phase

Version #4; 11/05/2019 
 
Page 11 of 24 
 
we expect 16 sessions of TMS treatments (3 days per week for 4 weeks, followed by 1 day a week for 4 
weeks) will take 8 weeks, allotting time for a weekend (as is conventional in this field), holidays and/or 
one missed appointment. In the event that an individual drops out before completing the 16 TMS sessions, 
the number of sessions received will be a covariate in the analyses. Cortical Targeting: After the MRI 
scans participants will be escorted into the Brain Stimulation room (30 feet away) where scalp 
localization will be performed for the TMS procedure. The Cartesian position of the coil (X,Y,Z) will be 
determined by standardized positions from the EEG 10-20 system: 1)  F3 (left DLPFC stimulation (Aim 
1)), 2) FP1 (MPFC stimulation (Aim 2)). The angular position of the coil (pitch, yaw, roll) will be 
determined by the individual’s cortical geography beneath FP1 and F3 using the individual’s T1 scan for 
guidance. The locations and coil orientation will be indicated on a nylon cap which will be worn during 
the TMS sessions. We will then determine the participant’s resting motor threshold (RMT, the minimal 
amount of stimulation required over the hand area of the primary motor cortex to induce contraction of 
the APB muscle of the hand 50% of the time) via the standardized PEST procedure (106, 107). During 
each TMS session, we will take a non-identifiable photo of the participants' forehead (eyes covered with 
an index card) to ensure the coil is correctly placed each time they return to the lab. This will be cross-
checked with the neuronavigation data.  
 
Strategy 1: iTBS to the left dlPFC. For intermittent theta burst stimulation (Aim 1), participants will 
receive 20 trains of stimulation over the dlPFC (middle frontal gyrus) (F3) (each train: 3 pulse bursts 
presented at 5Hz, 15 pulses/sec for 2 sec, 8 sec rest, 200 pulses/train; 110% RMT, MagPro; 600 pulses 
total) using a figure 8 coil (Coil Cool-B65 A/P). 
Strategy 2: cTBS to the vmPFC. For continuous theta burst stimulation (Aim 2), participants will 
receive 1 train of stimulation over the left frontal pole (FP1) (each train: 3 pulse bursts presented at 5Hz, 
15 pulses/sec for 40 sec, 600 pulses/train, 110% RMT, MagPro; 600 pulses total) using a figure 8 coil 
(Coil Cool-B65 A/P). This protocol has been shown to attenuate the mPFC and striatum in cocaine 
dependent individuals in the past (61-63) and has been more effective than 1200 or 1800 pulses of cTBS 
in attenuating depression (The time between the end of the TBS procedures and the beginning of the 
behavioral assessments, as well as the scalp-to-cortex distance (which effects the actual TMS dose given 
to the cortex) will be compiled and used as covariates in subsequent analyses.    
ACTIVE SHAM system. The MagVenture MagPro system has an integrated, active sham which passes 
current through two surface electrodes placed on the scalp. The electrodes will be placed on the left 
frontalis muscle for all sessions. A patient ID card will randomize participants to receive either real or 
sham stimulation. This system maintains blinding by a gyroscope in the coil which indicates to the 
clinical staff whether the coil should be rotated up or down for this participant once the card is entered 
into the machine. One side of the coil is active, the other is sham. The integrity of the double-blind 
procedure will be assessed by asking the patients and study personnel rate their confidence regarding 
whether they thought they received real or sham (scale 1-10).  
●Assessments: 
The 
primary 
dependent measures will be extracted from the Quantitative Sensory Testing for pain thresholds. Other 
assessments include: Brief Pain Inventory (BPI), the pain craving form, and subjective pain rating scales, 
delivered before and after TMS. Participants will also complete the Beck Depression Inventory (BDI-II), 
the Profile of Mood States (POMS), the Pittsburgh Sleep Quality Index (PSQI), the State-Trait Anxiety 
Inventory (STAI), and Barratt Impulsiveness Scale (BIS), which assesses anxiety and depression 
measures. Though these are not primary outcomes, the results will be used in post-hoc analyses of the 
data. All surveys will be filled out by the patient on tablet computers (Apple iPad/Microsoft Surface) and 
data entry will be done directly via Redcap Software.  ●MRI scanning: The MRI scanning session will 
last 30 minutes and will contain: 1) a high resolution anatomical image (T1-weighted MPRAGE (TR 1.9 
sec, TE 2.26 ms, 2x GRAPPA, 1 mm isotropic)), 2) resting state functional connectivity (TA 7 minutes, 
voxel size: 2.5 x 2.5 x 2.5, TR = 2.6 s, TE = 25 ms, flip angle = 60°, FOV = 224 mm × 224 mm, matrix 
size = 64 × 64),For each of the above strategies (Active rTMS or Active Sham) we will explore a 

Version #4; 11/05/2019 
 
Page 12 of 24 
 
series of SubAims designed to quantify the effects of rTMS on subjective pain, quantitative sensory 
testing, and brain reactivity to pain.   
SubAim 1: Evaluating Pain using Clinical Assessments   Quantitative Sensory Testing (QST). Using 
the Medoc ATS thermal stimulator (Medoc Ltd Advanced Medical Systems, Ramat Yishai, Israel), 3 
primary outputs will be compiled for each individual via the method of limits (54): sensory threshold, 
pain threshold, tolerance threshold. The thermode will be attached to the right forearm, and when the 
procedure begins it will begin heating from room temperature (32°C) at 0.2°C per second. Participants 
will indicate when they first detect the temperature change (sensory threshold), when it becomes painful 
(pain threshold), and when they can no longer tolerate the stimuli (tolerance threshold). When participants 
indicate tolerance, the operator will initiate rapid (>8°C per second) cooling. For safety, the thermode will 
be unable to exceed 51° and will initiate rapid cooling at that point. QST will be performed at two 
timepoints for each visit – prior to the initial MRI session and after the second MRI session.  Pain 
Questionnaire. In order to evaluate current levels of pain, we will ask participants to rate their current 
level of pain and discomfort (scale, 0 through 10), each time the participant comes in (Table 1). On days 
where the individual receives rTMS, they will fill out this assessment before and after each session. Pain 
and Craving Questionnaire: In addition to the Pain Questionnaire above, participants will also rate their 
urge to use a pain reliever (Scale 0 – 10) and the amount they would be willing to pay for a pain reliever 
(In US Dollars). This questionnaire will be used at the same time during each intervention visit as the Pain 
Questionnaire (Table 2).     
 
SubAim 2: Evaluating Pain using Neuroimaging Data At baseline we expect that people with chronic 
pain will have elevated activations in the Pain Network. This will be analyzed through the resting state 
connectivity network. Following sham stimulation, we do not anticipate a significant reduction of this 
response. Based on prior studies by our group in non-opiate dependent individuals, following LTP-like 
stimulation of the DLPFC, we expect a significant amplification of the DLPFC (% BOLD signal change), 
and a reduction of the Pain Network (dACC, anterior insula) reflecting the increased influence of 
executive processes. MPFC TMS however will likely not have as large of an effect on ECN engagement 
during the instruction to Control the pain.  
 
 
Data Analysis Plan. 
A. Quantitative Sensory Testing. The QST pain assessment produces 3 output variables: sensory 
threshold, pain threshold, tolerance threshold (all expressed in degrees Celsius). The hypothesis will be 
tested using a within-subject repeated measures design (time x treatment) wherein time is the repeated 
variable and Real or Sham TMS is the grouping variable. Given that the purpose of this pilot study is to 
develop effect sizes for a subsequent R01, we will derive least-squares means effect sizes of this strategy 
on these thresholds. Secondary analyses will evaluate the relationship between QST levels and the neural 
response to pain, as well as the relationship between QST values and evoked cortical responses. 
Integrating these measures together will provide a more complete picture of how cortical activity is able 
to modulate the pain response. 
B. Questionnaires and Evaluations. The Opiate Pain inventory produces 4 output variables of interest: 
level of discomfort, level of pain, urge to use opiates, amount willing to pay for an opiate. The hypotheses 
for the Aims will be tested using a within-subject repeated measures design (time x treatment) wherein 
time is the repeated variable and Real or Sham TMS is the grouping variable. Given that the purpose of 
this pilot study is to develop effect sizes for a subsequent R01, we will derive least-squares means effect 
sizes of our research strategy on these 4 variables, to determine the unique contributions of this 
intervention. 
C. Neuroimaging Data (Aim 2): Immediately following acquisition, functional structural data will be 
uploaded to a secure data server and converted to NIfTI format. All preprocessing and analyses will be 

Version #4; 11/05/2019 
 
Page 13 of 24 
 
performed using Statistical Parametric Mapping 12 (SPM12) in Matlab 2013 (Mathworks). Functional 
data will be corrected for magnetic field inhomogeneity and realigned (rigid-body, minimizing least 
squares differences) to the first image in the time series (Realign: Estimate and Unwarp). Non-linear 
deformations required for standard space normalization will be derived from each participant’s anatomical 
image via a unified segmentation approach (Segment). After the mean realigned and unwarped functional 
image is coregistered to the skull stripped anatomical image (Coreg: Estimate) forward deformations 
(subject space to MNI standard space) will be applied (Normalise: Write). Finally, the data will be 
smoothed by an 8 mm full width half maximum Gaussian smoothing kernel (Smooth).  Within-subject 
and between-group modeling. Data will be analyzed at the subject level using multivariate pattern 
analysis (Wager et al 2013 “An fMRI-Based Neurologic Signature of Physical Pain” new England Journal 
of Medicine).  The six motion parameters (translations and rotations) will be included in the design 
matrices 
as 
covariates 
to 
account 
for 
non-task 
signal. 
The hot and warm blocks of thermal stimulus, as well as rating events, will be separately modeled in a 
boxcar fashion. Resting State Connectivity will be measured to compare MRI scan 1 to scan 2 – 
immediately after the treatment. MRI scan 3 will also be compared to these scans to see if there is a 
sustainable reduction in pain activity between these networks.  Additionally factor analysis will be used to 
investigate the durability of the effects of each strategy on functional connectivity in each of the 3 Core 
networks (SN, ECN, DMN) using factor analysis longitudinally. Covariates: As an exploratory analysis 
we will also quantify the impact of several covariates which have previously been documented to affect 
the brain response to pain and pain thresholds (sex, Becks Depression Inventory score, length of time 
using chronic opiates). Although all participants will have taken their daily dose of opiates, which has a 
stable pharmacokinetic profile, we will also consider time since last dose. 
 
Expected (and alternative) Outcomes: 
A. Quantitative Pain Testing. Based on our pilot data, we expect an interaction between treatment (Real 
DLPFC of MPFC TMS vs. Sham) and time (Before vs. After rTMS) on the painfulness QST measure but 
no effect on sensory or tolerance levels. Alternative outcomes: It is possible that individuals will 
experience a small level of acute pain relief from their normal regimen of medication. We will be 
collecting information on opiate dose and timing at each visit to be used as potential covariates. Further, 
there is the possibility that pain tolerance will rise, possibly also reflecting improvements in executive 
function.  
 
B. Qualitative Pain Assessment. We expect reductions in pain and discomfort when comparing active vs 
sham. However, based on prior data in opiate dependent individuals, we expect the effect size of DLPFC 
rTMS in to improve measures of Control but not measures of mood, whereas MPFC will have a larger 
effect on mood. 
 
C. Neuroimaging. At baseline we expect that there will beelevated activations in the Pain Network in 
individuals with chronic pain. Following sham stimulation, we do not anticipate a significant reduction of 
this response. Based on prior studies by our group in non-opiate dependent individuals, following LTP-
like stimulation of the DLPFC, we expect a significant amplification of the DLPFC (% BOLD signal 
change), and a reduction of the Pain Network (dACC, anterior insula) reflecting the increased influence of 
executive processes. MPFC TMS however will likely not have as large of an effect on ECN engagement 
during the instruction to Control the pain.  
Alternative outcomes: Though pilot data suggest that a single treatment will acutely reduce self-reported 
pain, it is possible that the neural circuits in opiate dependent individuals do not have the same ‘plasticity 
potential’ as in controls. The results of the baseline cortical modulation assessment of pain (instruction to 
“control” the pain) will help resolve this alternative outcome. If we fail to replicate prior work showing 
DLPFC activation, this could reflect executive deficits (58), suggesting that the MPFC TMS will be more 
efficacious.  

Version #4; 11/05/2019 
 
Page 14 of 24 
 
 
Exploratory Analysis: We will evaluate if there are rate-dependent effects between baseline SN 
connectivity with the ECN and DMN and the efficacy of each TMS strategy on subjective pain. Data will 
be analyzed by using multivariate pattern analysis (MVPA) (2014). While the primary outcomes will be 
MRI V1 vs V2, we will also examine the relative ‘durability’ of the effects on pain by comparing the MRI 
data at the 1 month follow up between and within groups with factor analysis.  Integration of Brain 
based and Behavioral Based Outcomes with Gender and other Demographic Variables: Finally, we 
will compare the relative efficacy of these two types of TMS using the behavioral and neuroimaging 
measures. Specifically, we will determine the effect sizes for DLPFC and MPFC (relative to sham) 
stimulation on reducing the 1) the neural and 2) behavioral responses to pain, as well as 3) changes in 
clinical assessment metrics (see Approach). We will investigate the role of baseline cortical 
responsiveness on the pain response, as well as how changes in that evoked response are related to 
changes in both pain and craving measures. This will be specifically addressed as a factor of gender as 
well, given that there are established differences in sensitivity to pain and prevalence of opiate 
dependence between men and women.     
 
11.0 Specimen Collection and Banking (if applicable) 
Sources of Research Material:  
1. The material used for analysis in this protocol is of a verbal report, biologic specimen, and brain 
images.  All reports will be collected directly from the patients during the course of their 
participation in this study.  Verbal report data will be collected from direct subject interview, 
questionnaires, and computer tasks. Biologic samples include urine samples.  Urine samples are 
provided by natural means. Urine samples will be tested for metabolites in the CDAP laboratory 
located on the first floor of the Institute of Psychiatry.  
2. Upon their enrollment in the study, subjects will be assigned a study identification number that 
will subsequently be used to identify their data in lieu of other personal identifiers. Only the study 
PI(s) will have access to the database linking subjects’ names to their identification numbers. 
3. Data generated during the course of this study will be used for research purposes only. All data 
will be collected and transferred according to HIPAA guidelines. 
 
12.0 Data Management  
Data management, acquisition, and transmission:  
The Principal Investigator (PI) will be the primary party responsible for management, oversight, and 
accountability in terms of participant safety and consent. A conflict of interest will be avoided by 
secondary evaluation of records by a Monitoring Entity (ME) (aka. data safety monitoring board- DSMB) 
on a semi-annual basis. This Entity’s reporting will be supported by the South Carolina Translational 
Research Institute, MUSC's CTSA. Quality control will include regular data verification (Integrity of the 
Consent and HIPAA, scores on the Assessments, MRI scanning information), study progress and subject 
status, any adverse events, and any protocol deviations. Protocol adherence will be monitored by the 
MUSC Institutional Review Board, who will also be given access to the reports from the PI to the ME. 
 
Data entry methods:  
Data will be collected using REDCap™, and entered directly into the online portal to ensure security and 
prevent data loss.  
 
13.0 Provisions to Monitor the Data to Ensure the Safety of Subjects (if applicable) 

Version #4; 11/05/2019 
 
Page 15 of 24 
 
Quality control will include regular data verification (Integrity of the Consent and HIPPA, scores on the 
Assessments), study progress and subject status, any adverse events, and any protocol deviations. Protocol 
adherence will be monitored by the MUSC Institutional Review Board, who will also be given access to 
the reports from the PI. 
 
Responsible Conduct in Research Resources: At MUSC all faculty members and staff engaged in 
research must take an annual Responsible Conduct in research training module which includes the 
Collaborative 
Institutional 
Training 
Initiative 
on 
Protection 
of 
Human 
Subjects 
(https://www.citiprogram.org/) as well as modules customized to the facilities and expectations at MUSC. 
These resources, coupled with cross-departmental seminar series and NIH funded training opportunities in 
ethical conduct in research, provide an environment at the Medical University of South Carolina for Dr. 
Borckardt and the other study personnel on this proposal to obtain required annual training in human 
research ethics. 
 
All key personnel will undergo appropriate IRB training for dealing with human participants and will be 
trained by the PI in all aspects of the study interventions.  Personnel listed in this protocol (as well as any 
rotating medical students, graduate students, psychiatry residents or fellows that may be exposed to this 
investigation as part of their research training exposre) will be required to maintain their certification of 
HIPPA training and Protection of Human Participants in Research training on an annual basis.  Any new 
personnel without experience in human clinical research will be encouraged to attend the MUSC Core 
Clinical Research Training Course, which is offered live and online throughout the year. Through these 
measures we will ensure that all study staff will be trained and will maintain ongoing understanding of 
research ethics and the rights of the participant during the consenting process and throughout an 
individual's participation in the study. 
 
Data analysis plan: 
Data for this study (behavioral assessments, functional MRI measurements) will be acquired by the 
members of the Dr. Borckardt’s lab, including graduate students and research specialists. These 
individuals will also perform data under the guidance of the PI. Manuscript composition will be led by the 
PI, with the assistance of the research team.   
 
Quality assurance plan:  
The PI has weekly meetings with the research team to discuss qualitative comments received during data 
collection and any problems in data collection. Initial data analyses will examine distributions of variable 
scores, and comparability of baseline characteristics across conditions in case analyses need to be adjusted 
for these. Confidentiality protections are outlined below.  
 
Statistical review of the study, will be conducted by a faculty member from the MUSC Provost-sponsored 
Biostatistical Collaborative Unit (see Facilities) (including enrollment, retention, assessment inventories) 
annually.  Data collected in previous studies by our research group have demonstrated that after extended 
use in the MRI scanner environment (likely more than 5000 pulses) the strength of the induced magnetic 
field from the Magstim biphasic coil begins to drop in a non-linear fashion. Consequently, the intensity of 
the induced magnetic field from the Magstim coil will be assessed by study personnel and logged weekly 
(alongside with use records from that week, number of pulses, intensity of pulses).  This cumulative 
record of coil performance will be monitored and, when the intensity of the induced field had degraded 
10%, we will switch to a new, identical Magstim coil.  We do not anticipate this will occur within the 2-
year period of this project.  
 
Confidentiality and Privacy: 

Version #4; 11/05/2019 
 
Page 16 of 24 
 
Section 301(d) of the Public Health Service Act, November 4, 1988 provides a layer of protection for 
health data reported by participants that have volunteered for federally funded research studies.  Only 
members of the research team will have access to participant records. Records will be kept in a locked file 
cabinet in a locked office. Computer records are password protected and will identify participants by 
Patient ID number.  
 
Definition and Reporting of AEs/SAEs to the IRB/FDA/NIDA: 
An AE is defined as any untoward medical occurrence in a study subject administered rTMS that does not 
necessarily have a causal relationship with this treatment.  Any unwanted change, physically, 
psychologically or behaviorally, that occurs in a study participant during the course of the trial is an 
adverse event.  A Serious Adverse Event (SAE) is defined as an adverse event that has one of the 
following outcomes: death, life-threatening, inpatient hospitalization or prolongation of existing 
hospitalization, persistent or significant disability/incapacity, a congenital anomaly/birth defect.  
 
All unexpected Adverse Events (AEs) will be reported to the MUSC IRB and Committee on Human 
Research within 48-business hours. Serious AEs will be reported within 24-business hours. Follow-up of 
all unexpected and serious AEs will also be reported to these agencies. AEs/SAEs are documented and 
reported as per IRB requirements. Research staff will identify adverse events and obtain all available 
information to assess severity, seriousness, study relatedness, expectedness, outcome and the need for 
change or discontinuation in the study intervention. Adverse events are generally documented on AE 
Logs and AE Case Report Forms (CRFs). Additional relevant AE information if available will be 
documented in a progress note in the research record as appropriate to allow monitoring and evaluating of 
the AE. If the AE meets the definition for serious, appropriate SAE protocol specific reporting forms are 
completed and disseminated to the appropriate persons and within the designated timeframes as indicated 
above. For each AE/SAE recorded, the research staff will follow the AE/SAE until resolution, 
stabilization or until the participant is no longer in the study as stated in the protocol. We will report 
adverse events to the Medical MUSC IRB online per the IRB’s guidelines.   
 
Incidental Findings Standard Operating Procedure: 
Should an incidental finding occur, the posted CBI policy for incidental findings will be followed first and 
foremost (as posted on website on February 20, 2019) which states that CBI will: 
1. Immediately notify the Principal Investigator (PI) of the study. 
2. Request that the MRI technologist on duty transfer the study images to the clinical PACS 
system and notify the designated CBI radiologist. 
 
Following review, the radiologist will contact the PI, discuss the clinical significance of the 
 
findings, and  decide whether follow-up contact with the subject is necessary. 
 
Should the radiologist contact the PI in writing and recommend follow-up contact, the PI will do the 
following: 
1. Work with the research staff to identify the participant’s name and get contact information 
2. Contact one of the Study Personnel with a medical degree (MD or DO) regarding their 
availability to discuss the findings from the radiologist with the PI and with the participant.      
a. In the event that the PI and the study physician feel it is most appropriate for the physician 
to speak with the participant directly, the physician will be provided with the participant 
information as well as the radiologist report so they can speak with the subject and 
determine the appropriate course of action 

Version #4; 11/05/2019 
 
Page 17 of 24 
 
b. In the event that the PI and the study physician feel comfortable having the PI speak to the 
participant directly, the PI will contact the participant as soon as possible.   
3. A log will be kept for all attempts made to contact the subject along with detailed notes for 
these attempts 
In the event that an obvious neurological abnormality is observed that would comprise the validity of the 
data for the study, the subject will be excluded upon PI discretion. 
 
Reporting of IRB actions and ME/DSMB reports to NIDA 
Any adverse events will be immediately reported to both the MUSC IRB and NIDA should this study 
(R21 proposal) be awarded. All ME/DSMB reports will be submitted to NIH/NIDA annually.  
 
Report of changes or amendments to the protocol.  
Any changes to the proposal/protocol must be approved by NIDA.  Any amendments to the IRB protocol 
associated with the proposed work will be reported to NIDA should this proposal be awarded funding.  
 
Trial stopping rules: 
The protocol will immediately be paused following notification of a Serious Adverse Event (SAE). Per 
MUSC IRB policy, the Institutional Review Board and DSMB will be notified within 24 business hours 
following the SAE notification. SAEs will be reported to NIDA within 72 hours. Should the reported SAE 
be confirmed as directly related to the protocol, the trial will be terminated. The device manufacturer will 
be notified within 72 hours. Of note, there have been no clinical trials that have ever been stopped, nor 
SAE reported in the literature associated with the MagVenture device.   
 
Conflict of interest 
Neither the PI, nor members of the research team have any Conflicts of Interest directly related to this 
protocol.  The rTMS device used for the propose study are manufactured by MagVenture. 
 
14.0 Withdrawal of Subjects (if applicable) 
Risks of psychiatric assessments: 
All psychiatric assessments will be conducted by study personnel who have received formal training in 
clinical interviewing and have worked with substance dependent patients in the past.  
 
Participants may withdraw from the study at any time or may be withdrawn from the study if the PI feels 
it is in the best interest of the participant. In the event of a medical emergency, a research participant will 
be transported to the Emergency Department at Medical University of South Carolina, which is within 
two blocks of the CAIR and the Brain Stimulation Laboratory in the Institute of Psychiatry. If a 
psychiatric crisis occurs, the Department of Psychiatry will be contacted to arrange for either an 
emergency outpatient appointment or an in house psychiatric consult.  
 
15.0 Risks to Subjects  
Potential risks/benefits for participants 
The risks fall into three categories: risks associates with psychological assessment, risks associated with 
repetitive TMS and risks associated with MRI scanning.  
 
Risks of psychiatric interviewing (minimal risk):  

Version #4; 11/05/2019 
 
Page 18 of 24 
 
1. Some participants may get emotionally distraught when disclosing sensitive personal stories. Some 
participants may feel anxiety about disclosing substance use histories and reporting some aspects of their 
demographics. 
 
Risks associated with MRI scanning (minimal risk): 
1. The major potential risks for MRI are all subsumed under the risks for TMS and primarily include risks 
to individuals who have metallic implants, pacemakers, or pregnant women.  These individuals will be 
excluded from the study.   
2. Participants may feel restless or uncomfortable when lying in the MRI scanner.  
 
Risks associated with repetitive TMS (FDA-designated minimal risk): 
Potential Risks of TMS 
Repetitive TMS has been considered “non-significant risk” by the FDA  (2007) when applied at similar 
intensities, durations, and frequencies to those being used in this protocol. Additionally motor cortex and 
dorsolateral prefrontal continuous theta burst stimulation in a manner identical to this protocol has been 
designated minimal risk by the MUSC Institutional Review Board for healthy adults as well as individuals 
with opaite dependence.  
 
Potential risk of a seizure:  
In designing this experiment, we have followed the latest safety guidelines for TMS. Despite these 
precautions, there is a chance of a seizure as a result of rTMS. Eight seizures have been noted in previous 
studies, with six of them occurring in healthy volunteers without any history of seizures, brain tumors or 
traumatic brain injuries. All of these seizures have occurred during rTMS with the participant in the 
treatment chair and a trained operator on hand. All seizures have stopped by themselves without any 
medication. No participants have had any problems after the seizures. MUSC has a plan for dealing with 
fainting and seizures, and every TMS researcher involved in providing TMS treatment for this 
protocol (Key Personnel) will have to attend the MUSC Brain Stimulation Intensive training 
program wherein they will receive a Certificate of Completion after a written test of TMS didactics 
and safety measures as well as a skills test associated with collecting an accurate motor threshold (which 
is one of the largest factors that promotes safety). Additionally, if a participant has a seizure an emergency 
response team will be called. Most seizures, including those caused by rTMS, last less than 60 seconds 
and do not require any medication. Participants will be evaluated by a physician associated with the 
MUSC Brain Stimulation Laboratory following recovery from the seizure. Any participant who has a 
seizure cannot continue with the study.   
     
Other potential risks:  
   
1. Potential for scalp discomfort and headaches: Some people report mild discomfort when the 
magnetic pulses are applied over the scalp. A small number of people (~5%) report headache 
following rTMS. However, the headaches are temporary and manageable with common over-the-
counter pain remedies.  
2. Potential hearing loss: The TMS coil generates a high-energy click that may cause hearing 
damage. Humans exposed to TMS have shown temporary increases in auditory threshold 
(especially at high frequencies) lasting at least 5 minutes and less than 4 hours.  
3. Safety in case of pregnancy: This protocol will exclude pregnant women. The risks of using TMS 
with pregnant women are currently unknown. Please inform the research team if you are pregnant 
or think that you might have become pregnant during the study. A pregnancy test will be 
performed before the experiment begins.  

Version #4; 11/05/2019 
 
Page 19 of 24 
 
4. Potential for reflex syncopal event: Syncope is defined as a momentary loss of awareness and 
postural tone. It typically has a rapid onset, short duration, and spontaneous recovery.  Although 
syncopal episodes are very rare with TMS (less than 1%), they typically occur during the motor 
threshold procedure before the rTMS treatment has begun.  Individuals that are sleep deprived and 
have low or unstable blood pressure are at greater risk.   
5. Interaction with electrical or metal implants: Electrically, magnetically or mechanically activated 
implants (such as cardiac pacemakers), as well as clips on blood vessels in the brain may be 
affected by rTMS (as well as MRI) and cause pain or abnormal signal propagation. Therefore 
individuals that have these implants and devices or suspect that they may have pieces of metal in 
their eyes, head, or body (e.g. bullets, shrapnel, fragments from metallurgy) will be excluded from 
the study. 
16.0 Potential Benefits to Subjects or Others 
Potential benefits of proposed research 
1. Although there is no direct monetary or medical benefit to the participants, they will be 
monetarily compensated for the time and effort required to participate in the study.  From a 
biological perspective, they may benefit from the positive effects of real rTMS if they are 
randomized to those groups (iTBS and cTBS).  From a psychological perspective all patients 
will likely benefit from the additional time they will spend in contact with the study team when 
they will be surrounded by educational materials and an environment that is generally supportive 
and encouraging despite their struggle with substance use disorders – a resource these 
individuals often do not have in their home environments.  
2. The risks to subjects are reasonable in relation to the anticipated benefits they will gain. Risks to 
subjects can be satisfactorily minimized to keep the risk to benefit ratio acceptably low. 
Importance of the knowledge to be gained 
The proposed research is innovative in several ways. First, we are developing an alternative treatment 
strategy for pain, which involves non-pharmacologic modulation of circuits responsible for the perception 
of pain and craving.  This is a significant conceptual advance for the field of addiction and chronic pain 
management.   While LTP-like dlPFC TMS has been promising as a tool for pain in non-opiate dependent 
individuals, this proposal represents a critical next step in its development for an opiate dependent 
population.  The knowledge gained from these aims would be the basis for further examination in a larger 
Clinical Trial of TMS (R01 submission planned October 2018) and hasten the pipeline through which 
TMS could be developed as a *neural circuit, evidence based* treatment option for physicians and 
providers of pain management to opiate dependent individuals.  Second, while most TMS investigations 
focus on the relative efficacy of stimulation at a single site (or a single functional network), by evaluating 
2 Strategies in this proposal we will be uniquely positioned to advance the field.  Through these Aims we 
will determine if the effects of TMS on pain and craving are greater when the executive control circuit is 
amplified (Strategy 1, PMC) or when the DLPFC circuit is dampened (Strategy 2, Aim 2).   Third, we are 
using a novel stimulation profile, theta burst stimulation (supported by our preliminary data). This 
stimulation profile will reduce the total time of active stimulation relative to standard10 Hz rTMS, thus 
reducing patient burden. 
 
18.0 Drugs or Devices (if applicable)  
Repetitive TMS has been considered “non-significant risk” by the FDA (2007) when applied at similar 
intensities, durations, and frequencies to those being used in this protocol. Additionally medial prefrontal 
and dorsolateral prefrontal continuous theta burst stimulation in a manner identical to this protocol has 

Version #4; 11/05/2019 
 
Page 20 of 24 
 
been designated minimal risk by the MUSC Institutional Review Board for healthy adults as well as 
individuals with nicotine dependence.  
 
To safely administer TMS, every TMS researcher involved in providing TMS treatment for this protocol 
(Key Personnel) will have to attend the MUSC Brain Stimulation Intensive training program wherein they 
will receive a Certificate of Completion after a written test of TMS didactics and safety measures as well 
as a skills test associated with collecting an accurate motor threshold (which is one of the largest factors 
that promotes safety).   
 
References 
1. 
Quality CfBHSa. Behavioral health trends in the United States: Results from the 2014 National 
Survey on Drug Use and Health. HHS Publication No SMA 15-4927, NSDUH Series H-50. 2015. 
2. 
Center for Disease Control and Prevention NCfHS, National Vital Statistics, System, Mortality 
File. Number and Age-Adjusted Rates of Drug-poisoning Deaths Involving Opioid Analgesics and 
Heroin: United States, 2000–2014. In: Prevention CfDCa, editor. Atlanta, GA2015. 
3. 
Birnbaum HG, White AG, Schiller M, Waldman T, Cleveland JM, Roland CL. Societal costs of 
prescription opioid abuse, dependence, and misuse in the United States. Pain medicine. 2011;12(4):657-
67. doi: 10.1111/j.1526-4637.2011.01075.x. PubMed PMID: 21392250. 
4. 
Apkarian AV, Bushnell MC, Treede RD, Zubieta JK. Human brain mechanisms of pain perception 
and regulation in health and disease. Eur J Pain. 2005;9(4):463-84. doi: 10.1016/j.ejpain.2004.11.001. 
PubMed PMID: 15979027. 
5. 
Wager TD, Atlas LY, Lindquist MA, Roy M, Woo CW, Kross E. An fMRI-based neurologic 
signature of physical pain. N Engl J Med. 2013;368(15):1388-97. doi: 10.1056/NEJMoa1204471. 
PubMed PMID: 23574118; PubMed Central PMCID: PMCPMC3691100. 
6. 
Cauda F, Costa T, Diano M, Sacco K, Duca S, Geminiani G, Torta DM. Massive modulation of 
brain areas after mechanical pain stimulation: a time-resolved FMRI study. Cereb Cortex. 
2014;24(11):2991-3005. doi: 10.1093/cercor/bht153. PubMed PMID: 23796948. 
7. 
Taylor JJ, Borckardt JJ, George MS. Endogenous opioids mediate left dorsolateral prefrontal 
cortex rTMS-induced analgesia. Pain. 2012;153(6):1219-25. doi: 10.1016/j.pain.2012.02.030. PubMed 
PMID: 22444187; PubMed Central PMCID: PMCPMC3530383. 
8. 
Taylor JJ, Borckardt JJ, Canterberry M, Li X, Hanlon CA, Brown TR, George MS. Naloxone-
reversible modulation of pain circuitry by left prefrontal rTMS. Neuropsychopharmacology. 
2013;38(7):1189-97. doi: 10.1038/npp.2013.13. PubMed PMID: 23314221; PubMed Central PMCID: 
PMCPMC3656361. 
9. 
Borckardt JJ, Weinstein M, Reeves ST, Kozel FA, Nahas Z, Smith AR, Byrne TK, Morgan K, 
George MS. Postoperative Left Prefrontal Repetitive Transcranial Magnetic Stimulation Reduces Patient-
controlled Analgesia Use. Anesthesiology. 2006;105(3):557-62. PubMed PMID: 16931989. 
10. 
Galhardoni R, Correia GS, Araujo H, Yeng LT, Fernandes DT, Kaziyama HH, Marcolin MA, 
Bouhassira D, Teixeira MJ, de Andrade DC. Repetitive transcranial magnetic stimulation in chronic pain: 
a 
review 
of 
the 
literature. 
Arch 
Phys 
Med 
Rehabil. 
2015;96(4 
Suppl):S156-72. 
doi: 
10.1016/j.apmr.2014.11.010. PubMed PMID: 25437106. 
11. 
Lefaucheur JP, Antal A, Ahdab R, Ciampi de Andrade D, Fregni F, Khedr EM, Nitsche M, Paulus 
W. The use of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current 
stimulation (tDCS) to relieve pain. Brain Stimul. 2008;1(4):337-44. doi: 10.1016/j.brs.2008.07.003. 
PubMed PMID: 20633392. 
12. 
Moisset X, de Andrade DC, Bouhassira D. From pulses to pain relief: an update on the 
mechanisms of rTMS-induced analgesic effects. Eur J Pain. 2015. doi: 10.1002/ejp.811. PubMed PMID: 
26471248. 

Version #4; 11/05/2019 
 
Page 21 of 24 
 
13. 
Shei A, Rice JB, Kirson NY, Bodnar K, Birnbaum HG, Holly P, Ben-Joseph R. Sources of 
prescription opioids among diagnosed opioid abusers. Curr Med Res Opin. 2015;31(4):779-84. doi: 
10.1185/03007995.2015.1016607. PubMed PMID: 25661018. 
14. 
Barth KS, Maria MM, Lawson K, Shaftman S, Brady KT, Back SE. Pain and motives for use 
among non-treatment seeking individuals with prescription opioid dependence. Am J Addict. 
2013;22(5):486-91. doi: 10.1111/j.1521-0391.2013.12038.x. PubMed PMID: 23952895; PubMed Central 
PMCID: PMCPMC3748383. 
15. 
Siebner HR, Bergmann TO, Bestmann S, Massimini M, Johansen-Berg H, Mochizuki H, Bohning 
DE, Boorman ED, Groppa S, Miniussi C, Pascual-Leone A, Huber R, Taylor PC, Ilmoniemi RJ, De 
Gennaro L, Strafella AP, Kahkonen S, Kloppel S, Frisoni GB, George MS, Hallett M, Brandt SA, 
Rushworth MF, Ziemann U, Rothwell JC, Ward N, Cohen LG, Baudewig J, Paus T, Ugawa Y, Rossini 
PM. Consensus paper: combining transcranial stimulation with neuroimaging. Brain Stimul. 
2009;2(2):58-80. doi: 10.1016/j.brs.2008.11.002. PubMed PMID: 20633405. 
16. 
Denslow S, Lomarev M, George MS, Bohning DE. Cortical and subcortical brain effects of 
transcranial magnetic stimulation (TMS)-induced movement: an interleaved TMS/functional magnetic 
resonance imaging study. Biol Psychiatry. 2005;57(7):752-60. doi: 10.1016/j.biopsych.2004.12.017. 
PubMed PMID: 15820232. 
17. 
Fox MD, Buckner RL, White MP, Greicius MD, Pascual-Leone A. Efficacy of transcranial 
magnetic stimulation targets for depression is related to intrinsic functional connectivity with the 
subgenual cingulate. Biol Psychiatry. 2012;72(7):595-603. doi: 10.1016/j.biopsych.2012.04.028. PubMed 
PMID: 22658708; PubMed Central PMCID: PMCPMC4120275. 
18. 
Bohning DE, Shastri A, Lomarev MP, Lorberbaum JP, Nahas Z, George MS. BOLD-fMRI 
response vs. transcranial magnetic stimulation (TMS) pulse-train length: testing for linearity. J Magn 
Reson Imaging. 2003;17(3):279-90. doi: 10.1002/jmri.10271. PubMed PMID: 12594717. 
19. 
Bestmann S, Baudewig J, Siebner HR, Rothwell JC, Frahm J. Functional MRI of the immediate 
impact of transcranial magnetic stimulation on cortical and subcortical motor circuits. Eur J Neurosci. 
2004;19(7):1950-62. doi: 10.1111/j.1460-9568.2004.03277.x. PubMed PMID: 15078569. 
20. 
Barr MS, Farzan F, Wing VC, George TP, Fitzgerald PB, Daskalakis ZJ. Repetitive transcranial 
magnetic 
stimulation 
and 
drug 
addiction. 
Int 
Rev 
Psychiatry. 
2011;23(5):454-66. 
doi: 
10.3109/09540261.2011.618827. PubMed PMID: 22200135. 
21. 
Bellamoli E, Manganotti P, Schwartz RP, Rimondo C, Gomma M, Serpelloni G. rTMS in the 
treatment of drug addiction: an update about human studies. Behav Neurol. 2014;2014:815215. doi: 
10.1155/2014/815215. PubMed PMID: 24803733; PubMed Central PMCID: PMCPMC4006612. 
22. 
Gorelick DA, Zangen A, George MS. Transcranial magnetic stimulation in the treatment of 
substance addiction. Ann N Y Acad Sci. 2014;1327:79-93. doi: 10.1111/nyas.12479. PubMed PMID: 
25069523; PubMed Central PMCID: PMCPMC4206564. 
23. 
Grall-Bronnec M, Sauvaget A. The use of repetitive transcranial magnetic stimulation for 
modulating craving and addictive behaviours: a critical literature review of efficacy, technical and 
methodological 
considerations. 
Neurosci 
Biobehav 
Rev. 
2014;47:592-613. 
doi: 
10.1016/j.neubiorev.2014.10.013. PubMed PMID: 25454360. 
24. 
Politi E, Fauci E, Santoro A, Smeraldi E. Daily sessions of transcranial magnetic stimulation to the 
left prefrontal cortex gradually reduce cocaine craving. Am J Addict. 2008;17(4):345-6. doi: 
10.1080/10550490802139283. PubMed PMID: 18612892. 
25. 
Terraneo A, Leggio L, Saladini M, Ermani M, Bonci A, Gallimberti L. Transcranial magnetic 
stimulation 
of 
dorsolateral 
prefrontal 
cortex 
reduces 
cocaine 
use: 
A 
pilot 
study. 
Eur 
Neuropsychopharmacol. 2016;26(1):37-44. doi: 10.1016/j.euroneuro.2015.11.011. PubMed PMID: 
26655188. 
26. 
Trojak B, Meille V, Achab S, Lalanne L, Poquet H, Ponavoy E, Blaise E, Bonin B, Chauvet-
Gelinier JC. Transcranial Magnetic Stimulation Combined With Nicotine Replacement Therapy for 

Version #4; 11/05/2019 
 
Page 22 of 24 
 
Smoking Cessation: A Randomized Controlled Trial. Brain Stimul. 2015;8(6):1168-74. doi: 
10.1016/j.brs.2015.06.004. PubMed PMID: 26590478. 
27. 
Lorenz J, Minoshima S, Casey KL. Keeping pain out of mind: the role of the dorsolateral 
prefrontal cortex in pain modulation. Brain. 2003;126(Pt 5):1079-91. doi: 10.1093/brain/awg102. PubMed 
PMID: 12690048. 
28. 
Freund W, Klug R, Weber F, Stuber G, Schmitz B, Wunderlich AP. Perception and suppression of 
thermally 
induced 
pain: 
a 
fMRI 
study. 
Somatosens 
Mot 
Res. 
2009;26(1):1-10. 
doi: 
10.1080/08990220902738243. PubMed PMID: 19283551. 
29. 
Wager TD, Atlas LY, Leotti LA, Rilling JK. Predicting individual differences in placebo 
analgesia: contributions of brain activity during anticipation and pain experience. J Neurosci. 
2011;31(2):439-52. doi: 10.1523/JNEUROSCI.3420-10.2011. PubMed PMID: 21228154; PubMed 
Central PMCID: PMCPMC3735131. 
30. 
Cho SS, Strafella AP. rTMS of the left dorsolateral prefrontal cortex modulates dopamine release 
in the ipsilateral anterior cingulate cortex and orbitofrontal cortex. PLoS One. 2009;4(8):e6725. doi: 
10.1371/journal.pone.0006725. PubMed PMID: 19696930; PubMed Central PMCID: PMCPMC2725302. 
31. 
Borckardt JJ, Reeves ST, Weinstein M, Smith AR, Shelley N, Kozel FA, Nahas Z, Byrne KT, 
Morgan K, George MS. Significant analgesic effects of one session of postoperative left prefrontal cortex 
repetitive transcranial magnetic stimulation: a replication study. Brain Stimul. 2008;1(2):122-7. doi: 
10.1016/j.brs.2008.04.002. PubMed PMID: 19759838; PubMed Central PMCID: PMCPMC2744083. 
32. 
Brighina F, Piazza A, Vitello G, Aloisio A, Palermo A, Daniele O, Fierro B. rTMS of the 
prefrontal cortex in the treatment of chronic migraine: a pilot study. J Neurol Sci. 2004;227(1):67-71. doi: 
10.1016/j.jns.2004.08.008. PubMed PMID: 15546593. 
33. 
Brighina F, De Tommaso M, Giglia F, Scalia S, Cosentino G, Puma A, Panetta M, Giglia G, 
Fierro B. Modulation of pain perception by transcranial magnetic stimulation of left prefrontal cortex. J 
Headache Pain. 2011;12(2):185-91. doi: 10.1007/s10194-011-0322-8. PubMed PMID: 21350791; 
PubMed Central PMCID: PMCPMC3072504. 
34. 
Umezaki Y, Badran BW, DeVries WH, Moss J, Gonzales T, George MS. The Efficacy of Daily 
Prefrontal Repetitive Transcranial Magnetic Stimulation (rTMS) for Burning Mouth Syndrome (BMS): A 
Randomized 
Controlled 
Single-blind 
Study. 
Brain 
Stimul. 
2016;9(2):234-42. 
doi: 
10.1016/j.brs.2015.10.005. PubMed PMID: 26597930. 
35. 
Upadhyay J, Maleki N, Potter J, Elman I, Rudrauf D, Knudsen J, Wallin D, Pendse G, McDonald 
L, Griffin M, Anderson J, Nutile L, Renshaw P, Weiss R, Becerra L, Borsook D. Alterations in brain 
structure and functional connectivity in prescription opioid-dependent patients. Brain. 2010;133(Pt 
7):2098-114. doi: 10.1093/brain/awq138. PubMed PMID: 20558415; PubMed Central PMCID: 
PMCPMC2912691. 
36. 
Farrell MJ, Laird AR, Egan GF. Brain activity associated with painfully hot stimuli applied to the 
upper limb: a meta-analysis. Hum Brain Mapp. 2005;25(1):129-39. doi: 10.1002/hbm.20125. PubMed 
PMID: 15846813. 
37. 
Seeley WW, Menon V, Schatzberg AF, Keller J, Glover GH, Kenna H, Reiss AL, Greicius MD. 
Dissociable intrinsic connectivity networks for salience processing and executive control. J Neurosci. 
2007;27(9):2349-56. doi: 10.1523/JNEUROSCI.5587-06.2007. PubMed PMID: 17329432; PubMed 
Central PMCID: PMCPMC2680293. 
38. 
Paus T, Castro-Alamancos MA, Petrides M. Cortico-cortical connectivity of the human mid-
dorsolateral frontal cortex and its modulation by repetitive transcranial magnetic stimulation. Eur J 
Neurosci. 2001;14(8):1405-11. PubMed PMID: 11703468. 
39. 
Koski L, Paus T. Functional connectivity of the anterior cingulate cortex within the human frontal 
lobe: a brain-mapping meta-analysis. Experimental Brain Research. 2000;133(1):55-65. doi: 
10.1007/s002210000400. 
40. 
Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human 
motor cortex. Neuron. 2005;45(2):201-6. doi: 10.1016/j.neuron.2004.12.033. PubMed PMID: 15664172. 

Version #4; 11/05/2019 
 
Page 23 of 24 
 
41. 
Hanlon CA, Canterberry M, Taylor JJ, DeVries W, Li X, Brown TR, George MS. Probing the 
frontostriatal loops involved in executive and limbic processing via interleaved TMS and functional MRI 
at 
two 
prefrontal 
locations: 
a 
pilot 
study. 
PLoS 
One. 
2013;8(7):e67917. 
doi: 
10.1371/journal.pone.0067917. PubMed PMID: 23874466; PubMed Central PMCID: PMC3706588. 
42. 
Feil J, Zangen A. Brain stimulation in the study and treatment of addiction. Neurosci Biobehav 
Rev. 2010;34(4):559-74. doi: 10.1016/j.neubiorev.2009.11.006. PubMed PMID: 19914283. 
43. 
Wing VC, Barr MS, Wass CE, Lipsman N, Lozano AM, Daskalakis ZJ, George TP. Brain 
stimulation 
methods 
to 
treat 
tobacco 
addiction. 
Brain 
Stimul. 
2013;6(3):221-30. 
doi: 
10.1016/j.brs.2012.06.008. PubMed PMID: 22809824. 
44. 
Breedlove JL, A; Back, SE; Borckardt, JJ; Taylor,  JJ; Badran, BW; Sahlem, GL; Rostami, R; 
Brady, KT; George, MS; and Hanlon, CA., editor. 10 Hz rTMS May Reduce Pain and Craving in 
Prescription Opiate Dependent Individuals: a pilot study. Annual Meeting of the Society of Biological 
Psychiatry; May 14th-16th, 2015; Toronto, On. 
45. 
Nestler EJ. Molecular basis of long-term plasticity underlying addiction. Nature reviews 
Neuroscience. 2001;2(2):119-28. doi: 10.1038/35053570. PubMed PMID: 11252991. 
46. 
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, 
Dunbar GC. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and 
validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. The Journal of 
clinical psychiatry. 1998;59 Suppl 20:22-33;quiz 4-57. Epub 1999/01/09. PubMed PMID: 9881538. 
47. 
Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Annals of the 
Academy of Medicine, Singapore. 1994;23(2):129-38. Epub 1994/03/01. PubMed PMID: 8080219. 
48. 
Sobell LC, Sobell MB. Timeline Follow-Back. In: Litten RZ, Allen JP, editors. Measuring 
Alcohol Consumption: Psychosocial and Biochemical Methods. Totowa, NJ: Humana Press; 1992. p. 41-
72. 
49. 
Beck AT, Steer RA, Brown GK. Manual for the Beck Depression Inventory-II. San Antonio, TX: 
Psychological Corporation; 1996. 
50. 
Spielberger CD, Gorsuch RL, Lushene RH. State-trait Anxiety Inventory. Palo Alto: Consulting 
Psychologists Press; 1970. 
51. 
M. MD, M. L, F. DL. Profile of Mood States (POMS)–Revised Manual. San Diego, CA: 
Education and Industrial Testing Service; 1992. 
52. 
Mishory A, Molnar C, Koola J, Li X, Kozel FA, Myrick H, Stroud Z, Nahas Z, George MS. The 
maximum-likelihood strategy for determining transcranial magnetic stimulation motor threshold, using 
parameter estimation by sequential testing is faster than conventional methods with similar precision. The 
Journal of ECT. 2004;20(3):160-5. 
53. 
Borckardt JJ, Nahas Z, Koola J, George MS. Estimating resting motor thresholds in transcranial 
magnetic stimulation research and practice: a computer simulation evaluation of best methods. J ECT. 
2006;22(3):169-75. doi: 10.1097/01.yct.0000235923.52741.72. PubMed PMID: 16957531. 
54. 
Shy ME, Frohman EM, So YT, Arezzo JC, Cornblath DR, Giuliani MJ, Kincaid JC, Ochoa JL, 
Parry GJ, Weimer LH. Quantitative sensory testing: Report of the Therapeutics and Technology 
Assessment Subcommittee of the American Academy of Neurology. Neurology. 2003;60(6):898-904. doi: 
10.1212/01.wnl.0000058546.16985.11. 
55. 
Petersen KL, Rowbotham MC. A new human experimental pain model: the heat/capsaicin 
sensitization model. Neuroreport. 1999;10(7):1511-6. PubMed PMID: 10380972. 
56. 
Martin L, Borckardt JJ, Reeves ST, Frohman H, Beam W, Nahas Z, Johnson K, Younger J, Madan 
A, Patterson D, George M. A pilot functional MRI study of the effects of prefrontal rTMS on pain 
perception. Pain medicine. 2013;14(7):999-1009. doi: 10.1111/pme.12129. PubMed PMID: 23647651. 
57. 
Upadhyay J, Lemme J, Anderson J, Bleakman D, Large T, Evelhoch JL, Hargreaves R, Borsook 
D, Becerra L. Test-retest reliability of evoked heat stimulation BOLD fMRI. J Neurosci Methods. 
2015;253:38-46. doi: 10.1016/j.jneumeth.2015.06.001. PubMed PMID: 26072245. 

Version #4; 11/05/2019 
 
Page 24 of 24 
 
58. 
Gruber SA, Silveri MM, Yurgelun-Todd DA. Neuropsychological consequences of opiate use. 
Neuropsychol Rev. 2007;17(3):299-315. doi: 10.1007/s11065-007-9041-y. PubMed PMID: 17690984. 
59.   
Attal N, Cruccu G, Haanpää M, Hansson P, Jensen TS, Nurmikko T, Sampaio C, Sindrup S, 
Wiffen P. EFNS guidelines on pharmacological treatment of neuropathic pain. European journal of 
neurology. 2006 Nov 1;13(11):1153-69. PMID: 17038030  
60. Dunlop K, Hanlon CA, Downar J. Noninvasive brain stimulation treatments for addiction and major 
depression. Annals of the New York Academy of Sciences. 2017 Apr 1;1394(1):31-54. 
61. Hanlon CA, Dowdle LT, Austelle CW, DeVries W, Mithoefer O, Badran BW, George MS. What goes 
up, can come down: Novel brain stimulation paradigms may attenuate craving and craving-related neural 
circuitry in substance dependent individuals. Brain research. 2015 Dec 2;1628:199-209. 
62. Hanlon CA, Dowdle LT, Correia B, Mithoefer O, Kearney-Ramos T, Lench D, Griffin M, Anton RF, 
George MS. Left frontal pole theta burst stimulation decreases orbitofrontal and insula activity in cocaine 
users and alcohol users. Drug and Alcohol Dependence. 2017 May 30. 
63. Hanlon CA, Kearney-Ramos T, Dowdle LT, Hamilton S, DeVries W, Mithoefer O, Austelle C, Lench 
DH, Correia B, Canterberry M, Smith JP. Developing Repetitive Transcranial Magnetic Stimulation 
(rTMS) as a Treatment Tool for Cocaine Use Disorder: a Series of Six Translational Studies. Current 
Behavioral Neuroscience Reports. 2017:1-2. 
64. Chistyakov AV, Rubicsek O, Kaplan B, Zaaroor M, Klein E. Safety, tolerability and preliminary 
evidence for antidepressant efficacy of theta-burst transcranial magnetic stimulation in patients with major 
depression. International Journal of Neuropsychopharmacology. 2010 Apr 1;13(3):387-93.