The Effect of Dorsolateral Prefrontal Cortex Theta Burst Stimulation on Alcohol Cue Reactivity and Cognitive Control: a Double-blind, Sham Controlled Study of Heavy Alcohol Drinkers With a History of Alcohol Related Injury.
Phase: NA
Conditions: Alcohol Drinking, Alcohol Use Disorder, Trauma Injury, Alcohol Dependence, Alcohol Abuse
Sponsor: Wake Forest University Health Sciences

 
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Official Title: The Effect of Dorsolateral Prefrontal Cortex Theta Burst Stimulation on Alcohol Cue 
Reactivity and Cognitive Control: a Double-blind, Sham Controlled Study of Heavy Alcohol Drinkers 
With a History of Alcohol Related Injury. 
 
NCT04223154 
 
IRB-Approved Date:  8/25/20 
 
 

 
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Study Title: The effect of dorsolateral prefrontal cortex theta burst stimulation on alcohol cue reactivity 
and cognitive control: a double-blind, sham controlled study of heavy alcohol drinkers with a history of 
alcohol related injury. 
 
Principal Investigator, Co-investigator(s): Colleen Hanlon, PhD; Laura Veach, PhD 
 
Sponsor or funding source: Internal 
 
Background, Rationale and Context 
Background: Theta Burst Stimulation (TBS) is a patterned form of repetitive transcranial magnetic 
stimulation – a non-invasive technique which uses electromagnetic induction to discharge populations of 
neurons in the vicinity of the induced electrical field.  Although the exact electrophysiologic mechanism 
of TBS is not understood on a cellular level, the induced E-field is strong enough to reliably result in 
motor evoked potentials in a somatotopic manner. The focality of stimulation is related to the shape of the 
coil, wherein a typical figure-of-8 coil (as used in the proposed pilot project) affects approximately 10cm2 
of cortical surface and has a 1-2cm2 penetration depth (Deng et al 2010).   When this depolarizing current 
is strong enough however, it is possible to induce activity in monosynaptic targets of the neurons directly 
affected by the field.  In this manner, cortical pulses of TMS can be used to investigate frontal-striatal 
connectivity.  Although the 
effects of TBS on 
dopamine binding have not 
yet been assessed [Note: a 
project the PI would also 
like to do at Wake Forest 
in the near future], 
traditional fixed frequency 
10Hz stimulation to the 
left dLPFC appears to 
increase dopamine binding 
in the caudate (Strafella et 
al 2001), and dorsal medial 
PFC TMS increases 
dopamine binding in the 
cingulate and orbitofrontal 
cortex (Cho et al 2005).  In 
the first sham-controlled 
evaluation of single pulse 
TMS in the MRI scanner, 
we recently demonstrated 
that TMS pulses lead to a 
causal increase in BOLD 
signal specific to the 
caudate and the anterior cingulate cortex (Dowdle et al 2019).    
  
Intermittent TBS was FDA approved treatment for depression in 2018 – after an FDA-pivotal statement 
demonstrated that it was equipotent to traditional 10Hz stimulation which had been FDA-approved for 
over a decade (Blumberger et al 2018). For depression treatment it is now used in over 650 clinics in all 
50 states and covered by Medicare in 48 states (Centers for Medicare and Medicaid Services, Local 
Coverage Determinations). The evolving availability of clinical devices and trained staff represents a 
latent public health resource.   

 
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Application to AUD and Conceptual Model (Figure 1). Through this network of devices, evidence 
based TMS protocols for substance use disorders, including AUD, could be swiftly distributed to the 
public. Currently however, the alcohol research field lacks sufficient data to make a well-informed 
decision regarding the TMS strategy that is best suited for improving treatment outcomes. Developing a 
neural circuit based treatment tool for AUD is exciting and based in preclinical neuroscience 
research, the published data using TMS in AUD patients is highly variable.  As of January 2019, 
there were 12 studies published on the use of rTMS for alcohol addiction. The majority (9 of 12) have 
targeted the dLPFC, but have small sample sizes (less than 20 individuals) with limited sham-controls, 
and no neuroimaging biomarkers.   We have spent the last 7 years evaluating Strategy 1 – dampening 
alcohol craving and brain reactivity to alcohol cues among heavy alcohol drinkers at risk for AUD or 
relapse to alcohol use (Hanlon et al 2015, Kearney-Ramos, Lench et al 2018, Kearney-Ramos et at. 2018, 
Hanlon et al 2019).   These studies led to a formal double-blind sham-controlled clinical trial of mPFC 
cTBS in treatment-seeking alcohol users (NIAAA supported R01).  Unfortunately, however, this 
approach is associated with more pain at the stimulation site (forehead) which undermines its promise as a 
tool to be readily scaled to a larger population, and it is not clear that this improves the attentional bias 
towards alcohol cues among these individuals. Our goal is to try to advance this field by evaluating iTBS 
to the dLPFC as a novel, potent form of brain stimulation which may be able to attenuate limbic reactivity 
to alcohol cues, improve cognitive control in the presence of an alcohol cue, and be less painful than 
cTBS delivered to the vmPFC. 
 
Objectives 
Alcohol Use Disorder (AUD) is prevalent, devastating, and difficult to treat. The intransigence of AUD is 
readily apparent in the Trauma Unit of Wake Forest University Baptist Hospital, wherein 23% of trauma 
related admissions are associated with alcohol - higher than the national average of 16% (Nunn et al 
2016). Of these trauma related admissions, over 70% are estimated to have AUD and 41% will be likely 
be admitted to the trauma unit again within 5 years (Nunn et al 2016). While Dr. Veach (Co-I) and her 
team in the Department of Surgery have demonstrated that a brief counseling intervention on the inpatient 
trauma unit can decrease morbidity and recidivism (Veach et al 2018), the rates of AUD and relapse to 
drinking among these individuals remains very high (Veach et al 2000). With a growing knowledge of the 
neural circuits that contribute to relapse in AUD, there is an emerging interest in developing a novel, 
neural-circuit specific therapeutic tool to enhance AUD treatment outcomes. The long term goal of our 
multidisciplinary research team (Hanlon & Veach) is to develop an evidence-based brain stimulation 
treatment which can ultimately be prescribed to individuals that present to the Trauma Unit with AUD – 
decreasing their drinking and hospital recidivism (Future R01 topic).   
  
The competing neurobehavioral decision systems (CNDS) theory posits that in addiction, choice results 
from a regulatory imbalance between two decision-making systems (impulsive and executive). These 
behavioral systems are functionally linked to two functional connectivity networks which regulate the 
incentive salience of the alcohol cue (Salience Network) and cognitive flexibility required for a 
vulnerable individual to shift attention away from the alcohol cue (Central Executive Network) (Bickel et 
al 2016).  Modulating these competing neural circuits (e.g. either dampening the incentive salience 
associated with alcohol cues (Strategy 1) or amplifying cognitive control in the presence of a cue 
(Strategy 2) may render alcohol users less vulnerable to relapse (Figure 1). Over the past 7 years, Dr. 
Hanlon’s human brain stimulation research group has been focused on focused on Strategy 1 – 
dampening alcohol craving and brain reactivity to alcohol cues among heavy alcohol drinkers at risk for 
AUD or relapse to alcohol use (Hanlon et al 2015, Kearney-Ramos, Lench et al 2018, Kearney-Ramos et 
at. 2018, Hanlon et al 2019). These studies led to a formal double-blind sham-controlled clinical trial of 
mPFC cTBS in treatment-seeking alcohol users (NIAAA supported R01). Unfortunately, however, this 
approach is associated with more pain at the stimulation site (forehead) which undermines its promise as a 
tool to be readily scaled to a larger population, and it is not clear that this improves the attentional bias 
towards alcohol cues among these individuals. 

 
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Hence, the goal of this proposal is to evaluate Strategy 2 of the CNDS theory- increasing activity in 
executive control circuitry- as an innovative approach to dampening alcohol cue-reactivity (Aim 1) 
and improving cognitive control in the presence of an alcohol cue (Aim 2). This will be achieved 
through a double-blind, sham-controlled cohort study in 48 heavy alcohol drinkers with a history of 
alcohol-related injury. The brain reactivity to alcohol cues (Incentive Salience) and cognitive performance 
in the presence of an alcoholic beverage cue (Cognitive Control) will be measured immediately before 
and after participants receive real or sham intermittent theta burst stimulation (iTBS- a potentiating form 
of transcranial magnetic stimulation) to the dorsolateral prefrontal cortex (dLPFC iTBS).  iTBS is a high-
potency form of brain stimulation wherein two minutes of iTBS (600 pulses) leads to an increase in 
cortical excitability that lasts for approximately 30 minutes (Huang et al. 2005). In 2018, dLPFC iTBS 
was FDA-cleared as a treatment for major depressive disorder (wherein 30 sessions over 6 weeks lead to 
a sustained decrease in depressive symptoms for 6 months; Blumberger et al. 2018). In 2019, the first 2 
manuscripts were published demonstrating that iTBS decreases cue-reactivity to cocaine (Steele et al 
2019, Sanna et al 2019).  The goals of this pilot study are to quantify the acute effect of a single 
session of real or sham dLPFC iTBS on brain response to alcohol cues (Aim 1) and cognitive 
flexibility in the presence of an alcohol cue (Aim 2) among risky drinkers (“target engagement”).    
  
Aim 1: Evaluate the effect of dLPFC iTBS on alcohol cue-reactivity.  The blood-oxygen level 
dependent (BOLD) signal associated with exposure to alcohol cues will be measured before and after 
sham and real iTBS using a validated, patient-tailored alcohol/non-alcoholic beverage cue task.  
Hypothesis: cue-evoked functional connectivity in the dLPFC, ACC, amygdala, and ventral striatum will 
be attenuated after real but not sham iTBS. 
  
Aim 2: Evaluate the effect of dLPFC iTBS on cognitive performance in the presence of an alcohol 
cue.  Following the alcohol cue reactivity task all individuals will perform the well-known alcohol Stroop 
task (downloaded from the NIH toolbox) on a Tablet PC while a glass of the participant’s preferred 
alcoholic beverage (beer, wine, liquor) is placed within 5 feet of the participant (but out of arms length). 
This will occur before and after TBS. The participant will not be allowed to consume the drink. 
Hypothesis: Stroop accuracy and reaction time will be impaired at baseline, but this difference will be 
attenuated by real (but not sham) iTBS to the dLPFC (three way mixed model ANOVA, correcting for 
multiple comparisons).    
 
Methods and Measures 
 
Design 
Our primary goal is to determine the extent to which one session of dLPFC iTBS can attenuate 
limbic circuitry involved in alcohol cue-reactivity (Aim 1) and cognitive control in the presence 
of an alcohol cue (Aim 2) among heavy alcohol users with a history of risky drinking behavior.  
This will be tested in a cohort of 48 heavy alcohol users, recruited through the resources of the 
Wake Forest Trauma Unit Registry and from the community at large through advertisements. 
This double-blind, sham-controlled study will involve 1 Screening visit and 1 TBS/MRI Scanning 
Visits. At the scanning/stimulation visit, functional MRI data will be collected before and after 
exposure to a session of real or sham theta burst stimulation (Figure 1). TBS will be applied over 
the left dorsolateral prefrontal cortex (landmark based on EEG 10-20 system: F3). A series of 
clinical assessments of drinking behavior and other relevant psychosocial and demographic 
measurements will also be collected (Table 1). We will test the hypotheses that TBS over the 
dLPFC will attenuate the neural response to alcohol cues (Aim 1) and improve cognitive 
performance in the presence of an alcoholic beverage cue (Aim 2).  The results of these aims will 
be further evaluated in terms of their relationship to alcohol drinking severity and demographic 
factors. These data will be preliminary data for a subsequent R01 focused on the sustained effects 

 
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of multiple sessions of TBS as a tool to decrease drinking among individuals with AUD and 
lowering morbidity and hospital recidivism among these patients.  
 
Setting 
Interdisciplinary Research Team: The Principal Investigator, Dr. Colleen Hanlon is a professor in 
the Department of Cancer Biology leading a new human brain stimulation research group at 
Wake Forest. She has expertise in neuroscience, human neuroimaging and brain stimulation in 
substance dependent individuals. Dr. Laura Veach is an associate professor in the Department of 
Surgery wherein she leads a comprehensive screening and brief intervention research program 
designed to identify and decrease alcohol use among individuals that present to the Inpatient 
Trauma Unit.   
 
All study activities will take place at Wake Forest University of Health Sciences. 
 
Dr. Hanlon’s primary office and research laboratory is located in the Clinical Neuromodulation 
Laboratory in the Department of Cancer Biology at Biotech Place. Dr. Hanlon’s lab space will 
include a room dedicated for all research related activities including a space for screening 
participants and a space dedicated for TMS stimulation.  
 
The majority of the contents of this study, however, will take place at the MRI center located on 
Medical Center Boulevard on the main campus of Wake Forest Baptist Health. This will utilize 
the 3T scanner in the MRI center and will have an outfitted setup including a laptop computer and 
desk for participant interviewing, as well as a TMS device. 
 
Finally, recruitment efforts will come from associated clinics at Wake Forest University of Health 
Sciences, including the Department of Psychiatry and the Inpatient Trauma Unit. Collaborative 
efforts will be maximized in order to recruit subjects from the associated Wake Forest University 
Trauma Unit Registry and from the community at large.  
 
In response to COVID-19: During COVID-19, interactions with study subjects will take place 
through videoconferencing. Prior to any remote consent/screening videoconference visit, the 
participant will be sent a copy of the ICF via mail/email to sign while the virtual meeting is taking 
place. Once this is signed, the participant will mail/email this back to the study staff to sign 
before proceeding with any research related activities.  
 
Subjects selection criteria 
Forty eight heavy alcohol users between 21 and 70 years old will be recruited through the resources 
of the Trauma Registry and the Piedmont Triad area. Participants will be prescreened by phone for 
eligibility. Potentially eligible participants will be invited for an in-person screening visit where, after 
signing informed consent they will receive a detailed evaluation and urine toxicology screen for illicit 
drugs. Individuals that remain eligible will then undergo the Stimulation/Scanning (see below). 
 
Inclusion Criteria 
1. Ages 21-70. 
2. Alcohol use disorder identification test (AUDIT) score >7 or a clinician-determined risk 
score of Moderate to Severe on the Screening, Brief Intervention, and Referral to Treatment 
(SBIRT).  
3. Drink at least 15 standard sized alcohol beverage servings per week sometime in the past 
month or have had a blood alcohol level of 140+ on admission to the trauma unit following 
injury.  
 

 
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Exclusion Criteria 
1. Current use of prescription or illicit psychoactive drugs (except marijuana or nicotine) known 
to decrease seizure threshold by self-report in the last 30 days.  
2. Currently meets DSM-V criteria for substance use disorder for a substance other than alcohol, 
marijuana, or nicotine. 
3. Has current suicidal or homicidal ideation.  
4. Not currently in or at risk for withdrawal, as indicated by CIWA-Ar >5.  
5. History of seizures and/or seizure disorder(s).  
6. Females of childbearing potential who are pregnant (by urine HCG), planning to become 
pregnant, nursing, or who are not using a reliable form of birth control. 
7. Any other violation of MRI/TMS safety measures. 
8. Unable to read and understand questionnaires, assessments, and the informed consent. 
9. No presence of metal objects in the head/neck.  
10. History of traumatic brain injury resulting in hospitalization, loss of consciousness for more 
than 10 minutes, and/or having ever been informed he/she has an epidural, subdural, or 
subarachnoid hemorrhage. 
 
Sample Size 
To determine the minimum number of participants necessary we performed a power calculation 
for the experiment based on our prior (Kearney-Ramos et al 2018). Based on the mean and 
standard deviation of mPFC activity in that study, Aim 1 will require 22 participants in both the 
real iTBS group and the sham iTBS group (95% power using two sided p < 0.05 level of 
significance). Assuming some loss of functional MRI data to movement artifacts (10%) we are 
proposing to enroll 48 participants (24 per group (real vs sham; 16 women (33%), 32 men (66%) 
based on prevalence of AUD in the US population. Integrity of the sham-control. The integrity of 
the blind will be assessed at the end of each visit with a standardized questionnaire regularly used 
in clinical trials of rTMS treatments. The randomization scheme for the study will be developed 
and monitored by a biostatistician associated with the Comprehensive Cancer Center’s 
Biostatistical Shared Resource (to be named), and will be given to a member of the study team 
that has no contact with the participant. This person will set the MagVenture sham-controlled 
TMS system up before the PI, Co-I or research assistant enter the room with the patient. The data 
will be analyzed by the PI, Co-I and research assistant who will remain blinded until the end of 
the study.  
 
Based on recruitment history from similar intervention studies in these individuals at Wake Forest 
Baptist hospital we anticipate that we will be able to recruit 3-4 participants per month (12-16 
months = 48 participants). We have planned for 2 months of initial implementation and quality 
control assessment of the MRI scanning paradigm. Recruitment will commence in month 3 and 
likely continue through month 19. Data analysis (blinded) for Aim 1 (preprocessing, functional 
connectivity assessment) and Aim 2 (analysis of quality, rigor, and basic signal detection) will be 
ongoing. Months 20-24 will be spent performing final analyses, unblinding, preparing data for an 
R01 application and integrating outcomes with the clinical and preclinical projects within the 
WF-TARC in order to plan for future translational collaborations.    
 
Interventions and Interactions  
Visit 1. Informed Consent and Screening Assessments: All informed consent and Privacy procedures are 
done in accordance with Good Clinical Practice Guidelines and all study procedures will be approved by 
the Wake Forest Institutional Review Board before they are executed. Study personnel will review the 
consent and HIPAA documents with the participant and obtain a signature. Following this procedure 

 
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several assessments related to drug use history, past medical history will be administered at Visit 1. 
Several rating scales assessing alcohol use severity, craving, and past month drinking history will be 
administered at the screening visit and updated at each subsequent visit.   
  
As typically done in cue-induced craving studies for both Visit 1 and Visit 2, study personnel will ensure 
that craving levels are at or below baseline before the participant finishes the visit.   
  
Visit 2: Stimulation/Scanning Visit T1 MPRAGE: Participants will be scanned using a Siemens 3.0T 
Skyra (Siemens Medical, Erlangen, Germany) MRI scanner with a 32-channel head coil. High-resolution 
T1-weighted structural images will acquired using a magnetization prepared gradient echo (MPRAGE) 
sequence [TR/TE=1900ms/2.34ms; FOV=220mm; matrix=256x256 voxels; 192 slices; slice 
thickness=1.0mm with no gap; final resolution=1mm3 voxels]. This sequence will be acquired before and 
after TBS in order to maximize coregistration at each scanning session.    
 
 
 
Alcohol Cue-reactivity task: The alcohol cue reactivity task which has been used by our group in the past 
(Schacht et al 2013, Kearney-Ramos et al 2018) will be administered in the MRI scanner as a block 
design using E-Prime software (Psychology Software Tools, Inc.). The total task time was 12 mins and 
consisted of six 120second epochs. Each epoch includes alternating 24-second blocks of four task 
conditions: Alcohol Cue, Neutral Beverage Cue, Blur, and Rest. Respectively, these task conditions 
included images of alcohol-related stimuli customized for each group (e.g.  liquor bottle); neutral stimuli 
(e.g.  water bottle); blurred stimuli acting as visual controls matched by color and hue; and a fixation 
cross for alert rest periods. T2* multiband EPI Acquisition. Functional images will be acquired with a 
multislice multiband gradient-echo echo planar imaging (EPI) sequence [TR/TE=1200ms/35ms; 
FOV=192mm; matrix=64x64 voxels; 36 slices; slice thickness=3mm with no gap; final resolution=3mm3 
voxels]. Each functional run will consist of 656 time points. 
 
Cognitive Interference in the presence of an alcoholic beverage cue task: An abnormally high attentional 
biases towards alcohol‐associated cues have been observed in alcohol‐dependent patients and is related to 
poor treatment outcomes (review: Field & Cox 2008). This bias towards alcohol cues impairs an 
individual’s ability to withhold responding for alcohol, narrows their behavioral repertoire, and slows 
performance on cognitive tasks.  One of the most well-established tasks for measuring cognitive 
performance and interference is the Stroop Color-Word Naming Task.   During the Stroop task, 100 
words will be presented are presented on a computer screen in a serial manner. Participants are asked to 
name the color of each word presented while ignoring the meaning of the word itself. Error rates and 
reaction times are the primary dependent measures. Previous studies have shown that heavy alcohol users 

 
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drinkers respond more slowly after exposure to alcohol-related priming conditions (Cox et al 1999, Cox et 
al 2003). Consequently, after the fMRI alcohol cue reactivity task and before the Stroop task, a glass of 
the participant’s preferred alcoholic beverage (beer, wine, liquor) will be placed within 5 feet (but out of 
arm’s length) of the participant. It will remain there for the length of the task, but the participants will not 
be allowed to drink it and the beverage will be discarded at the end of the study visit.  This paradigm will 
be repeated before and after iTBS.   
 
iTBS administration with neuronavigation: For TBS targeting the 
Cartesian position of the coil (X,Y,Z) will be determined by standardized 
positions from the EEG 10-20 system: F3 will be used for the left dlPFC 
targeting. The angular position of the coil (pitch, yaw, roll) will be 
determined by the individual’s cortical geography beneath 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. During each 
TMS session, we will utilize a Brainsight Neuronavigation suite to ensure that the coil is placed in the 
same position at each session at that the participant’s head does not move away from the coil during 
stimulation. The procedures for motor threshold, performing cortical localization, standardized 
procedures, blinding, and training regimens for all staff, as well as safety are consistent with our prior 
publications. We will also publish a Standard Operating Procedure and video file as with any publications 
that arise from this project. The decision to utilize probabilistic as opposed to anatomical or functional 
MRI scans was made for consistency with our promising preliminary data. Additionally, targeting based 
on the 10-20 system is easily scalable in the clinic. Nonetheless, we will be examining the deviation of 
this target from those identified with individualized network parcellation, and the association to treatment 
outcome.   
 
For intermittent theta burst stimulation (iTBS), participants will receive stimulation over the left dLPFC  
(each train: 3 pulse bursts presented at 5Hz, 15 pulses/sec for 2 sec, 8 sec rest, 600 pulses/session; 110% 
RMT, MagPro; 30 min inter session interval) using a figure 8 coil (Coil Cool-B65 A/P). During each real 
and sham TBS session the amplifier output will be escalated (“ramping” in 5% increments over 30 
seconds) from 80% to 110% RMT to enhance tolerability. To further ensure feasibility for AUD 
participants, sessions will be made available on nights and weekends and all visits will be associated with 
compensation for travel/parking and time.  
 
ACTIVE SHAM system: The MagVenture MagPro system has an integrated active sham that passes 
current through two surface electrodes placed on the scalp. The electrodes are placed on the left frontalis 
muscle under the coil for both the real and sham stimulation sessions. To assess the integrity of the blind 
(active sham) a questionnaire will be given to both the patients and to the research staff to evaluate their 
opinion on whether they received real or sham, their level of confidence (Likert scale 1-10), and their 
rationale (text entry). Pooled accuracy from prior work in our collaborator’s laboratory was 47.6% 
suggesting that individuals were not aware of the stimulation being received.   
 
Drug Screens: At the scanning/stimulation visits (Visit 1 and 2) a multidrug urine panel will be given to 
all participants (Quickvue 5-panel urine drug screen, Quidel, San Diego, CA). Individuals with a positive 
urine drug screen for opiates, stimulants, or benzodiazepines will be rescheduled for another visit and no 
treatment will be given on that day. If they test positive for these substances at the rescheduled visit, they 
will then be excluded from the study.   
 

 
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Remuneration: Total compensation is up to $125 per participant. Individuals will receive $25 for the 
Screening and $100 for TBS/MRI Visit. Partial compensation will be given to individuals that complete a 
portion of the TBS/MRI Visit. Additionally, while complimentary parking is provided at the MRI Center, 
money is budgeted to provide bus passes or ridesharing service fees for participants in need of 
transportation.  
 
Payment will be made using a pre-paid debit card called Greenphire ClinCard. It works like a bank debit 
card. Participants will be given a debit card and each time they receive a payment for participation in this 
study, the money will be added to the card after each completed visit. 
 
The card may be used at any store that accepts MasterCard or cash can be removed at a bank machine. 
However, there may be fees drawn against the balance of the card for cash withdrawals (ATM use) and 
inactivity (no use for 6 months). Participants will be given the ClinCard Frequently Asked Questions 
information sheet that answers common questions about the debit card. Participants will also receive 
letters with additional information on how to use this card and who to call if there's any questions. 
 
The debit card system is administered by an outside company in conjunction with the Wake Forest Office 
of Clinical Research (OCR) who will distribute the cards in sealed envelopes to study staff prior to a 
participant’s screening visit. The company, Greenphire, will be given the participant's name and social 
security number. They will use this information only as part of the payment system. The information will 
not be used for any other purposes and will not be given or sold to any other company. Greenphire will 
not receive any information about the participant's health status or the study in which they are 
participating. 
 
Outcome Measure(s)/Analytical Plan 
Cognitive Interference in the presence of an alcohol beverage cue task: It is hypothesized that individuals 
will have slower color-naming responses for alcohol words compared to neutral words at baseline, but 
this effect size will be lower following real versus sham iTBS (mixed model analysis of variance, error 
rate and reaction time, before and after TBS, 2 groups: real iTBS and sham iTBS). 
 
Neuroimaging Preprocessing: MRI data will be preprocessed using SPM12 (Wellcome Department of 
Cognitive Neurology, London, UK) implemented in Matlab 7.14 (MathWorks, Inc., Natick, MA). MR 
Images will be first converted from DICOM format to 4D NIfTI files and motion corrected (Realign: 6 
parameter rigid-body realignment to first image in each timeseries using a least-squares approach). 
Normalization parameters, bias correction and anatomical tissue maps will be determined simultaneously, 
using the Segment toolbox. Individual anatomical images will be stripped of their skulls by masking the 
bias-corrected image with the combined tissue masks of grey matter, white matter, and CSF. The 
functional images derived from realignment will be coregistered, through the mean image, to the skull-
stripped anatomical image (Coregister: Estimate, using normalized mutual information).  
Coregistered images will be then normalized (Normalize: Write) to MNI template space with the 
nonlinear warps derived from the Segment tool. Finally, functional images will be masked (to remove the 
skull) and smoothed (8mm FWHM Gaussian kernel) to facilitate subsequent between-subject analysis. 
 
Generalized Psychophysiological Interaction (gPPI): gPPI will be used to investigate task-modulated 
patterns of functional connectivity (FC) during the alcohol cue reactivity task. Regions-of-interest (ROIs) 
comprising frontal-striatal circuitry as well as elements of the Saleince Network and Central Executive 
Network will be identified from the standard Automated Anatomical Labeling (AAL) Atlas. These 
included the vmPFC (AAL: left and right Frontal_Med_Orb), left caudate (AAL: Caudate_L), right 
caudate (AAL: Caudate_R), left putamen (AAL: Putamen_L), right putamen (AAL: Putamen_R), left 
insula (AAL: Insula_L), right insula (AAL: Insula_R), and anterior cingulate cortex (AAL: left and right 
Cingulum_Ant). These ROI masks will then be used in CONN Toolbox to extract ROI timecourses from 

 
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the fMRI data for subsequent gPPI computation. The Drug/Alcohol vs. Neutral contrast βs from the Pre- 
and Post-Real cTBS and Pre- and Post-Sham cTBS were entered into a twoway ANOVA and subsequent 
t-tests to determine the effect of treatment on changes in drug cue-evoked FC. More details on the 
analysis can be found in prior publications from our group (Kearney-Ramos et al 2018).   
 
Results will be analyzed initially using descriptive statistics. Comparison between groups will be done 
using chi square tests for proportions, and t-tests or ANOVA procedures for continuous variables.  
Regression analysis will be performed to identify independent outcome predictors. Other inferential 
statistical analysis will be conducted as appropriate. 
 
Relationship with the WF-TARC Goals:  
Alcohol dependence is a chronically progressing and relapsing disorder that is associated with harm for 
the users, their families, the communities, the justice system, and the health care system. Continued 
progression from casual use through high and dependent use is likely due to a combination of factors that 
contribute to uncontrolled drinking in the presence of an alcohol cue.  While several pharmacotherapies 
have been developed for alcoholism, for many individuals these approaches are not sufficient. 
Consequently, of the thousands of alcohol-related admissions to emergency departments and trauma units 
nationwide each year, most of whom are chronic heavy drinkers, up to 41% will return to the hospital 
again within 5 years. For these individuals, it may be necessary to take a more powerful and targeted 
treatment approach to break the strong, sensitized, and potentiated response that they have to alcohol-
related cues.    
 
Functional neuroimaging studies in alcoholics have demonstrated that cue-reactivity and craving is 
associated with elevated activity in a network of limbic regions including the mPFC, ACC, and ventral 
striatum, but that activity in these areas can be attenuated by ‘top-down’ cognitive control networks, such 
as the dorsolateral prefrontal cortex node of the Central Executive Network.  Despite a wealth of rodent 
and non-human primate literature demonstrating a causal link between activity in these cortical and 
subcortical brain regions and heavy alcohol consumption, there are no neural-circuit-based interventions 
available to treat drinking in our patients. Transcranial magnetic stimulation has some promise – 
especially theta burst stimulation which is a highly potent form of TMS- very little work has been done to 
apply this technique to heavy alcohol drinkers. These individuals, especially those that have engaged in 
risky drinking behavior that led to injury are very vulnerable to relapse, recidivism, and poor health 
outcomes overall.  Consistent with the translational research emphasis of the WFTARC and the theme of 
vulnerability throughout the Center projects, this pilot project seeks to evaluate the acute effects of iTBS 
to the dLPFC as a tool to decrease alcohol cue reactivity and increase cognitive performance in the 
presence of alcohol cues among heavy alcohol users at high risk for negative health consequences of 
drinking.    
  
Public Health Significance 
Repetitive TMS is already an FDA approved treatment for depression and is growing in clinical use and 
acceptance, with machines located throughout the US and emerging insurance reimbursement. Non-
invasive brain stimulation may prove to be a valuable adjuvant to behavioral and pharmacotherapy 
therapy for alcohol abuse as it is the only non-pharmacological non-invasive way we have to directly 
target the regions of the brain that are involved in craving and cognitive control over drinking.  Before 
moving forward with slow and expensive clinical trials however, it is important to have an understanding 
of the effects of a single session of TBS on alcohol cue reactivity (Aim 1) and cognitive control in the 
presence of alcohol cues – a situation that recovering alcoholics face every day as they navigate their 
communities and form social bonds with others who may engage in social drinking (Aim 2).  
 
Human Subjects Protection 
Risks to subjects: 

 
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Protocol date: 08/18/2020 
11 
The risks fall into four categories: risks associated with psychological assessment, risks associated with 
repetitive TMS, risks associated with MRI scanning, and risks associated with randomization and alcohol 
related cues.  
 
Risks of Psychiatric Interviewing (minimal risk): Some participants may get emotionally distraught 
when disclosing sensitive personal information. Some participants may feel anxiety about disclosing 
abundance use histories of alcohol and reporting some aspects of their demographics. 
 
Risks Associated with MRI Scanning (minimal risk): 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. In addition, 
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 proposed 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 IRB for healthy adults as well as individuals with opiate 
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 WFUHS 
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 extensive TMS training from the PI on 
the study 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 Wake 
Forest 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.  
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 

 
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Protocol date: 08/18/2020 
12 
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. Although the pain has not 
reported to be significant protocol-approved research study members will conduct a thorough TMS 
safety questionnaire. This questionnaire will be checked and updated throughout the course of the 
study. 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, and fragments from metallurgy) will be excluded 
from the study in order to minimize any discomfort and abnormal signal propagation. 
 
Risks regarding Randomization and Alcohol Related Cues: 
Given that participants will be exposed to alcoholic beverages, there may be an added risk of induced 
cravings. However, it should be noted that the alcohol cues that participants will be exposed to are not as 
powerful as the daily cues that participant’s encounter in their normal living environment. In addition, 
participants that will be randomized receive the placebo treatment may prove to be less effective than real 
study treatment(s) or other available treatments.  
 
Risks regarding Confidentiality:  
Despite efforts to maintain subjects’ anonymity and confidentiality, there is always some minimal risk of 
people other than the study investigators gaining access to your health information. Every effort will be 
made to ensure that your health information will be collected and stored in a manner that ensures the 
highest level of protection of confidentiality. 
 
Protocol for participants expressing suicidal ideation: All study team members performing the Becks 
Depression Inventory will have received online training from the Suicide Prevention Resource Center 
(https://training.sprc.org). Completion documentation will be saved on the laboratory drive. In the event 
that a participant expresses a desire to kill themselves (selects answer #2 or #3 on question #9 of the 
Becks Depression Inventory), the trained study team member will ask them about the level of detail of 
their thoughts.  If the participant has a suicide plan to kill himself/herself, the study staff will recommend 
he/she speaks with the suicide hotline and initiate contact with the suicide prevention hotline (Cardinal 
Innovations at 1-800-939-5911) while the individual is in their presence. If the participant refuses to talk 
to the hotline and leaves, the study staff will call 911. A member of the study team will initiate contact 
with a local, licensed clinician while the individual is in their presence. If the licensed clinician deems 
necessary, they will dispatch a mobile crisis unit to the location to further assess and transport the 
participant to the hospital for a full mental health assessment and involuntary 72-hour hold, if needed. The 
study staff member will also contact the PI via phone, email, or text as soon as possible to inform them of 
the situation. 
 
Subject Recruitment Methods 
Participants will be identified and recruited through members of the study team and the trained counselors 
and staff of the Wake Forest Department of Surgery’s inpatient trauma unit in an appropriate manner with 
particular sensitivity surrounding their admission and PHI. If the potential participant is interest, they will 
screened and consented during their admission, serving as Visit 1. Additionally, heavy alcohol users with 
a history of risky drinking behavior will be recruited through the resources of the Wake Forest Trauma 
Unit Registry and community advertising. The MRI scans and TMS sessions during Visit 2 will both be 
performed at the MRI center on the WFUBMC main hospital campus. The study team will try to 
coordinate study visits on the same day as outpatient clinic follow up in Janeway Tower from their recent 
inpatient admission, as to make it easier on the participant. A meal voucher of $10 will be provided for 
the participant to eat in the hospital cafeteria, should they so choose. 
 

 
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13 
Additionally, 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 WFU 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. 
 
Informed consent will be reviewed with the potential participant by a member of the key personnel on this 
visit.  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. The 
consent and HIPAA process will be done in Dr. Hanlon’s research laboratory and facility.   
 
Informed Consent 
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 in a private, quiet screening room in the Clinical Neuromodulation Laboratory 
space in Dr. Hanlon’s research 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. 
 
Confidentiality and Privacy 
Confidentiality will be protected by collecting only information needed to assess study outcomes, 
minimizing to the fullest extent possible the collection of any information that could directly identify 
subjects, and maintaining all study information in a secure manner.  To help ensure subject privacy and 
confidentiality, only a unique study identifier will appear on the data collection form.  Any collected 
patient identifying information corresponding to the unique study identifier will be maintained on a 
linkage file, store separately from the data.  The linkage file will be kept secure, with access limited to 
designated study personnel.  Following data collection subject identifying information will be destroyed 
three years after closure of the study, consistent with data validation and study design, producing an 
anonymous analytical data set.  Data access will be limited to study staff.  Data and records will be kept 
locked and secured, with any computer data password protected.  No reference to any individual 
participant will appear in reports, presentations, or publications that may arise from the study. 
  
Data and Safety Monitoring 
The principal investigator will be responsible for the overall monitoring of the data and safety of study 
participants. The principal investigator will be assisted by other members of the study staff. 
 
Data and Safety Monitoring 
The principal investigator (PI) will be the primary party responsible for data management, oversight, and 
accountability in terms of participant safety and consent. Quality control will include regular data 
verification (Integrity of the Consent and HIPAA, scores on assessments), study progress, subject status, 
adverse events, and protocol deviations. Protocol adherence will be monitored by the Wake Forest IRB, 
who will also be given access to the reports from the PI to the ME. 
 
 
 
 
 

 
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Protocol date: 08/18/2020 
14 
Plans for Interim Analysis of Efficacy Data: Data from this study will be analyzed when a 50% 
recruitment goal is obtained. Final analysis will occur when all TMS visits have been completed. 
 
Responsibility for Data and Safety Monitoring: The PI and protocol-approved research team are all 
responsible for data and safety monitoring. The PI will be most involved in data and safety oversight. The 
PI will discuss data integrity and inquire about safety/patient tolerance in weekly meetings with the 
research team.  
 
Data Entry Methods: Data will be collected using REDCap™, which is a secure web application for 
building and managing online surveys and databases. REDcap™ supports online or offline data capture 
for research studies and operations. Participants and protocol-approved study personnel will enter data 
directly into the online portal to ensure security and prevent data loss.  
 
Data Analysis Plan: Data for this study (behavioral assessments) will be acquired by protocol-approved 
members of the research team, including graduate students and research specialists. These individuals will 
also perform data management and analysis under the guidance of the PI. Manuscript composition will be 
led by the PI and Co-Is, with the assistance of the research team.   
 
Quality Assurance Plan: Weekly meetings will be held between the PIs and research team to discuss 
any data-related problems as well as qualitative comments received during data collection. Initial data 
analyses will examine distributions of variable scores, and comparability of baseline characteristics across 
conditions, any necessary adjustments to analyses will be made. Confidentiality protections are outlined 
below.  
 
Statistical review of the study will be conducted annually by a Wake Forest biostatistician (including 
enrollment, retention, assessment inventories).  
 
Definition and Reporting of AEs/SAEs to the IRB/NIH: An adverse event (AE) is defined as any 
untoward medical occurrence in a study subject who was administered rTMS but 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 AEs will be reported to the Wake Forest Institutional Review Board (IRB) and Committee 
on Human Research within 48-business hours. Serious AEs will also 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 AEs and obtain all 
available information to assess severity, seriousness, study relatedness, expectedness, outcome, and the 
need for change or discontinuation in the study intervention. AEs are documented on AE Logs and AE 
Case Report Forms. Additional relevant AE information, if available, will be documented in a progress 
note and stored in the research record as appropriate to allow monitoring and further evaluation. 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 Wake Forest IRB online per the IRB’s guidelines.   
 
Collection and Reporting of AEs and SAEs: As mentioned above, all AEs/SAEs are documented and 
reported as per IRB requirements. Research staff will identify AEs, verify event with the participant, and 

 
Protocol version: 4.0 
Protocol date: 08/18/2020 
15 
obtain all available information to assess severity, seriousness, study relatedness, expectedness, outcome, 
and the need for change or discontinuation in the study intervention. AEs are documented on AE Logs 
and AE Case Report Forms. Additional relevant AE information, if available, will be documented in a 
progress note and stored in the research record as appropriate to allow monitoring and further evaluation. 
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. If applicable, copies of medical records and injury reports will be retrieved and safely stored in the 
subjects file. De-identified copies of reports will be sent to the Wake Forest IRB and ME/DSBM. 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.  
 
Reporting of Unanticipated Problems, Adverse Events or Deviations: Any unanticipated problems, 
serious, and/or unexpected AEs, deviations or protocol changes will be reported within 24-72 business 
hours, depending on severity, by the principal investigator or designated member of the research team to 
the Wake Forest IRB, ME/DSMB and to the sponsor, NIH. 
 
Management of SAEs or Other Study Risks: As described above, SAEs will be immediately reported, 
within 24 business hours, to the ME/DSBM, sponsor and Wake Forest IRB. For each SAE recorded, the 
research staff will follow the SAE until resolution, stabilization, or until the participant is no longer in the 
study as stated in the protocol. If applicable, copies of medical records and injury reports will be retrieved 
and safely stored in the subjects file. De-identified copies of reports will be sent to the Wake Forest IRB, 
ME/DSBM, and NIH. 
 
Reporting of IRB Actions and ME/DSMB Reports to NIH: Any IRB actions and ME/DSMB reports 
will be reported to both the Wake Forest IRB and the NIH Institute supporting the study following the 
sponsor’s report submission guidelines, should this study be awarded.  
 
Report of Changes or Amendments to the Protocol: Any changes to the proposal/protocol must be 
approved by the NIH Institute supporting the study. Any amendments to the IRB protocol associated with 
the proposed work will be reported to NIH should this proposal be awarded funding.  
 
Trial Stopping Rules: The protocol will immediately be paused following notification of a SAE. Per 
IRB policy, the IRB and ME/DSMB will be notified within 24 business hours following the SAE 
notification. SAEs will be reported to NIH 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 business hours. Of note, according to the literature associated with the MagVenture device, 
there have been no clinical trials stopped or SAEs reported.   
 
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 proposed study is manufactured by 
MagVenture. 
 
 
 
Reporting of Unanticipated Problems, Adverse Events or Deviations 
Any unanticipated problems, serious and unexpected adverse events, deviations or protocol changes 
will be promptly reported by the principal investigator or designated member of the research team to 
the IRB. 
 
 
 

 
Protocol version: 4.0 
Protocol date: 08/18/2020 
16 
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OMB No. 0925-0001 and 0925-0002 (Rev. 09/17 Approved Through 03/31/2020)