Identifying Electrophysiological Targets for Transcranial Magnetic Stimulation in Cocaine Use Disorder
Phase: NA
Conditions: Cocaine Use Disorder
Sponsor: The University of Texas Health Science Center, Houston

IRB NUMBER: HSC-MS-21-0813 
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Identifying Electrophysiological Targets for Transcranial Magnetic Stimulation in Cocaine Use 
Disorder 
 
NCT05631548 
 
Version Date: 09/11/2023 
 
This protocol describes both a pilot study and a main trial, which are registered as two separate 
records. Refer to pages 5-8 and 11,12 for the pilot study registered as ClinicalTrials.gov record 
NCT05631548. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol Title: 
Identifying Electrophysiological Targets for Transcranial Magnetic Stimulation 
in Cocaine Use Disorder 
 
Principal Investigator: 
Dr. Heather Webber 
 
Co-Investigators: 
Dr. Joy Schmitz, Dr. Scott Lane, Dr. Robert Suchting, Dr. Joao de Quevedo, Dr. 
Michael Weaver 
Study Coordinator: 
Jessica Vincent 
 
Population: 
Pilot Study: N = 5 participants with cocaine use disorder 
Main Trial: N = 75 participants 
 
Number of Sites: 
Single site 
 
Study Duration: 
Pilot Study: 1 year 
Main Trial: 5 years 
 
Subject Duration: 
Pilot Study: 3-4 days 
Main Trial: 5 days 
 
Project Summary 
 
Cocaine addiction is an often unremitting condition that leads to negative health outcomes1. Poor treatment 
responsivity may reflect measurable cocaine-induced brain changes, such as alterations in the dopamine reward system 
and hypoactivation of the prefrontal cortex2. Despite well-known effects of chronic cocaine use, treating deficits in 
dopamine functioning with pharmacological agents has been largely unsuccessful. There are currently no FDA-approved 
medications for the treatment of cocaine use disorder (CUD). Transcranial magnetic stimulation (TMS) is an approved 
treatment for several psychiatric disorders. Recent research shows promise for the use of TMS for CUD3,4. 
Despite considerable promise, there are addressable issues for optimizing treatment with TMS. The first issue 
has to do with stimulation sites. In accordance with the depression literature, the majority of rTMS studies have 
stimulated dlPFC to rectify the prefrontal hypoactivation commonly observed in addiction. Other prefrontal structures 
involving emotional and reward functioning are also potential sites for TMS5, including dorsomedial PFC (dmPFC) and its 
connections to anterior cingulate cortex (ACC). dmPFC is a promising target for TMS, as cocaine users show reduced 
dmPFC and ACC activity in response to pleasant emotional images/monetary outcomes6–8, and reduced functional 
connectivity of mesocorticolimbic circuits9. A second issue involves identifying relevant biomarkers for TMS effects. Two 
event-related potential (ERP) components that are sensitive to treatment change (RewP and LPP)10,11 and capture 
reward/emotional processing could potentially serve as biomarkers for assessing the effects of iTBS relative to sham. 
Measuring both RewP and LPP will provide critical information on whether TMS alters overall reward functioning or a 
bias toward drug rewards compared to non-drug rewards. We propose to conduct the first study that assesses the 
effects of iTBS to the dmPFC on physiological measures of reward functioning. This pilot study is aimed at establishing 
feasibility for a larger clinical trial. Recruitment of participants for the larger main trial will begin upon receiving NIH 
grant funds (application currently under review) and will specifically compare iTBS to the dlPFC and dmPFC to sham (no 
stimulation). 
 
Background Information 
 
Cocaine use disorder (CUD) is a significant public health problem for which treatments are only moderately 
effective. 
Chronic use of psychostimulants leads to changes in neural circuitry, including the dopamine reward system2. 
These changes in neural function are in part responsible for the hallmark features of stimulant addiction: increased 

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sensitivity to drug cues due to sensitization12, reduced executive functioning due to reduced prefrontal activity13, and 
withdrawal-induced reduced sensitivity to natural rewards due to hypodopaminergic tone14. Despite these well-known 
effects of stimulant use, treating deficits in reward functioning have largely failed. There are no FDA-approved 
medications for the treatment of CUD. Alternative approaches that directly target neural circuits may hold promise for 
treating CUD-related deficits. 
 
Transcranial Magnetic Stimulation (TMS) is a promising treatment for CUD. 
TMS is an approved treatment for depression, obsessive compulsive disorder, and nicotine use15,16. Clinical 
research has also shown promising results for the use of rTMS (repetitive TMS) in the treatment of CUD3. It is well 
known that cocaine addiction is associated with changes in prefrontal (e.g., dorsolateral prefrontal cortex [dlPFC], 
orbitofrontal cortex, and anterior cingulate cortex[ACC])5,17–19 functions including executive and emotional control, 
inhibition, decision-making, and processing of motivationally salient stimuli13. As a result, the majority of TMS studies 
aim to increase the activity of the prefrontal cortex by applying excitatory stimulation to the left dlPFC. Anatomically, 
stimulation of pyramidal neurons in dlPFC could also rectify changes in reward system networks observed with chronic 
use of drugs, as it projects to midbrain dopamine cells within the ventral tegmental area and substantia nigra. The 
hypothesized result would be an increase in dopamine within the nucleus accumbens20. 
Preliminary evidence in humans supports this hypothesis. Multiple sessions of active rTMS of 5-15 Hz to dlPFC 
appear to reduce self-reported craving, cocaine positive urines, and other unwanted symptoms3,4,21–27. In addition to 
traditional 10/15Hz rTMS, intermittent theta burst stimulation (iTBS) has also shown early success in lowering cocaine 
use and craving. Importantly, iTBS protocols take about 3 minutes to complete compared to the 15 minutes it takes for a 
15Hz protocol and has similar clinical effectiveness for treatment of depression28. Steele et al. (2019) reported iTBS to 
left dlPFC reduced cocaine use and craving29, while Sanna et al. (2019) reported no differences in 15 Hz stimulation 
compared to iTBS to the bilateral PFC on cocaine use30. Taken together, iTBS to either area could be useful in treating 
CUD. 
TMS to dorsomedial PFC (dmPFC) is a potential therapeutic target for CUD. While dlPFC has been the 
conventional target for CUD based on the depression literature, recent studies have provided preliminary evidence that 
TMS to dmPFC could be beneficial in treating depressive symptoms31–33. Similar to depression, dmPFC is also implicated 
in reduced emotional and reward functioning in addiction. For example, functional connectivity in emotional and reward 
circuits are reduced in cocaine dependent individuals, including medial PFC with amygdala and dmPFC with 
hippocampus9. Similarly, fMRI response to pleasant images is reduced in the dmPFC in cocaine users compared to 
healthy controls7. More broadly, studies have shown that medial PFC and ACC are reduced in response to differences in 
monetary outcomes compared to controls6,8,34,35. Yet, no studies have directly compared dlPFC and dmPFC in a sham- 
controlled design for CUD. 
Electroencephalogram (EEG) is a relevant and useful biomarker of TMS effects on brain function. 
While some research has looked at the effects of TMS on neuroimaging measures36–41, thus far, the majority of 
TMS studies have focused on subjective measures of craving as the main outcomes. However, evidence suggests that 
subjective measures may not capture the substantial heterogeneity in risk for relapse3, especially in persons with 
substance use disorders, who may lack insight42. Despite longstanding debate in the literature, there is no accepted self- 
report measure of craving. Recognizing these limitations, researchers have turned to psychophysiological responses as 
an indirect measure of craving. 
The current proposal will utilize event-related potentials (ERPs) as objective biomarkers to assess the effects of 
TMS on overall reward sensitivity and cue reactivity, two main constructs associated with CUD treatment outcomes43,44. 
ERPs directly measure brain activity with excellent temporal precision and reliability45. ERP paradigms are well- 
researched and widely used, with published guidelines for best practices46. In our work leading up to this proposal, we 
have successfully integrated EEG measurements into the clinical trials research setting and have demonstrated how ERP 
components can be used to classify cocaine users based on risk for relapse47. The Reward positivity (RewP) and the late 
positive potential (LPP) are ERP components associated with reward and emotional processing and are ideal candidate 
biomarkers of treatment response. 
Reward sensitivity as a target in treating CUD with TMS. The RewP is an ERP component that occurs over the 
medial fronto-central electrodes ~250-350ms after reward feedback48 and is more positive to wins compared to losses. 
The RewP is thought to reflect a reward prediction error signal from midbrain dopamine neurons to the ACC48–55. 

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Research has linked dopamine with the generation of the RewP56–60, and thus, is theorized to be an indicator of overall 
reward sensitivity or anhedonia61,62. In fact, anhedonia has been shown to account for a significant amount of variance in 
predicting RewP amplitude in individuals with CUD63. Recent evidence suggests that the time-domain RewP effects are 
better described by decomposition into theta (3-7Hz) and delta (<3 Hz) activity using time frequency analysis64–66. Theta 
and delta activity may represent different aspects of reward feedback processing67–70, with theta indexing simple 
stimulus characteristics and delta capturing complex features such as expectancy and magnitude of reward66,71. 
Importantly, only delta-related activity is associated with depressive symptoms62, and thus, could be key in evaluating 
reward sensitivity in CUD. The RewP is sensitive to TMS manipulation72,73, is reliable48,74, and is known to change with 
treatment11,75, and thus, is well positioned to serve as a biomarker of change in reward sensitivity observed after TMS 
treatment. While prior studies demonstrated TMS effects on the RewP when stimulating dlPFC72,73, stimulation to dmPFC 
may be optimal given the connection between ACC and dmPFC76,77. 
Cue reactivity as a target in treating CUD with 
TMS. The LPP is an ERP component occurring over 
the centro-parietal electrodes (starting ~400ms post 
stimulus) that is larger to unpleasant and pleasant 
compared to neutral images78,79. The LPP is thought 
to be marker of motivated attention toward 
emotionally salient cues and cue reactivity80, as 
studies in drug users show that the LPP is enhanced 
in response to drug cues10,81–84 and is associated 
with craving84. The LPP is thought to arise from a 
complex network of brain areas, including the visual 
cortex, amygdala, prefrontal cortex, and insula85–87. 
Further, visual representations of rewarding stimuli 
are mediated by the dopamine system88 and thus, 
LPP could be altered by TMS manipulation via these 
networks. Importantly, the LPP changes with 
treatment and abstinence status89 and is altered by 
TMS over the PFC. In one study, prior to treatment 
cocaine users displayed a larger LPP response to 
drug compared to pleasant images, and this pattern 
flipped after treatment10. Therefore, the LPP may 
serve as a biomarker of cue reactivity change 
observed after TMS treatment. Specifically, measuring 
both RewP and LPP will provide critical information on whether TMS alters overall reward functioning or a bias toward 
drug rewards compared to non-drug rewards. It is unknown if stimulation to the dlPFC or dmPFC would be more 
effective in manipulating the LPP amplitude. fMRI studies of cue reactivity implicate dlPFC and dmPFC in the processing 
of drug cues in addiction90, so both stimulation sites should have an effect on LPP to drug/non-drug cues. 
Preliminary Data. The following preliminary studies indicate the feasibility of the trial and ability of the team to 
carry out the proposed research. Support for utilizing EEG to assess reward sensitivity and cue reactivity in CUD: We are 
currently completing a NIDA-funded F32 project (1F32DA048542) titled “Using event-related potentials to predict 
treatment outcomes in cocaine use disorder”. This project is utilizing identical EEG tasks to elicit the RewP and LPP at a 
baseline assessment before participants receive treatment of CUD. Fig 1 displays the LPP waveforms collected from this 
project on the Picture Viewing Task and the RewP waveforms from the Doors Task. Fig 1 shows variability in the LPP 
amplitude, suggesting that individuals with higher LPP at baseline may be more likely to benefit from TMS treatment 
compared to those with smaller LPPs (i.e., they have more room to reduce LPP response). Fig 1 also shows preliminary 
data collected from the Doors Task, showing a typical RewP response (more positive to wins, negative to losses). 
Together, these results highlight the feasibility of utilizing these ERP components to assess reward sensitivity and cue 
reactivity in CUD and the ability of the team to collect high quality and relevant EEG data in a clinical setting. 
 
Summary of Significance 

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The current study will provide critical preliminary data for a larger clinical trial that will test the effects of iTBS to 
the dlPFC and iTBS to the dmPFC compared to sham on both cocaine use and physiological measures of reward 
functioning. The pilot study will focus on assessing the effects of dmPFC alone, as prior studies have already indicated 
that iTBS to the dlPFC can alter EEG91,92. We hypothesize that reward sensitivity and cue reactivity, as measured by RewP 
and LPP, respectively, will demonstrate utility as biomarkers of TMS effects. There is an urgent need to improve 
treatments for CUD in the wake of recent trends indicating rising cocaine use and overdose deaths93. Research indicates 
that a decreased RewP to wins and increased LPP to cocaine cues are potential targetable physiological patterns for TMS 
manipulation. This proposal is significant because it will 1) establish feasibility of a novel stimulation site utilizing a 
biomarker approach and 2) lay the ground work for a future larger clinical trial comparing the novel site to a traditional 
site and sham. For the main study, we will compare the effects of dmPFC to dlPFC and sham. We hypothesize that 
dmPFC compared to dlPFC or sham will lead to greater changes in EEG measures of reward functioning (i.e., RewP and 
LPP). 
 
Aims and Hypotheses 
Pilot Study 
Specific Aim 1: To assess the effects of active iTBS to dmPFC on EEG measures of reward sensitivity and cue reactivity. 
Hypothesis 1a. Primary hypothesis: iTBS will increase the amplitude of the RewP and switch the drug>pleasant LPP bias 
to pleasant>drug compared to sham iTBS. 
 
Specific Aim 2: To assess the effects of active iTBS to dmPFC on cocaine craving in cocaine users. 
Hypothesis 2a: Primary hypothesis: iTBS to dmPFC compared to sham iTBS will reduce cocaine craving (Minnesota 
Cocaine Craving Scale) in cocaine users. 
 
Primary Outcome Measures 
 
1. Reward sensitivity as assessed by the Reward Positivity – the RewP is an EEG component that will be 
measured immediately before and immediately following iTBS sessions on the test day. 
2. Cue reactivity as assessed by the Late Positive Potential to drug vs. pleasant cues – the LPP is an EEG 
component that will be measured immediately before and immediately following iTBS sessions on the test days. 
 
Secondary Outcome Measures 
 
1. Craving – craving will be assessed immediately before and immediately following iTBS sessions on the test 
days. 
2. Pain – pain will be assessed via a Visual Analogue Scale (1-10) immediately before and immediately following 
iTBS sessions on the test days. 
3. Cognitive function – a brief assessment of cognitive function will be included immediately before and after 
the iTBS sessions on the test days. 
 
Main Trial 
 
AIM 1: Assess effects of iTBS to left dlPFC and dmPFC compared to sham on reward sensitivity. 
Primary Hypothesis 1a: Active iTBS relative to sham will increase the amplitude of the RewP/delta power to rewards 
compared to non-rewards. 
Exploratory Hypothesis 1b: iTBS to dmPFC will result in a greater increase in the RewP/delta power compared to dlPFC. 
 
AIM 2: Assess effects of iTBS to left dlPFC and dmPFC compared to sham on motivated attention. 
Primary Hypothesis 2a: Active iTBS relative to sham will switch the drug>pleasant LPP bias. 
Exploratory Hypothesis 2b: iTBS to dmPFC will result in a greater increase in LPP to pleasant images. 

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EXPLORATORY AIM 3: Identify individual differences in iTBS response with baseline characteristics. 
Exploratory Hypothesis 3a: We will explore CUD severity, impulsivity, and craving as predicters of iTBS effects. 
 
Primary Outcome Measures 
 
1. Reward sensitivity as assessed by the Reward Positivity – the RewP is an EEG component that will be 
measured immediately before and immediately following iTBS sessions on the test day. 
2. Cue reactivity as assessed by the Late Positive Potential to drug vs. pleasant cues – the LPP is an EEG 
component that will be measured immediately before and immediately following iTBS sessions on the test days. 
 
Secondary Outcome Measures 
 
1. Craving – craving via the Minnesota Cocaine Craving scale will be assessed immediately before and 
immediately following iTBS sessions on the test days. 
2. Pain – pain will be assessed via a Visual Analogue Scale (1-10) immediately before and immediately following 
iTBS sessions on the test days. 
3. Cognitive function – a brief assessment of cognitive function will be included immediately before and after 
the iTBS sessions on the test days. 
4. Behavioral reward learning – participants will complete the Pavlovian Go/No-Go task before and after iTBS 
sessions. 
5. Anhedonia – the Snaith Hamilton Pleasure Scale (SHAPS) will be collected before and after iTBS sessions. 
 
 
Study design 
Pilot Study 
Pilot Design. Five individuals will serve as pilot subjects to assess protocol feasibility prior to launching the main 
trial (currently under review at NIH). We will enroll five individuals with CUD. The pilot subjects will complete the 
screening intake through our currently approved protocol (HSC-MS-05-0322) and a two-day test session. Each 
participant will complete two test days: A) iTBS to dmPFC and B) sham iTBS. The order (dmPFC or sham) of test days will 
be counterbalanced and double-blind. Recruitment of additional 75 participants for the main trial will begin upon 
receiving NIH grant funds (application currently under review). 
Overall Research Strategy. Pilot participants (N = 5) with a primary CUD diagnosis will complete screening and 
baseline assessments prior to undergoing a two-day within-subjects pre-post EEG design. Participants will complete an 
EEG session, undergo the iTBS session (either dmPFC or sham), and then repeat the EEG session. The iTBS intervention 
will consist of 2 3-minute sessions with a 15-20-minute interval in between sessions. 
Participants, Recruitment, and Setting. The study will be conducted at the Center for Neurobehavioral Research 
on Addiction (CNRA), where Dr. Joy Schmitz has been running treatment and non-treatment studies for CUD for over 10 
years. The TMS portion of the study will be conducted in the Treatment Resistant Mood Disorders Clinic, where Dr. de 
Quevedo uses TMS to treat depression and mood disorders. Recruitment will follow typical CNRA protocols, including 
calls from protocol number HSC-MS-05-0322, and additionally distribute unique study flyers locally. Eligible participants 
will be between the ages of 18 and 65. Potential participants will attend an in-person intake over several days to 
determine eligibility based on the Structured Clinical Interview for DSM-5 (SCID)94, Colombia Suicide Severity Rating 
Scale (C-SSRS)95, Assault & Homicidal Danger Assessment Tool96, urine drug screening, breath alcohol testing, a urine 
pregnancy test, and a TMS safety screen. Eligibility criteria will be assessed through our CPHS approved “General 
Evaluation of Eligibility for Substance Abuse/Dependence Research” protocol (HSC-MS-05-0322) and will be conducted 
by licensed counselors and research assistants. Please see Table 1 for the Schedule of Assessments regarding the general 
evaluation protocol. Individuals meeting moderate or severe criteria for substances other than cocaine, cannabis, or 
nicotine will be excluded. Other exclusionary criteria are: unstable psychiatric disorder, medical conditions 

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contraindicated to TMS (e.g., medical implants, history of seizure or seizure disorder, medications lowering the seizure 
threshold, neurological conditions, moderate-to-severe heart disease), pregnancy, hairstyles incompatible with the EEG 
net, and head injury with loss of consciousness. See Protection of Human Subjects for a more detailed description of 
eligibility criteria. 
 
Table 1. Schedule of Assessments – Pilot Study 
General Evaluation to 
assess eligibility 
(1-2 days) 
Study Visits 
(2 days) 
Structured Clinical Interview for 
DSM-5 
X 
Urine drug screen 
(UDS)/breathalyzer 
X 
X 
Pregnancy test 
X 
X 
Colombia Suicide Severity Rating 
Scale/Assault & Homicidal 
Danger Assessment Tool 
X 
TMS Safety Screen 
X 
Timeline Follow Back 
X 
X 
Montreal Cognitive Assessment 
(MoCA)4 
X 
EEG Tasks1 
X 
iTBS2 
X 
Minnesota Cocaine Craving 
Scale 
X 
Snaith-Hamilton Pleasure Scale 
X 
Safety Measures3 
X 
Note. 1EEG tasks are collected before and after 2 sessions of iTBS – 3 
minutes of resting EEG data, the Picture Viewing Task, the Doors Task. 2iTBS 
– two sessions of iTBS, separated by 15-20 minutes rest. Either sham iTBS or 
iTBS to dmPFC. 3Safety Measures – hours of sleep, Cocaine Selective 
Severity Assessment (CSSA; withdrawal), and AE/SAE form will be collected 
prior to iTBS. AE/SAE form will be completed both before and after iTBS 
sessions. 4 MoCA performed prior to 1st iTBS session and after 2nd iTBS 
session. 
 
Payment and Compensation. Participants will be paid $35 for the screening/intake visits, plus compensation for 
parking/bus passes. Participants will receive $150 for each EEG/TMS evaluation days. 
Baseline Screening. Participants will receive a psychiatric evaluation during the first week including a complete 
psychiatric diagnosis using the Structured Clinical Interview for DSM-5 (SCID-5) administered by trained licensed 
professional counselors under the supervision of a licensed clinical psychologist. Screening will include urine sample for 
urinalysis testing for drugs of abuse and pregnancy. In addition to the general evaluation, participants will complete the 
TMS Adult Safety Screen per Keel et al97. Upon completion of this intake evaluation, eligible participants will be invited 
to participate in the study. 
TMS Session. The PI or a trained research assistant/nurse under the supervision of Dr. Joao de Quevedo, will 
perform the TMS at the Treatment-Resistant Mood Disorders Program at UTHealth, adjacent to the CNRA. TMS will be 

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will be collected using a 64-channel actiCAP 
delivered with a MagVenture Mag Pro R30 with the Cool-B70 A/P coil with active liquid cooling and active/sham sides 
(Farum, Denmark). A member of the CNRA not involved in the study will be the only person aware of the randomization 
results and will program the system to ensure double blinding.). For dmPFC, we will measure approximately 25% of the 
nasion-inion distance, or Talairah coordinates X 0 Y+60 Z+6032,98. The first session will begin with the acquisition of the 
resting motor threshold (rMT; lowest stimulus intensity that elicits a visible twitch on 50% of the trials) on the 
contralateral hand. iTBS (triplet 50 Hz bursts, repeated at 5 Hz, 2 sec on and 8 sec off; 600 pulses per session) will be 
delivered at 80% of the rMT and will last ~3 minutes, consistent with current EEG-iTBS single day protocols73,99. The 
intensity can be lowered if the participant cannot tolerate the stimulation. Each participant will receive 2 sessions with a 
15-20 minute interval between sessions100. Participants will complete the EEG protocol before the first iTBS session 
(baseline) and immediately following the two stimulation 
sessions. This will conclude participation for the 
pilot participants. 
EEG Protocol. During the tasks described below, EEG 
electrode cap, amplified with BrainAmp MR and digitized using 
Brain Vision Recorder (Brain Products, Munich). Before 
collection, impedances will be maintained below 50 k(OHM). 
The sampling rate will be 500 Hz and data will be filtered with 
.1 Hz high-pass and 100 Hz low-pass filters. Resting data will be 
collected for 3 minutes (90-seconds eyes open and 90-seconds 
eyes closed). After collection, data reduction will be performed 
with a combination of programs including Brain Vision Analyzer 
2, MATLAB (EEGLab; PCA Toolkit) and BESA. Both traditional 
windowed ERP (mean amplitude) and TFA approaches will be 
used to analyze the RewP. The LPP will be defined as the mean amplitude between 400-800ms post stimulus. 
Reward Sensitivity: The Doors Task59 will be used to elicit the RewP component, representing reward 
sensitivity47,60. The task is a guessing game, where participants guess which door contains a reward behind it. After 
selecting a door, the participants are notified if they found the prize by a green arrow pointing up or if they did not find 
the prize by a red arrow pointing down. Unknown to the participants, winning and losing outcomes are presented 50% 
of the time in a random order. The RewP is larger in response to rewards (wins) than non-rewards (losses). Self-reported 
anhedonia (Snaith Hamilton Pleasure Scale; SHAPS) will also be assessed as a secondary measure of reward sensitivity in 
addition to the RewP. 
Cue Reactivity: The Picture Viewing Task will be used to elicit the LPP, reflecting the motivational salience of a 
stimulus. During this task, participants are asked to view a slideshow of images including pleasant, unpleasant, neutral, 
and cocaine-related images61. Pleasant and unpleasant images elicit a more positive LPP amplitude than neutral 
images55. In cocaine users, the LPP is also larger to cocaine images compared to neutral images, similar to pleasant and 
unpleasant images 10,101. 
Other Measures. 
Cocaine Use. Urine samples will be collected at the study visit and tested for the cocaine metabolite, 
benzoylecgonine (BE). Samples containing ≥ 300 ng/ml of BE will be considered positive. Additionally, the Timeline 
Follow Back102 method will be used as a secondary self-reported measure of daily cocaine use in the month prior to 
participating in the study. These measures will be used to assess severity of cocaine use. 
Cocaine Craving. Cocaine craving will be measured using the Minnesota Cocaine Craving Scale (MCCS)103. The 
MCCS is a widely used and reliable self-report measure of craving for cocaine, with 3 subscales (craving intensity, 
frequency, duration) and will be assessed before and after the EEG session. 
Cognitive Function. The Montreal Cognitive Assessment (MoCA)104 assesses multiple cognitive domains including 
attention, concentration, executive functions, memory, language, visuospatial skills, abstraction, calculation, and 
orientation. The MoCA will be administered twice on each study session day, prior to the first iTBS session and after the 
second iTBS session. Alternative equivalent forms will be used for the pre- and post-tests. 
Safety outcomes. We will collect the following before the iTBS sessions: hours of sleep, UDS/TLFB, breathalyzer, 
the AE/SAE form, pain, and the Cocaine Selective Severity Assessment (CSSA – a measure of withdrawal). The AE/SAE 
form and pain will also be completed after the iTBS session. See Table 2 for the Study Visit Timeline. 
iTBS to dmPFC 

Table 2. Study Visit Timeline – Pilot Study 
Assessment 
Length of Time 
Details 
Assess safety: 
5-10 min 
UDS, TLFB, pregnancy, sleep, CSSA, C-SSRS, AE/SAE form 
Cognitive 
Assessment 
10 min 
MoCA 
Fit EEG cap: 
30 min 
Measure & place cap on head, gel electrodes 
Complete EEG 
Session 1: 
35 min 
Resting EEG, Doors Task, Picture Viewing Task 
Assess rMT: 
10 min 
Collect resting motor threshold 
iTBS Session 
1: 
3 min 
iTBS to dmPFC or sham iTBS 
Rest: 
15-20 min 
Sit quietly 
iTBS Session 2 
3 min 
iTBS to dmPFC or sham iTBS 
Assess safety: 
5-10 min 
AE/SAE form 
Cognitive 
Assessment 
10 min 
MoCA 
Complete EEG 
Session 2: 
35 min 
Resting EEG, Doors Task, Picture Viewing Task 
 
Main Trial 
 
Design. The proposed study will use a within-subjects cross over design as shown in Fig 2. Non-treatment-seeking adults 
with a primary CUD diagnosis (N = 75) will complete screening and baseline assessments prior to completing three 
separate iTBS days (sham, dlPFC iTBS, or dmPFC iTBS), order counterbalanced across participants. On each day, EEG will 
be collected before and after 3 iTBS successive sessions (15-minutes between sessions). Days will be spaced at least 24- 
hours apart and will be completed within 2 weeks. We will aim to consent 115 participants to achieve 75 completed. 
 
Setting and Participants. The study will be conducted at the Center for Neurobehavioral Research on Addiction (CNRA) 
in Houston, TX. Participants will be recruited through print, radio, and internet advertisements in the local media. 
Eligible participants will be non-treatment-seeking adults (ages 18-65) meeting DSM-5 criteria for current moderate-to- 
severe CUD. Potential participants will attend a multiday intake to determine eligibility based on a clinical interview 
(Structured Clinical Interview for DSM-5 (SCID)94, Columbia-Suicide Severity Rating Scale (C-SSRS)95, Assault and 
Homicidal Danger Assessment Tool105), urine drug screening, breath alcohol testing, urine pregnancy test, and TMS 
safety screen97. Individuals meeting moderate or severe criteria for substances other than cocaine, cannabis, or nicotine 
will be excluded. Other exclusionary criteria are: unstable psychiatric disorder, medical conditions or medications 
contraindicated to TMS (e.g., medical implants, history of seizure, see Protection of Human Subjects for a full list), 
pregnancy, impending incarceration, and inability to read or write. Day-of TMS session requirements will include: 
negative UDS for any substance other than cocaine and cannabis, 0% blood alcohol level, and > participants’ typical 
number of hours of sleep (Safety Outcomes). Appointments will be rescheduled if these criteria are not met. Participants 
will receive compensation for travel and study visits to promote retention, including $35 for the screening, escalating 
payments ($40/hour for 1st 
session, $45/hour for 2nd 
and $50/hour for 3rd) for 
completion of the EEG/iTBS 
sessions, and $10 per visit 
for parking. 
 
TMS protocol. The PI or a 
trained research 
assistant/nurse under the 
supervision of Dr. Joao de 
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Quevedo (Biosketch), will perform the TMS at the Treatment-Resistant Mood Disorders Program at UTHealth, adjacent 
to the CNRA. TMS will be delivered with a MagVenture Mag Pro R30 with the Cool-B70 A/P coil with active liquid cooling 
and active/sham sides (Farum, Denmark). A member of the CNRA not involved in the study will be the only person aware 
of the counterbalanced order and will program the system to ensure double blinding. For dlPFC, we will measure 
position F3, using probabilistic EEG placement. For dmPFC, we will measure approximately 25% of the nasion-inion 
distance, or Talairah coordinates X 0 Y+60 Z+6032,98. The first session will begin with the acquisition of the resting motor 
threshold (rMT; lowest stimulus intensity that elicits a visible twitch on 50% of the trials) on the contralateral hand. iTBS 
(triplet 50 Hz bursts, repeated at 5 Hz, 2 sec on and 8 sec off; 600 pulses per session) will be delivered at 110% of the 
rMT and will last ~3 minutes. The amplitude of the TMS can be lowered if the participant cannot tolerate the 
stimulation. The stimulation will start at a lower percentage and ramp up over time to acclimate participant to the 
feeling of stimulation. Each participant will receive 3 sessions per visit with a 15-20 minute interval between sessions to 
increase the likelihood of detecting acute effects100. Participants will complete the EEG protocol before the first iTBS 
session (baseline) and immediately following stimulation sessions (Table 1). 
 
Measures. 
Baseline Measures. Urine samples will be collected at each study visit and tested for the cocaine metabolite, 
benzoylecgonine (BE) and other drugs of abuse. Samples containing ≥ 300 ng/ml of BE will be considered positive. 
Additionally, self-reported substance use will be assessed using the Timeline Follow Back102 to assess cocaine use 
severity (number of days used in the past 30 days). Impulsivity will be measured with the Barratt Impulsiveness Scale 
(BIS-11)106. Cocaine craving (below) will also be measured at baseline. 
 
Table 3. Schedule of Activities by Visit (Order of Study Visit Number counterbalanced and 
randomized across participants) Main Trial 
Sham 
dmPFC1 
dlPFC2 
Study Visit 
Intake/Baseline 
1 
2 
3 
Screening Measures 
Informed Consent 
X 
SCID DSM-5 
X 
Addiction Severity Index 
X 
Drug History KMSK 
X 
TMS Safety Screen 
X 
Safety Measures 
Urine Pregnancy Test (UPT) 
X 
X 
X 
X 
Urine Drug Screen (UDS) 
X 
X 
X 
X 
Breathalyzer 
X 
X 
X 
X 
Vitals 
X 
X 
X 
X 
Concomitant Medications Tracking Log 
X 
X 
X 
X 
Columbia Suicidal Severity Rating Scale 
(C-SSRS) 
X 
X 
X 
X 
Danger Assessment Tool 
X 
X 
X 
X 
Cocaine Selective Severity Assessment 
(CSSA) 
X 
X 
X 
Hours of Sleep 
X 
X 
X 
TMS Side Effects Questionnaire* 
X 
X 
X 
Pain Visual Analogue Scale (VAS)* 
X 
X 
X 
Montreal Cognitive Assessment (MoCA)* 
X 
X 
X 
TMS 
Intermittent theta burst stimulation 3x with 
15-minute intervals in between 
X 
X 
X 
Study Manipulation Measures 
Blinding Question 
X 
X 
X 
Main Outcomes 
EEG (Doors Task & Picture Viewing 
X 
X 
X 

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Task)* 
Behavioral Reward (Pavlovian Go/No-Go)* 
X 
X 
X 
Other Measures/Outcomes 
Minnesota Cocaine Craving Scale 
(MCCS)* 
X 
X 
X 
X 
Snaith-Hamilton Anhedonia Scale 
(SHAPS)* 
X 
X 
X 
X 
Cocaine Use Timeline Follow Back (TLFB) 
X 
X 
X 
X 
Barratt Impulsiveness Scale (BIS-11) 
X 
PROMIS Sleep Disturbance/Impairment 
X 
X 
X 
Profile of Mood States (POMS) 
X 
X 
X 
Delay Task* 
X 
X 
X 
Cocaine Purchasing Task 
X 
1dorsolateral prefrontal cortex; 2dorsomedial prefrontal cortex; * measured before and after 
TMS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EEG Measures. During the tasks described below, EEG will be collected using a 64-channel actiCAP electrode cap, 
amplified with BrainAmp MR and digitized using Brain Vision Recorder (Brain Products, Munich). Impedances will be 
maintained below 50 k(OHM). The sampling rate will be 500 Hz and data will be filtered with .1 Hz high-pass and 100 Hz 
low-pass filters. Data reduction will be performed with Brain Vision Analyzer 2, MATLAB, and BESA. Both ERP (mean 
amplitude) and TFA approaches will be used to analyze the RewP. While the main hypotheses will look at delta power, 
we will also examine changes in other frequencies, including theta, in exploratory analyses. The LPP will be defined as 
the mean amplitude between 400-800ms post stimulus47,81 and a difference score (cocaine minus pleasant) will be used 
to assess LPP bias. 
 
Reward Sensitivity. The Doors Task59 will be used to elicit the RewP. Participants guess which door contains a reward 
behind it. After selecting a door, the participants are notified if they won by a green arrow pointing up or if they lost by a 
red arrow pointing down. Unknown to the participants, winning and losing outcomes are presented 50% of the time in a 
random order. Self-reported anhedonia (Snaith Hamilton Pleasure Scale; SHAPS) will also be assessed at each visit as a 
secondary measure of reward sensitivity. 
 
Cue Reactivity. The Picture Viewing Task will be used to elicit the LPP, reflecting the motivational salience of a stimulus. 
During this task, participants are asked to view a slideshow of images including pleasant, unpleasant, neutral, and 
cocaine-related images61. 
 
Cocaine Craving. Cocaine craving will be measured using the Minnesota Cocaine Craving Scale (MCCS)103. The MCCS is a 
widely used and reliable self-report measure of craving for cocaine. It will be assessed before and after each iTBS 
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Behavioral Reward Learning. Participants will complete a Pavlovian Go/No-Go task to assess Pavlovian influences on 
instrumental learning107–110. In the first “learning” phase, participants learn whether to press a button or withhold a 
response to receive a monetary reward or avoid a loss. In the second “transfer” phase, participants perform a forced 
choice task, where each of the predictive cues in the learning phase are paired with each other. Participants must select 
the “most rewarding” cue. 
 
Delay Discounting and Cocaine Demand. Both delay discounting and cocaine demand are measures that provide 
information about cost-benefit trade-offs and are often associated with substance use outcomes. Previous studies have 
shown that TMS might alter these principles111. The delay task will specifically measure delay discounting and will consist 
of 5 questions about whether the participant would hypothetically like to receive less money now or more money later 
112. The cocaine purchasing task will be used to assess how much cocaine the participant would be willing to use given 
incremental cost of cocaine113,114. 
 
Safety/Other outcomes. We will collect the following day-of measures before iTBS sessions: Profile of Mood States 
(POMS)115, hours of sleep, Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance 
(SD) and Sleep-Related Impairment (SRI) short forms116,117, UDS/TLFB, breathalyzer, withdrawal (Cocaine Selective 
Severity Assessment; CSSA118), and the TMS AE/SAE form. The TMS AE/SAE form will also be completed after iTBS 
sessions. The Montreal Cognitive Assessment (MoCA)104 will be used to assess for changes in cognition and will be 
administered before and after the 3 iTBS sessions. 
 
Analysis Plan 
Pilot Study 
Data Analytic Strategy. 
Statistical Modeling. Analyses will primarily rely on generalized linear modeling (GLM) with a random intercept for 
participant. This model may fit normally or non-normally distributed outcomes as needed (e.g., Binomial with logit link 
for dichotomous outcomes). Analyses will be performed in Mplus110 and R111 via packages lme4112, mediation113, rstan114, 
and brms115. Inferences and Assumptions. Bayesian inference will be used to directly evaluate the probability of the 
alternative hypothesis (i.e., that an effect of TMS exists). As a default, weakly informative priors will be used for all 
analyses (e.g., regression coefficients: b ~N[µ=0,σ2=10]; error/dispersion terms: ~Half-Normal[µ=0,σ2=10]) in order to 
emphasize the influence of the present data on posterior probabilities (PP). Sensitivity analyses will test a range of prior 
distributions to ascertain the degree to which analyses are robust to prior specifications119. Evaluation of posterior 
distributions will permit statements regarding the probability that effects of varying magnitudes exist, given the data. 
Bayesian models will be evaluated via PP threshold guidelines in the literature120,121 suggesting that PP = 75% to 90% 
indicates moderate evidence, PP = 91% to 96% indicates strong evidence, and PP = 97% or above indicates very strong to 
extreme evidence. Bayesian analyses calibrate probability in terms of the prior distribution and are less influenced by 
multiple comparisons due to observation of the Likelihood Principle122. However, additional analyses will employ 
regularization (e.g., “horseshoe” priors) with best practices suggested by the literature123–125 to maximize the robustness 
of any identified effects. Bayesian convergence and modeling assumptions will be evaluated by effective sample size, 
scale reduction factors ("rhat"), and posterior predictive checking. Violated assumptions will be addressed via model re- 
specification, variable transformation, robust estimation, stratification, and/or coefficient scaling where appropriate. 
 
Specific Analyses. Aim 1. iTBS to dmPFC compared to sham will increase the amplitude of the RewP and switch the 
drug>pleasant LPP bias to pleasant>drug. GLM will model RewP amplitude as a function of time (pre vs. post iTBS 
session) and location (dmPFC or sham). GLM will model LPP amplitude as a function of time (pre vs. post iTBS sessions), 
condition (i.e., image type [pleasant, unpleasant, cocaine, and neutral]), and location (dmPFC or sham). Aim 2. iTBS will 
reduce cocaine craving (Minnesota Cocaine Craving Scale). GLM will model craving as a function of time (pre vs. post 

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iTBS sessions) and location (dmPFC or sham). Non-Primary Measures. Secondary analyses will also model pain and MoCA 
scores as a function of time (pre vs. post iTBS sessions) and location (dmPFC or sham). 
 
Sample Size and Power Analysis. The current pilot study is focused on evaluating the feasibility of the current approach 
with respect to recruitment, retention, assessment procedures, and implementation. Although preliminary statistical 
analyses will evaluate the magnitude of any changes observed over time, these are not expected to provide a 
meaningful estimate that would generalize beyond the small sample observed here. By providing evidence for feasibility, 
the present study will inform a subsequent study with formal hypothesis testing. This approach to pilot studies119 is 
explicitly in line with current literature on trial design. 
 
Main Trial 
 
General Data Analytic Strategy 
Statistical Modeling. Analyses will rely on generalized linear modeling (GLM) with multilevel (GLMM) components 
where necessary to evaluate predictor-outcome relationships. These models may fit normally or non-normally 
distributed outcomes as needed (e.g., Binomial with logit link for dichotomous outcomes). GLMM may also account for 
correlated observations via inclusion of random effects (e.g., a level 2 intercept). Preliminary analyses will use GLM to 
evaluate relationships between baseline sample characteristics, predictors, and outcomes prior to formal hypothesis 
testing. Confounders are defined as any sample characteristics that demonstrate relationships with both the predictor 
and outcome in a given model120,121. Subsequent models will be tested with and without adjustment for each potential 
confounder; if resulting inferences are different, we will report both models; otherwise, we retain the simpler model. 
Moderation analyses will evaluate the potential influence of essential covariates and other baseline sample 
characteristics (including sex) by examining their higher-order interactions with model predictors. Analyses will be 
performed in R122 via packages lme4123, rstan124, and brms125. 
 
Probability and Inference. Following the statistical literature126, analyses will use dual frequentist and Bayesian 
inference. Frequentist results yield the probability of the data (or data more extreme), given the null hypothesis, while 
Bayesian results directly yield the probability of an alternative hypothesis127,128. As a default, weakly informative priors 
will be used for all Bayesian analyses (e.g., regression coefficients: b ~N[µ=0,σ2=10]; error/dispersion terms: ~Half- 
Normal[µ=0,σ2=10]) in order to emphasize the influence of the present data on posterior probabilities (PP). Sensitivity 
analyses will test a range of prior distributions to ascertain the degree to which analyses are robust to prior 
specifications129. Evaluation of posterior distributions will permit statements regarding the probability that effects of 
varying magnitudes exist, given the data. With respect to multiple comparisons, frequentist analyses will evaluate all a 
priori defined primary outcomes (listed by name in the Specific Analyses) at the α=0.05 (two-tailed) significance level 
and will employ false discovery rate (FDR) to control for Type I error across any exploratory or post hoc analyses. 
Bayesian models will be evaluated via PP threshold guidelines in the literature130,131 suggesting that PP = 75% to 90% 
indicates moderate evidence, PP = 91% to 96% indicates strong evidence, and PP > 97% indicates very strong/extreme 
evidence. Bayesian analyses calibrate probability in terms of the prior distribution and are less influenced by multiple 
comparisons due to observation of the Likelihood Principle132. However, additional analyses will employ regularization 
(e.g., “horseshoe” priors)133–135 to maximize the robustness of any identified effects. 
Modeling Assumptions. Evaluation of assumptions for frequentist models will use graphical evidence (e.g., residual 
plots) and formal statistical tests. Bayesian convergence and modeling assumptions will be evaluated by effective 
sample size, scale reduction factors ("rhat"), and posterior predictive checking. Violated assumptions will be addressed 
via model re-specification, variable transformation, robust estimation, stratification, and/or coefficient scaling where 
appropriate. Intention-to-treat (ITT) primary analyses will included all randomized participants; follow-up analyses may 
evaluate modified ITT samples should specific participants merit exclusion (e.g., randomized but never initiated the 
trial). A per protocol analysis will complement the primary ITT analysis as due diligence. Missing data patterns will be 
evaluated using Little's Test of Missing Completely at Random (MCAR)136 for continuous outcomes and the Park and Lee 
approach137 for discrete outcomes. Models will handle missingness via maximum likelihood, explicit modeling of 
missingness138, and/or imputation with sensitivity analyses to evaluate the robustness of findings. Each approach is 

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robust to ignorable missingness (i.e., missing completely at random and missing at random). Pattern-mixture modeling 
will be used to address identified non-ignorable missing data patterns139. 
 
Specific Analyses 
All statistical models (described below) will account for correlated observations via the best-fitting structure of random 
effects (i.e., lowest information criteria) found when fitting level-2 intercepts and/or slopes) for repeated measures 
(where necessary) and statistically control for potential confounders as defined above. Outcome variables will be 
modeled as difference scores to account for the pre/post design (i.e., post-iTBS minus pre-iTBS). 
Hypothesis 1a (Primary): Active iTBS relative to sham will increase the amplitude of the RewP/delta power to rewards 
compared to non-rewards. GLMM will model the change in amplitude of the RewP/delta power to rewards as a function 
of iTBS condition, with random effects to account for repeated measures. 
Hypothesis 1b (Exploratory): iTBS to dmPFC will result in a greater increase in the RewP/delta power compared to 
dlPFC. Follow-up testing of the model described above for Hypothesis 1a will evaluate pairwise comparisons between 
iTBS conditions. 
Hypothesis 2a (Primary): Active iTBS relative to sham will switch the drug>pleasant LPP bias. GLMM will model the 
change in LPP bias as a function of iTBS condition. 
Hypothesis 2b (Exploratory): iTBS to dmPFC will result in a greater increase in LPP bias (i.e., greater LPP to pleasant 
images compared to cocaine images). Follow-up testing of the model for Hypothesis 2a will evaluate pairwise 
comparisons between iTBS conditions. 
Hypothesis 3a (Exploratory): Analyses will explore baseline CUD severity, impulsivity, and craving as predicters of iTBS 
effects on EEG. GLMM will model EEG outcomes as a function of the interaction between iTBS condition and each 
named predictor (in separate models): baseline CUD severity, impulsivity, and craving, controlling for constituent main 
effects. 
Sample Size and Power Analysis 
The current proposal is powered with respect to the primary hypothesis in the study (Hypothesis 1a). G*Power v. 3.1.9.4 
provides calculations from the frequentist perspective via a within-factor repeated measures model, a simplified version 
of the GLMM described above. Assuming a correlation among repeated measures r = 0.50 and two-tailed α = 0.05, the 
current feasible sample size N = 75 provides 80% power to detect an effect size as small as Cohen’s f = 0.149 
(comparable to a small-to-moderate Cohen’s d = 0.30). These estimates also broadly apply to Hypothesis 2a. Bayesian 
analyses proposed above will then provide a complementary analysis of all models that yields probabilistic estimates for 
all model effects, even in the context of relatively smaller sample sizes140 (i.e., the available data for subgroup analyses 
or higher-complexity models). 
 
 
Protection of Human Subjects 
Inclusion Criteria: 
1. be between 18 and 65 years of age at the time of the first study visit (iTBS session day) 
2. meet DSM-5 criteria for current cocaine use disorder of at least moderate severity (≥ 4 symptoms) 
3. have at least 1 positive urine BE specimen (≥ 300 ng/mL) during intake 
4. be able to understand the consent form and provide written informed consent 
5. be able to provide the following verifiable information for a minimum of 2 contact persons: full legal name, 
email address, local mailing address, and as applicable, home, work, and cell phone numbers 
Exclusion criteria: 
1. current DSM-5 diagnosis for substance use disorder (of at least moderate severity) other than cocaine, 
marijuana, or nicotine 
2. in the opinion of the principal investigator (PI), the presence of any medical, neurological, psychiatric, or physical 
condition, disease, or illness that, may: (a) compromise interfere, limit, effect or reduce the subject’s ability to 
complete the study; or (b) adversely impact the safety of the subject or the integrity of the data 

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3. has current or recent (within 3 months of potential enrollment) suicidal ideation, suicidal behavior, homicidal 
ideation or a homicidal plan sufficient to raise subject safety concerns based on the following assessments 
according to the PI: 
a. SCID-5 
b. C-SSRS Screener – Answers YES to Questions 3, 4, 5, or 6 
c. Assault & Homicidal Danger Assessment Tool – Key to Danger > 1 
4. medical implants contraindicating TMS (i.e., aneurysm clips or coils, stents, implanted stimulators, implanted 
vagus nerve or deep brain stimulators, implanted electrical devices such as pacemakers or medication pumps, 
electrodes for monitoring brain activity, cochlear implants for hearing, any magnetic implants, bullet fragments, 
any other metal device or object implanted in your body closer than 30 cm from the coil) 
5. history of brain surgery 
6. history of an intracranial lesion or any medical or neurological diagnosis/condition associated with increased 
intracranial pressure (i.e., Idiopathic Intracranial Hypertension/Pseudotumor Cerebri) OR any of the following 
symptoms within 30 days of enrollment: headaches > 15 days/month, loss of vision or decreased vision 
7. moderate-to-severe heart disease 
8. history of stroke 
9. is taking any antidepressant or antipsychotic medication at a dose above the maximum recommended dose or 
at a dose deemed to be potentially unsafe according to the PI; has taken any of the following medications, which 
are known to increase the risk of seizures, within 1 week of study enrollment; or does not agree to abstain from 
taking the following medications during study participation: 
1. clozapine141 
2. chlorpromazine141 
3. bupropion 
4. clomipramine hydrochloride 
5. amoxapine 
6. maprotiline hydrochloride 
7. diphenhydramine 
8. stimulants other than cocaine including the following: 
a. Dextroamphetamine and amphetamine 
b. Dextroamphetamine 
c. Lisdexamfetamine dimesylate 
d. Methamphetamine 
e. Methylphenidate 
9. tramadol 
10. isoniazid 
10. having conditions of probation or parole requiring reports of drug use to officers of the court 
11. personal history of epilepsy or seizure disorder and/or family history including a first-degree relative 
12. serious head injury with loss of consciousness 
13. impending incarceration 
14. pregnant or nursing for female patients 
15. inability to read, write, or speak English 
16. for adolescent aged participants (18-21 only): any risk factor for neurocardiogenic syncope (history of syncope/ 
presyncope related to noxious stimuli, anxiety, micturition, or posture)? 
17. hair style that is incompatible with EEG nets 
 
Potential Risks 
 
TMS. There are several potential risks of TMS administration. The most serious risk is risk of seizure or prolonged seizure 
(convulsive status epilepticus [CSE]), although most seizures associated with TMS are self-limiting. Overall, the risk of 
seizures is very low with TMS (< 1%) and specifically iTBS (<.02%)142. The risk of seizures should be low for the 
participants that are eligible for this study, as conditions and medications that lower the seizure threshold will be 

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exclusionary. Hearing impairment can occur without protection; however, the risk of this is extremely low in this study, 
as proper hearing protection will be used. There is also a risk for manic switch or psychotic episode, especially in patients 
with bi-polar disorder. Individuals with bipolar disorder or schizophrenia/psychotic symptoms will not be included in the 
study. There are also risks associated with magnetic field effects on functioning of other medical devices, but individuals 
with any medical implant will be excluded from the study. While the risks associated with TMS in substance using 
populations is still being evaluated, there are now several studies showing safety of TMS for these 
populations3,24,25,27,29,30,40,143. There is also a risk that TMS can affect cognitive functioning, such as working memory and 
executive function. However, the current literature on iTBS specifically is suggestive of improvement of cognitive 
functioning with iTBS to the prefrontal cortex, rather than harm. A recent systematic review reported that 6/8 iTBS 
studies showed significant improvements in working memory and executive function144. There is also one study showing 
that iTBS to the prefrontal cortex improved both working memory and executive function in stimulant users145. Other 
more common but milder risks include discomfort at the stimulation site, headache and neck pain, tingling, spasms, or 
twitching of facial muscles, and lightheadedness during the actual administration of TMS. These side effects usually 
rapidly disappear after stimulation. Sometimes headaches can persist after the TMS session is over and can be treated 
with over-the-counter medications. 
Diagnostic Procedures. Items on certain questionnaires and interviews might be perceived as psychologically 
discomforting to some participants. While participants may be uncomfortable reporting these issues, the risks of serious 
sequelae are extremely low. There are also risks concerning loss of confidentiality. 
EEG Session. Participants in the EEG session may experience skin irritation from the placement of the sensors, which is 
usually minor and goes away after a few hours. The presentation of emotional images and drug images in the Picture 
Viewing Task (e.g., mutilations or violence) may cause an affective response, which typically subsides rapidly after image 
presentation. Participants are shown example images beforehand and agree to watch the slideshow. They can also ask 
for the slideshow to be stopped at any time. Participants may also feel tired or bored while participating in the EEG 
session. 
 
Adequacy of Protection against Risks 
 
TMS. Participants will be made aware of the risks of TMS administration. We will primarily protect against TMS risks by 
excluding individuals from the study who are at risk for seizure or manic/psychotic episodes. Additionally, safety 
measures will be taken at each visit by the PI, trained research assistant, or nurse, including the AE/SAE form. We will 
also measure hours of sleep and recent drug/alcohol use to assess day-of eligibility criteria. Our risk mitigation strategy 
regarding a seizure/CSE, includes the following: 1) staff/PI/physician education about the signs and symptoms focal 
seizure with or without awareness and generalized seizure, 2) in the rare event of a seizure, the staff will perform the 
following: a) stop TMS immediately, b) turn subject on their side to reduce chance of aspiration, c) protect the 
participant from falling or hitting their head or other injury, d) call 911, e) time the length of the seizure. In the event of 
a seizure, anti-seizure medication may be administered, at the discretion of the physician present. The CNRA outpatient 
clinic is situated on the south side of the Texas Medical Center, a 2.1 square mile medical district. There are several 
options for emergency rooms, all within 2 miles. The study physicians (Dr. de Quevedo and Michael Weaver) will be 
available via phone to address additional patient safety issues. Participants experiencing any severe side effects from the 
TMS administration will be referred to the study physician for examination and recommendations before continuation 
of the TMS administration. Participants experiencing the more common, milder side effects such as headache or neck 
pain, will be monitored and referred to the study physician if symptoms do not subside or improve with over-the- 
counter analgesic. In the unlikely event that the participant cannot tolerate the side effects (such as facial twitching), the 
intensity can be lowered to reduce these effects. 
Diagnostic Procedures. The potential risk of participant discomfort associated with collection of sensitive information 
will be described in the informed consent process. Further, while participants may be uncomfortable reporting these 
issues, the risks of serious sequelae are extremely low. Confidentiality will be protected in several ways. All information 
collected solely for research purpose will be kept in locked, restricted access files. Participant records will be coded and 
filed by a number code. Participant identities will not be revealed in any publication of the data. Individual participant 
information will be transferred to outside sources only with the express written request of the participant. Participants 
will receive a copy of their signed consent form. 

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EEG Session. Before applying the EEG net, we will show participants how it feels to have the blunted needle (which is 
used to inject gel into the sensors) come in contact with the skin. We will ask participants frequently if applying the 
sensors is bothering them and will stop at the request of the participant. The consent form details what types of images 
will be shown on the screen and they will be told that we can stop the experiment at any time if they no longer want to 
view the images. The participants are instructed to notify the experimenter of an adverse emotional reactions and if a 
participant experiences an adverse emotional reaction to the images, the task will be stopped immediately. The 
participant will meet with a study therapist before leaving the CNRA to make sure it is safe for them to leave. 
 
 
Potential Benefits of the Proposed Research to Participants 
 
There are no potential benefits to the individuals participating in this pilot portion of the study. All assessment and 
treatment services provided in the main trial of this study will be at no cost to the participant. Based on prior studies, 
the treatment may help in lowering cocaine use. Participants will be informed of any new information discovered during 
the study that might impact their treatment for CUD or other problems. 
 
 
Data and Safety Monitoring Plan 
Data Monitoring 
The data will be collected and stored as described in the research strategy and protection of human subjects, 
and will follow the typical protocols set in place by the Center for Neurobehavioral Research on Addiction (CNRA). The 
CNRA protocols include: 1) staff training, 2) weekly audit of data collection/entry by the CNRA Quality Assurance 
Manager, 3) medical screening with results reviewed by on-site physician, 4) use of standardized assessments, 5) 
collaboration with Dr. Suchting who oversees data analysis and management. All data entry forms will only be accessible 
to trained research staff and will require double entry. Dr. Webber will be responsible for ensuring the above-mentioned 
protocols are in place before and during the proposed study. 
 
Safety Monitoring 
 
The CNRA has a DSM Board set for all CNRA studies. The PI will be responsible for making the DSM Board aware 
of the new protocol upon study initiation and for yearly update meetings. The DSM Board members will consist of the 
following individuals: Jan Blalock, Ph.D., Dept. of Behavioral Science, MD Anderson Cancer Center; William E. Fann, M.D., 
Dept. of Psychiatry, Baylor College of Medicine; Claudia Pedroza, M.D., Dept. of Pediatrics, UTHealth; and Daryl Shorter, 
M.D., Dept. of Psychiatry, Baylor College of Medicine. These individuals have served previously on the DSMB at the 
CRNA and have the relevant expertise and experience in monitoring clinical trials. The members of the DSM Board will 
be responsible for: 1) reviewing the research protocol and plans for data and safety monitoring, 2) evaluating the study 
progress, including data quality, participant recruitment rates, retention rates, outcome and adverse experience data, 
and risk versus benefit profile, 3) making recommendations to terminate or make changes to the trial because of safety 
concerns, and 4) ensuring protect the confidentiality of the trial data and the results of monitoring. 
 
All Adverse events (AE) will be collected and reported to the PI on a daily basis. AEs are collected before and 
after the iTBS sessions on the study visit day. As most side effects are minor and disappear rapidly after iTBS 
administration, participants will be told to contact the study coordinator if side effects persist after treatment at home 
with over-the-counter analgesics. The study physician will be informed of any relevant AEs following TMS and will 
determine course of treatment or discontinuation of the study, if necessary. AEs will be reported to the CPHS on an 
annual basis. Serious adverse events (SAE) will be reported immediately (verbally within 24 hours) to the CPHS, DSMB, 
and to NIDA (if funded). A written report will follow within three days and will include: date of the AE, description of the 
AE, severity rating (Grade 1 to 4), assessment of cause, whether the AE indicates an increased risk for current or future 
participants, and whether changes to the informed consent form are necessary. 

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