Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study
Phase: NA
Conditions: Healthy Volunteer
Sponsor: National Institute on Drug Abuse (NIDA)

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 1 of 72 
 
 
Protocol Title: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot 
Study 
Abbreviated Title rTMS equipment testing and pilot  
Protocol Number 14-DA-N186 
Date of This Submission/Version: November 30, 2018/Version 7.0 
Principal Investigator: 
 
 
Medical Advisory Investigator: 
 
Associate Investigators: (list all) 
Name, Degree 
Branch/Institute 
Bldg/Rm 
Phone 
Email  
Thomas Ross, PhD 
NRB, NIDA-IRP 
BRC/07A719 
443-740-2645 
tross@mail.nih.gov  
Yihong Yang, PhD 
NRB, NIDA-IRP 
BRC/07A709 
443-740-2648 
yihongyang@mail.nih.gov  
Karen McCullough, MS 
OCD, NIDA-IRP 
BRC/01A231 
443-740-2363 
kmccullo@mail.nih.gov  
Betty Jo Salmeron, MD 
NRB, NIDA-IRP 
BRC/07A717 
443-740-2651 
bsalmeron@mail.nih.gov  
Elise Lesage, PhD 
Ghent University, Dept. 
of Experimental 
Psychology 
Henri Dunantlaan 
2, B-9000 Gent, 
Belgium 
+32 (0)9 264 
6432 
elise.lesage@ugent.be 
 
 
 
 
Elliot A. Stein, PhD 
NRB, NIDA-IRP 
BRC/ 07A711A 
443-740-2650 
estein@intra.nida.nih.gov  
Name, Degree 
Branch/Institute 
Bldg/Rm 
Phone 
Email  
Osama Abulseoud, MD
NRB, NIDA-IRP
BRC/07A705
443-740-2732
abulseoudoa@mail.nih.gov   

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 2 of 72 
 
Research Contact:     
Elliot A. Stein, PhD 
NRB, NIDA-IRP 
BRC/ 07A711A 
443-740-2650 
estein@intra.nida.nih.gov  
 
Total requested accrual: (separately specify planned accrual for each subject group)      
140 Healthy Volunteers  
 
(140 enrollees for 50 completers)  
Project Uses Ionizing Radiation:    No   Yes (attach RSC/RDRC documentation) 
 
 
 
Medically-indicated only 
 
 
 
Research-related only 
 
 
 
Both 
IND/IDE 
 
 
 
 No   
Yes (attach FDA documentation) 
 
 
Drug/Device/#__ __ 
 
 
Sponsor: __________________________ 
Durable Power of Attorney   
 No   
 Yes  
 
Multi-institutional Project  
 No   
 Yes  
 
 
 
 
 
 
Data and Safety Monitoring Board  
 No   
Yes  
 
Technology Transfer Agreement    No   
 Yes  
Agreement type and number __DTA____ Expiration Date____N/A_________ 
 
Samples are being stored   
 No   
 Yes  
Flesch-Kincaid reading level of consent form (s): __8.7___  
(exclude boilerplate in assessing reading level) 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 3 of 72 
 
 
Medical Coverage Level: 
 
TMS administration session(s): Level 3 - The MAI or covering clinician* must be present 
within the study building 
Other protocol hours (non-TMS days): Level 5 - The MAI is available by beeper or phone.  
*Kathy Lightfoot, PA-C is designated as covering clinician for this protocol. 
Level 1 - The MAI administers all drugs and remains physically present in the experimental 
room during all or part of study session as determined by the Clinical Director. 
Level 2 - The MAI must be physically present in the experimental room during all or part of 
study session as determined by the Clinical Director.  
Level 3 - The MAI must be present within the study building.  
Level 4 - The MAI must be on the study campus.  
Level 5 - The MAI is available by beeper or phone.  
 
 
 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 4 of 72 
 
I. Précis 
Objective: To establish an effective repetitive transcranial magnetic stimulation (rTMS) protocol 
for stimulating circuits relevant for addiction. Specifically, we will develop stimulation parameters 
and outcome measures for rTMS of the anterior cingulate cortex (ACC) with a specialized TMS 
coil: the HAC coil (Brainsway Ltd.). Various parameters of rTMS stimulation (frequency and 
intensity) will be varied, and the sensitivity of behavioral tasks and MRI measures to this 
stimulation will be determined. The objective of this protocol is therefore to allow for the 
development, assessment and refinement of rTMS parameters for stimulating ACC targets. In 
addition, outcome measures will be developed to capture the effects of this stimulation. Results 
from this development protocol will be applied to subsequent cognitive imaging protocols. 
 
Study population: Up to 50 healthy, non-smoking adults will be tested in several conditions over 
up to two weeks. Subjects must fit exclusion/inclusion criteria for TMS and MRI. We expect 140 
subjects to be enrolled to arrive at a number of 50 who complete the protocol. 
 
Design: Within-subject design with each subject completing up to 10 rTMS sessions. 
Outcome measures: In a first phase, the outcome measure will be the behavioral response on a task 
that relies on the ACC. In a second phase, outcome measures will be the effects on MR measures. 
These will include task-related blood oxygen level-dependent (BOLD) responses, as well as 
resting state BOLD fMRI. Other MR measures, such as magnetic resonance spectroscopy (MRS) 
and arterial spin labeling (ASL), will also be explored as potential biomarkers. 
 
 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 5 of 72 
 
II. Table of contents 
I. Précis ........................................................................................................................................... 4 
II. Table of contents ........................................................................................................................ 5 
III. Background ............................................................................................................................... 7 
A) 
The problem ..................................................................................................................... 7 
B) 
Transcranial magnetic stimulation (TMS) and therapeutic developments....................... 7 
C) 
The anterior cingulate cortex as a target for addiction ..................................................... 8 
D) 
The H-coil for “deep rTMS” ............................................................................................ 9 
E) 
Safety data on the H-coil .................................................................................................. 9 
F) 
An H-coil for anterior cingulate stimulation: the HAC coil ........................................... 12 
IV. Study Objectives ..................................................................................................................... 13 
V. Study Design and Methods ...................................................................................................... 14 
A) 
Study overview ............................................................................................................... 14 
B) 
Recruitment .................................................................................................................... 17 
C) 
Screening ........................................................................................................................ 17 
D) 
Study procedures ............................................................................................................ 18 
1. 
Baseline session: ......................................................................................................... 18 
2. 
rTMS sessions 1-10 .................................................................................................... 19 
3. 
Task ............................................................................................................................ 21 
4. 
rTMS procedures ........................................................................................................ 22 
5. 
Relationship to other protocols ................................................................................... 24 
E) 
End of participation ........................................................................................................ 24 
VI. Inclusion and Exclusion Criteria ............................................................................................ 24 
A) 
Description of the study population ............................................................................... 24 
B) 
Inclusion criteria ............................................................................................................. 24 
C) 
Exclusion criteria............................................................................................................ 25 
VII. Clinical and Laboratory Methods .......................................................................................... 27 
VIII. Collections and Storage of Human Specimens or Data ....................................................... 28 
IX. Statistical Analysis.................................................................................................................. 28 
X. Additional considerations ........................................................................................................ 30 
XI. Subject Safety monitoring ...................................................................................................... 31 
A) 
Parameters to be monitored ............................................................................................ 31 
B) 
Criteria for individual subject withdrawal from the study: ............................................ 32 
XII. Outcome measures: ............................................................................................................... 33 
XIII. Human Subjects Protection .................................................................................................. 33 
A) 
Regulatory and ethical consideration ............................................................................. 33 
B) 
Subject Selection ............................................................................................................ 33 
C) 
Exclusion of children ..................................................................................................... 34 
D) 
Exclusion of other vulnerable populations ..................................................................... 34 
E) 
Justification of sensitive procedures .............................................................................. 35 
F) 
Safeguards for vulnerable populations ........................................................................... 35 
G) 
Qualifications of investigators ....................................................................................... 35 
H) 
Consent documents and process ..................................................................................... 36 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 6 of 72 
 
Designation of those obtaining consent ................................................................................ 36 
Consent procedure ................................................................................................................ 36 
Consent documents ............................................................................................................... 37 
XIV. Evaluation of Risks/Discomforts and Benefits ratio............................................................ 37 
A) 
Anticipated Benefit ........................................................................................................ 37 
B) 
Risks and discomforts .................................................................................................... 38 
1. 
Tasks completed inside and outside of the scanner: ................................................... 38 
2. 
rTMS ........................................................................................................................... 38 
Magnetic stimulation ............................................................................................................ 38 
Seizure................................................................................................................................... 38 
Acoustic noise ....................................................................................................................... 40 
3. 
MRI scanning ............................................................................................................. 42 
4. 
Mock Scanner ............................................................................................................. 42 
C) 
Overall Risk Determination ........................................................................................... 43 
XV. Protection of participants’ Privacy and Confidentiality ........................................................ 43 
A) 
Medical records: ............................................................................................................. 43 
B) 
Research Records/Data. ................................................................................................. 43 
C) 
Stored Samples. .............................................................................................................. 44 
XVI. Study Agents/Interventions.................................................................................................. 44 
XVII. Event Characterization and reporting to the IRB, Clinical Director (CD) and Sponsor .... 44 
XVIII. Data and Safety monitoring Plan ...................................................................................... 44 
XIX. Data/Records Management .................................................................................................. 45 
XX. Compensation ........................................................................................................................ 46 
XXI. Quality Assurance ................................................................................................................ 46 
A) 
Quality Assurance Monitor: ........................................................................................... 46 
B) 
Quality Assurance Plan .................................................................................................. 46 
XXII. Alternatives to participation or Alternative therapies ........................................................ 47 
XXIII. Conflict of Interest ............................................................................................................ 47 
A) 
Distribution of NIH Guidelines ...................................................................................... 47 
B) 
Conflict of interest .......................................................................................................... 47 
C) 
Role of a commercial company or sponsor .................................................................... 47 
XXIV. Technology Transfer ......................................................................................................... 47 
XXV. References .......................................................................................................................... 48 
XXVI. Appendices ........................................................................................................................ 56 
A) 
Appendix 1: Eligibility checklist.................................................................................... 56 
B) 
Appendix 2: Recruitment materials ............................................................................... 58 
C) 
Appendix 3: Fact Sheet .................................................................................................. 63 
D) 
Appendix 4: TMS information sheet .............................................................................. 65 
E) 
Appendix 5: rTMS questionnaires ................................................................................. 69 
 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 7 of 72 
 
III. Background  
A) The problem 
Repetitive Transcranial magnetic stimulation (rTMS) is a promising technique to target neural 
networks in addiction. In particular, the recent development of novel H-coils introduces the ability 
to reach deeper brain areas that play key roles in addiction, such as the anterior cingulate cortex 
(ACC). However, an effective set of stimulus parameters for ACC stimulation with the HAC coil 
has not yet been developed. Therefore, it is crucial that optimal stimulation parameters, and 
appropriate output measures are established during a pilot phase, before further protocols are 
developed. 
B) Transcranial magnetic stimulation (TMS) and therapeutic developments 
Over the last decades, transcranial magnetic stimulation (TMS) has become a prominent method 
in neuroscience, both as a research tool and recently also as a treatment method (Hallett, 2007). 
TMS is a non-invasive neurostimulation technique that works by applying magnetic pulses over 
the scalp. These pulses are produced by passing an electrical current through an electromagnetic 
coil (TMS coil). The current induces a magnetic field in the underlying brain tissue. Various forms 
of TMS protocols have been developed, with single-pulse TMS eliciting responses that last about 
100microseconds, and repetitive TMS having the potential to induce longer-lasting effects (Hallett, 
2007). rTMS can be used to disrupt or enhance processing in the targeted region, depending on the 
stimulation frequency. Specifically, low low-frequency rTMS (1Hz) is associated with inhibitory 
effects and high-frequency stimulation rTMS (>5Hz, but more usually 10-20 Hz) is associated 
with excitatory effects (Hallett, 2007). In fundamental research, TMS has become a prominent tool 
to study brain physiology, thanks to its ability to causally affect brain function in a non-invasive 
and relatively pain-free manner. In therapeutic settings, rTMS protocols have been used to induce 
long-term effects in the tissue targeted and connected regions.  
The  therapeutic application of rTMS is best described for treatment-resistant depression, but has 
also been explored in other disorders (Wassermann & Zimmermann, 2012). RTMS has been 
studied in the treatment of depression for almost two decades and daily rTMS over left dorsolateral 
prefrontal cortex (DLPFC) is now an FDA-approved treatment (Wassermann & Zimmermann, 
2012). George et al. (1995)  and Pascual-leone, Rubio, Pallardó, and Catalá (1996) were amongst 
the first to report an improvement in the symptoms of treatment-resistant depressive patients 
following rTMS (20Hz and 10Hz respectively, over left dorsolateral prefrontal cortex). By 2010, 
141 studies had been published on successful rTMS in the treatment of depression (Polley, 
Navarro, Avery, George, & Holtzheimer, 2011). Among the more notable was a multi-site 
randomized placebo-controlled safety and efficacy trial with 301 patients, which found high-
frequency rTMS to be an effective treatment for treatment-resistant depression (10Hz, left DLPFC, 
4-6 weeks; O’Reardon et al., 2007). A recent  meta-analysis of randomized, double-blind and 
sham-controlled trials also confirms the efficacy of high-frequency rTMS over left DLPFC in 
treating depression (Berlim, van den Eynde, Tovar-Perdomo, & Daskalakis, 2013). The vast 
majority of effective stimulation protocols for depression target left dorsolateral prefrontal cortex, 
use high-frequency TMS (10Hz or 20Hz) at intensities of 100-120% of resting motor threshold 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 8 of 72 
 
(the intensity of stimulus over motor cortex required to obtain a motor response in a muscle at rest) 
for 3 to 6 weeks; Polley et al., 2011). However, positive effects of rTMS in depression have also 
been found with low-frequency (1Hz) right DLPFC stimulation (Bares et al., 2009; Menkes, 
Bodnar, Ballesteros, & Swenson, 1999), with high-frequency dorsomedial TMS (Downar et al., 
2013b; Salomons et al., 2013), and in a single study using 3Hz rTMS over posterior parietal cortex 
(Schutter, Laman, van Honk, Vergouwen, & Koerselman, 2009). Over the years, there has been a 
clear trend towards longer courses of treatment and higher stimulation intensities, as both 
parameters have been associated with a better response (Aleman, 2013; Hadley et al., 2011; Polley 
et al., 2011). 
Therapeutic effects of rTMS have also been explored in other conditions. In particular, auditory 
hallucinations in schizophrenia have been successfully reduced with low-frequency rTMS over the 
left temporo-parietal cortex (Hoffman et al., 2005; Hoffmann et al., 2000; Slotema, Aleman, 
Daskalakis, & Sommer, 2012). Therapeutic applications in other areas are sparse and have only 
very recently started to be studied. For example, high-frequency right DLPFC stimulation has been 
associated with improvement in the core symptoms of post-traumatic stress disorder (Cohen et al., 
2004). In addiction, right high-frequency stimulation of DLPFC was shown to lead to a reduction 
in craving in a population of cocaine dependent subjects (Camprodon, Martínez-Raga, Alonso-
Alonso, Shih, & Pascual-Leone, 2007), while high-frequency left DLPFC stimulation was shown 
to reduce nicotine cue craving (Li et al., 2013b). RTMS could have significant potential as an 
interventional tool in addiction (Feil & Zangen, 2010; Jansen et al., 2013). 
C) The anterior cingulate cortex as a target for addiction 
The ACC is crucially involved in craving (Kühn & Gallinat, 2011), a key predictor for relapse 
(Doherty, Kinnunen, Militello, & Garvey, 1995). Recruitment of the ACC is related to craving in 
abstinent smokers (Wang et al., 2007), alcoholics (Wilson, Myles, Grasby, & Nutt, 2006), and 
cocaine addicts (Goldstein & Volkow, 2011), with increased ACC response predictive of relapse 
(Wilson et al., 2006). There is evidence for a direct link between ACC hyperactivity and craving. 
In a real-time fMRI study, nicotine-dependent subjects were able to reduce their craving, which 
resulted in a reduction of BOLD in the ACC (Li et al., 2013a). A single-case study using TMS 
over the ACC in an alcoholic patient lead to a transient reduction in craving (De Ridder, Vanneste, 
Kovacs, Sunaert, & Dom, 2011). These data suggest that an experimental reduction in ACC 
activity could prevent relapse by reducing craving. 
The dorsal ACC is plays a major role in cognitive control and response inhibition, which are 
compromised in addiction (Garavan, Ross, & Stein, 1999; Kaufman, Ross, Stein, & Garavan, 
2003). In contrast to its hyperactivity when presented with drug-related cues, the dorsal ACC is 
hypoactive in addicted individuals when they engage in inhibitory control tasks, which strongly 
recruit ACC in control subjects (Goldstein et al., 2007; Hester & Garavan, 2004). From a network 
perspective, the ACC is thought to be part of the salience network, which modulates the relative 
salience of external cues (such as a cognitive task) or internal cues (such as hunger or craving; 
Sutherland, McHugh, Pariyadath, & Stein, 2012). The imbalance between internally cued and 
externally cued networks has been proposed to underlie some of the negative cognitive 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 9 of 72 
 
consequences of addition (Sutherland et al., 2012). TMS may have the potential to restore 
functional connectivity with ACC which may be compromised during addiction. An avenue worth 
exploring is therefore whether TMS can normalize the connectivity patterns between these 
networks and thus alleviate the cognitive side-effects of abstinence. 
In sum, the modulation of the ACC could have therapeutic benefits in addiction. Notably, 
modulation of the ACC response to drug-relates cues could reduce craving and thereby prevent 
relapse. Moreover, if ACC stimulation can normalize the balance between externally and internally 
cued neural networks, the negative cognitive side-effects of abstinence may be reduced.  
D) The H-coil for “deep rTMS” 
Transcranial magnetic stimulation of the ACC is challenging because the structure lies several 
centimeters below the cortical surface. To reach such deeper regions with TMS, increased current 
must be passed through the coil.  This has the consequence of producing a much greater magnetic 
field (and thus greater stimulation) in superficial brain regions as well, with potentially negative 
effects.  The need for TMS coils that can stimulate deeper regions while minimizing the effects in 
more superficial regions has led to the development of novel coil types, such as the H-coils 
(Brainsway, Ltd.). The H-coil was designed to stimulate deep regions of the brain without 
requiring high voltage (Roth, Zangen, & Hallett, 2002). With this configuration, the magnetic field 
does not diminish as quickly as a function of distance.  Therefore, functional activation of deep 
regions can occur at lower voltage settings and with less activation of more superficial regions 
(Zangen, Roth, Voller, & Hallett, 2005). The H-coil has recently been FDA-approved for the 
treatment of depression (FDA, January 2013). 
E) Safety data on the H-coil 
 
Initial tests: 
 
An initial study of safety using healthy volunteers used two types of H-coil, one stimulating 
primarily the left prefrontal region and one stimulating bilaterally (Levkovitz et al., 2007). All 
subjects received 3 days of 10Hz (1s every 20s, repeated 42 times) and 20Hz stimulation (1s every 
20s, repeated 42 times), each for 3 days. This double-blind, randomized, controlled study 
demonstrated that the stimulation was well-tolerated at frequencies of 10Hz and 20Hz with no 
significant adverse effects, no changes in cognitive abilities, and no changes in mood.    
 
The coil was then tested in several different patient groups to assess safety and potential 
therapeutic effects.  First, a double-blind, randomized study of 65 patients with Major Depressive 
Disorder (MDD) randomized patients to different coils and different stimulation parameters 
(Levkovitz et al., 2009). Stimulation was administered for 2 seconds (40 pulses) and this train was 
repeated 42 times with an inter-train interval (ITI) of 20sec, for a total of 1680 pulses daily, 5 
times/week for 4 weeks. The results demonstrated that the stimulation with the H-coil was well-
tolerated in this population, and that left DLPFC stimulation at 20Hz and 120% of motor threshold 
(MT) was effective in decreasing depressive symptoms.    

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 10 of 72 
 
 
In a second open label, safety and feasibility add-on study of 19 bipolar patients, 20 Hz stimulation 
at 120% MT was administered for 2 seconds (40 pulses) and this train was repeated 42 times with 
an intertrain interval (ITI) of 20sec, for a total of 1680 pulses daily, 5x/week for 4 weeks (Harel et 
al., 2011).  One patient suffered a generalized seizure lasting 10 seconds on the 19th treatment day.  
She was taking Lithium for her bipolar disorder.  Of note, this stimulation protocol employed high-
frequency 20Hz stimulation, which has been shown to increase the risk of seizures (Wassermann, 
1998). There were no other complications or adverse events.    
 
A third double-blind, randomized, controlled study of 12 patients with blepharospasm (dystonia 
of eyelid opening/closing) received stimulation with the H-coil at 100%MT at 0.2Hz (Kranz, 
Shamim, Lin, Kranz, & Hallett, 2010). The position of the H-coil was adjusted to target the anterior 
cingulate cortex and a low stimulation rate was chosen to decrease excitability in this region.  There 
were no adverse events, and no changes in blood pressure, heart rate, or respiratory rate.   
Finally, an open label study of 8 patients with schizophrenia used a left-sided H-coil positioned 
over the temporoparietal junction to determine if stimulation could decrease the occurrence of 
auditory hallucinations (Rosenberg, Roth, Kotler, Zangen, & Dannon, 2011).  The protocol used 
1Hz (inhibitory) stimulation at 110% MT for 10 minutes daily for 10-20 days. The stimulation was 
well tolerated, with one patient experiencing a transient headache.  Overall, when used with 
stimulation parameters that are within safety guidelines (Rossi, Hallett, Rossini, & Pascual-Leone, 
2009), the H-coil appears to be safe and well-tolerated.  
 
Summary data from Brainsway 
 
From 2003 through Spring, 2010, 455 patients and healthy volunteers have been treated in 
Brainsway studies using the TMS H-coil device for different clinical conditions, including major 
depressive disorder (MDD), schizophrenia, bipolar disorder, addiction (cigarette smoking, 
cannabis), blepharospasm, Parkinson’s disease, and post-traumatic stress disorder (PTSD) 
(Brainsway, Ltd., unpublished data). 
 
345 of these 437 subjects were treated with high frequency (10-20 Hz) and high intensity (<120% 
MT) TMS, for a total of 5760 sessions and 241,014 pulse trains.  
 
138 of these 345 subjects received TMS treatments (1,682 sessions, 71,800 pulse trains) without 
concomitant psychotropic medications that may lower the seizure threshold.  One of these subjects 
experienced a tonic-clonic seizure lasting 2 minutes after receiving rTMS 20 Hz and 120% MT to 
the prefrontal cortex (Levkovitz et al., 2009).    
 
207 of these 345 subjects received TMS treatments (4,078 sessions, 169,214 pulse trains) in 
addition to concomitant medications that may lower the seizure threshold.  Three of these subjects 
experienced seizures, all of whom received TMS at high frequency (20 Hz). 
 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 11 of 72 
 
110 of these 455 subjects were treated with low frequency (0.2-1 Hz), high intensity TMS 
(including 5 who also received high frequency treatment), for a total of 538 sessions (average 
session duration 15 min) and 1449 pulses.  None of these subjects experienced a seizure or any 
serious adverse event. 
 
Recent published studies using the H-coil 
 
 
A clinical study compared the MT of the abductor pollicis brevis (APB) muscle with the H-coil 
and figure 8 coil in 6 healthy volunteers (Zangen et al., 2005). One subject reported a mild, 
transient headache.  There were no other side effects, including no change in cognitive or hearing 
abilities. 
 
 
In a subsequent experiment, the H-coil was used to deliver pulses at 1 Hz over 20 sec over five 
different scalp locations in 3 subjects. The intensity of stimulation was 120% of motor threshold, 
the interval between the 20-s trains was 2 min and the total number of trains was 10. One of the 
three subjects experienced a 30 dB hearing loss at 4000 Hz in the left ear that was stable for 10 
months and appears permanent. The earplug protection had fallen out for a short period of time 
during the study (Zangen et al., 2005). The H-coil magnetic field penetrated to a depth of 5-6 cm, 
compared to 1.5-2 cm with a standard figure 8 coil. 
 
A safety study compared the H1-coil, H2-coil, standard figure-8 coil (Quadstim; The Magstim 
Company, Ltd.), and sham coil in 32 healthy subjects (Levkovitz et al., 2007). Subjects were 
randomly assigned to one of four groups: H1 coil (n = 9), H2 coil (n = 9), figure eight coil (n = 8), 
sham coil (n = 9). All subjects participated in three treatment sessions, one session per day on days 
1 (0.05 Hz [1 pulse every 20 seconds]), 3 (10 Hz), and 5 (20 Hz). rTMS was well tolerated, with 
no major side-effects. There were no scalp lesions and no changes in auditory threshold (measured 
by audiograms).  Computerized cognitive tests found no deterioration in cognitive function, except 
for transient impairment of spatial recognition memory with the H1 coil on the first day of rTMS 
(i.e., at 0.05 Hz), but not on the following treatment days.  There were no significant emotional or 
mood alterations, except for reports of “detachment” which were experienced by subjects 24-36 
hours after the last H1 coil stimulation, but not following stimulation with H2 coil stimulation.  
 
A recently published study evaluated the H coil in the treatment of medication-free patients with 
treatment-resistant major depressive disorder (MDD) (Levkovitz et al.,  2009). Three different H-
coil designs were tested: 23 subjects received H1 (predominantly unilateral), 21 H2 (bilateral), and 
19 H1L (unilateral).  53 patients completed the study. The treatment protocol consisted of a drug 
taper period of 10 to 14 days, followed by 5 days a week of prefrontal rTMS (20 Hz, 2 sec on, 20 
sec off, for 20 minutes, i.e., 1680 stimuli) for 4 consecutive weeks (i.e., 20 treatment sessions). 
Eight of the 18 patients who completed the study with the H1L coil received treatment at 110% of 
MT; the rest received 120% of MT.  There were no reports of seizures, neurological problems, 
hearing loss, visual changes, or changes in blood pressure. Ten patients reported headaches 
relieved by non-opioid analgesics during the first week of treatment. There was no impairment of 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 12 of 72 
 
cognitive function (sustained attention, visuospatial memory, cognitive planning, spatial working 
memory) or psychomotor speed between the beginning and end of treatment.  One patient 
committed suicide 5 days after the last treatment. The Ethics Committee concluded that there was 
no link between the suicide and the rTMS treatment.  
 
A recently completed study evaluated 5 days a week rTMS treatment for 4 weeks with the H1 coil 
(20 Hz at 120% of motor threshold over the DLPFC) in patients with treatment-resistant MDD 
who are also taking anti-depressants (Isserles et al., 2011). The study protocol consists of an initial 
phase of daily treatment for four weeks, followed by a maintenance phase of once weekly 
treatments for four consecutive weeks.  57 patients enrolled in the study, with 46 receiving at least 
10 TMS sessions and 20 completers. One patient suffered a brief, self-limiting seizure during his 
second treatment (see above). The only other side effect was mild, transient headaches, some 
requiring treatment with “common analgesics,” in several patients, usually during the first week.  
One patient withdrew because of headaches. 
 
Two recently published case series involved 13 depressed outpatients (3 taking concurrent anti-
depressants) treated with the H-1 coil over the DLPFC at 20 Hz (120% of MT) (Rosenberg, 
Shoenfeld, Zangen, Kotler, & Dannon, 2010a; Rosenberg, Zangen, Stryjer, Kotler, & Dannon, 
2010b).  The following adverse events occurred (each in one subject): worsening insomnia 
(leading to study withdrawal), transient dizziness and nausea, transient numbness in right temporal 
and cervical zones, trembling of lower limbs (resolved with lowering intensity to 100% of MT), 
foul smell and sensation of bad taste (with the former continuing for 40 days after treatment 
cessation).  No subject had seizure or other serious adverse event. 
 
In summary, present data indicate that the use of the H-coil is associated with the same risk profile 
as other TMS coils. 
F) An H-coil for anterior cingulate stimulation: the HAC coil 
Over 15 H-coil designs have been created thus far, each tailored to stimulate a specific brain region 
(Roth, Pell, & Zangen, 2013b). Tests by the manufacturer indicate that tissue up to 6cm deep can 
be stimulated with these coils, based on measurements in phantom model of the human head 
(Levkovitz et al., 2009; Roth et al., 2013a; Roth, Amir, Levkovitz, & Zangen, 2007).  
The HAC coil is specifically designed to target medial prefrontal regions including the ACC. 
Given the role of medial prefrontal cortical structures in the integration of reinforcing stimuli and 
goal-directed behavior and its role in addiction, ACC stimulation has therapeutic potential in cue 
craving and addictive behaviors. 
Tests of the HAC coil in a phantom indicate that these medial prefrontal cortex structures can 
indeed be effectively reached (see Figure 1), and the HAC coil is being used for experimental 
purposes in a number of laboratories. However, the ability of the HAC coil to effectively stimulate 
ACC tissue has not been assessed. Specifically, the conditions under which these target regions 
can be successfully stimulated are yet to be determined. Moreover, appropriate behavioral and 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
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neuroimaging outcome measures for ACC stimulation have not yet been identified. Thus, prior to 
using the HAC coil in further protocols to evaluate potential addiction treatments, a feasible and 
effective stimulation protocol must be developed.  
 
 
Figure 1:  Pseudocolored field maps for the HAC H-coil indicating the electrical field in a saline 
phantom (Brainsway, LTD.). Regions in red indicate regions induced currents of 100V/m, the level 
required to activate neuronal tissue (Roth et al., 2007). 
IV. Study Objectives 
The aim of these pilot investigations is to establish an anterior cingulate cortex rTMS protocol 
with the HAC coil, and to determine which behavioral and MRI measures can capture the effects 
of this stimulation. The objective is to establish of a set of effective stimulation parameters for the 
use of the HAC coil, to establish a behavioral task that is sensitive to the TMS stimulation, and to 
assess which MRI measures are affected by TMS stimulation. These pilots will form the basis of 
further investigations, which will use the stimulation parameters and outcome measures obtained 
under this protocol.  

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
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The pilot study will consist of two phases. In the Phase A of the pilot, TMS parameters will be 
modulated, and TMS effects on behavioral tasks that recruit the ACC will be assessed. This phase 
will result in (1) a set of stimulus parameters that effectively affect behavior on an ACC-sensitive 
behavioral task, and (2) the behavioral task. In Phase B of the pilot, the TMS parameters will be 
applied between two MRI scanning sessions, and TMS effects on MRI measures will be assessed. 
In both phases, we will test for short-term after-effects following a single dose of rTMS. Candidate 
outcome measures will be compared prior and immediately following TMS. Participants will be 
observed for two hours after stimulation. 
Following the determination of an effective ACC stimulation protocol, a hypothesis-driven 
protocol will be submitted that will apply this stimulation protocol in with the general aim of better 
understanding the underlying circuitry in addiction. 
 
V. Study Design and Methods 
A) Study overview 
 
Two phases can be distinguished (see Figure 2). In a first behavioral phase (Phase A), stimulation 
parameters will be varied in order to establish a protocol that effectively stimulates ACC, as 
demonstrated by an effect in a behavioral task that is ACC-dependent. The second phase (Phase 
B) of the pilots will assess the sensitivity of various MRI measures to the stimulation. At least, 
these fMRI measures will include task-based fMRI (using an MRI-adapted version of the 
behavioral task) and resting state fMRI. The resting state BOLD signal can be used to assess 
changes in functional connectivity between the targeted tissue and other brain areas, as well as to 
measure fractional ALFF, a proxy for the intensity of regional spontaneous activity (Zou et al., 
2008). Other MR measures will include MR spectroscopy and ASL. Both of these MR measures 
have been used to capture TMS effects (Michael et al., 2003; Moisa, Pohmann, Uludağ, & 
Thielscher, 2010) and have potential as biomarkers of effective rTMS. Using MR spectroscopy, 
levels of glutamate and other neurometabolites can be compared before and after stimulation. 
There is some evidence for rTMS-induced modulation of glutamate levels following high-
frequency rTMS (Luborzewski et al., 2007; Michael et al., 2003). ASL is used as a proxy for 
neuronal activity, and different rTMS protocols have been linked to modulations of neuronal 
activity in the targeted tissue as well as connected regions in an interleaved TMS/fMRI design 
(Moisa et al., 2010).  
 
In the unlikely event that a behavioral effect is found in Phase A, but no MR effect is found in 
Phase B, this would indicate that the behavioral effect may have been spurious. In this case, we 
may reiterate the first step (Phase A). If the range of stimulation parameters for the first behavioral 
task is exhausted and no behavioral effect is found, a number of MRI sessions may be undertaken 
to assess whether the most intensive stimulation of the range (120% of motor threshold) is able to 
affect the ACC, as assessed by ASL or resting state BOLD (fALFF) measures. 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
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Figure 2. Two phases of pilot tests for repetitive transcranial magnetic stimulation (rTMS) over 
the anterior cingulate cortex (ACC). In Phase A (blue) stimulation parameters will be varied until 
an effect on a behavioral ACC-dependent task is seen. Phase B (green) will explore whether the 
neural correlates of rTMS stimulation can be captured using various MR measures. Solid lines 
represent planned tests. Dashed lines represent the reprisal of Phase A in the unlikely event that 
behavioral effects cannot be replicated in the MRI scanner, which would indicate that initial Phase 
A behavioral results were likely spurious. 
Due to the nature of single-session rTMS, stimulation effects are expected to be transient, with 
effects lasting 15-30 minutes after stimulation (Chen et al., 2003). Therefore, a single session 
cannot all of the proposed outcome measures. Due to the exploratory nature of the pilot sessions, 
the precise stimulation parameters are yet to be determined (see Phase A). At a minimum, we will 
investigate the effectiveness of both 1Hz and 10Hz rTMS, at intensities of 100% and 110% of MT. 
The initial parameter range is outlined in Table 1. 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
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1Hz 
rTMS 
10Hz 
rTMS 
  
Sham 
100% 
110% 
120% 
Sham 
100% 
110% 
120% 
Flanker 
A  
B 
 C 
D 
E 
F 
G 
H 
MR Flanker  
A*  
B* 
 C* 
D* 
E* 
F* 
G* 
H* 
MR Rest 
A**  
B** 
 C** 
D** 
E** 
F** 
G** 
H** 
ASL/MRS 
A*** 
B*** 
 C***
D*** 
E*** 
F*** 
G*** 
H*** 
 
Table 1. Frequency and intensity range (expressed as % of motor threshold) and assessment tools. 
Letters and asterisks represent the conditions, with the letter representing the stimulus parameters 
and the asterisk representing the type of outcome measure. Blue indicates behavioral phase, Green 
indicates MRI phase. 
 
While stimulation parameters such as intensity and frequency will be varied, clear boundaries are 
put in place with regards to stimulation parameters and number of sessions per person. These 
boundaries seek to minimize the possibility of adverse events. They will also avoid potential 
stimulation aftereffects lasting longer than the day of the experiment. 
Parameter boundaries: 
 Number of rTMS visits: Subjects will not participate in more than 10 rTMS sessions 
under this protocol. There will be no more than 3 consecutive days with an rTMS session. 
If subjects have participated in this or other rTMS studies, there must be at least two weeks 
between the time of the last TMS session and the time of first rTMS session under this 
protocol. Note that the baseline session is not included in this total of 10, because this 
session will not include rTMS. There is no evidence to suggest that more or more frequent 
rTMS sessions would lead to adverse effects or effects lasting beyond the sessions, but we 
chose these parameter boundaries to maximize compliance and not to unduly burden 
participants. 
 Number of rTMS sessions per day: Subjects will not receive more than 1 rTMS session 
per day. There will be at least 20 hours between stimulation sessions. As a rule of thumb, 
single session rTMS effects are expected to extend past the end of the stimulation for about 
the same time as the duration of the session (Chen et al., 2003; Thut & Pascual-Leone, 
2010). 
 Number of consecutive days with rTMS sessions: There will be no more than 3 TMS 
sessions on consecutive days. In studies investigating effects of rTMS on depression, 
therapeutic effects lasting longer than 24 hours have been reported from 5 consecutive days 
of active rTMS onwards (Conca et al., 2002; Polley et al., 2011). Restricting the number 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 17 of 72 
 
of consecutive TMS days to 3 (of which at least one is a Sham session) minimizes the 
probability of inducing longer-term effects. 
 Length of rTMS stimulation session: The length of rTMS stimulation will not exceed 30 
minutes. No explicit guidelines exist regarding the absolute length of a session, but there 
are no data to suggest that longer TMS sessions are associated with larger risk, provided 
other parameters (number of pulses, pulses per train, inter-train duration) are within 
guidelines (Rossi et al., 2009). 
 Stimulation intensity: Stimulator intensity shall not exceed 120% of tibialis anterior (leg) 
motor threshold (MT). Because our stimulation target, like the motor representation of the 
lower extremities, is situated on the medial longitudinal fissure, we will measure leg motor 
threshold. The 2009 TMS safety guidelines (Rossi et al., 2009) do not speak to the use of 
intensities relative to leg motor threshold. However, TMS studies targeting ACC have 
safely used stimulus intensities ranging from 100% to 120% of leg motor threshold 
(Downar et al., 2013a; Harmer, Thilo, Rothwell, & Goodwin, 2001; Hayward et al., 2007; 
Hayward, Goodwin, & Harmer, 2004; Kranz et al., 2010; Salomons et al., 2013). Dr. 
Jonathan Downar has stimulated ACC with the highest intensity of this range in over 300 
patients thus far, without serious side-effects (Jonathan Downar, personal communication). 
We also consulted with Dr. Mark Hallett, co-author of the most recent safety guidelines, 
on the use of stimulus intensities relative to leg motor threshold and he agreed it is 
reasonable to think that these parameters would be appropriate, but, in the absence of 
published literature, there is no assurance. (Mark Hallet, personal communication). Dr. 
Hallett is a TMS expert, co-inventor of the H-coil, and Independent Safety Monitor for this 
protocol.  
 Stimulation frequency: Frequency of the TMS pulses will vary between 1Hz and 10 Hz. 
Safety guidelines recommend using frequencies under or equal to 20Hz (Rossi et al., 2009). 
 Pulse train and inter-train interval: appropriate inter-train intervals and pulse durations 
will be used as per the safety guidelines for rTMS (Rossi et al., 2009) and parameters used 
in previous studies with H-coils (Krause, Enticott, Zangen, & Fitzgerald, 2012). For 
example, for the 10 Hz stimulation the pulse train duration will not exceed 32 pulses and 
there will be 20 second inter-train intervals (Rossi et al., 2009).  For the 1 Hz session there 
will be continuous 1 Hz stimulation, similar to that used in Krause et al. (2012). 
B) Recruitment 
Participants will be recruited from the general population through advertising in city, regional or 
campus newspapers, flyers, via referrals, or radio and television advertisements (See Appendix 2 
for recruitment advertisements) under the aegis of protocol 06-DA-N415). Participants will also 
be recruited from among past candidates for NIDA-IRP studies if written consent to be re-
contacted has been obtained.  
C) Screening 
 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
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Screening will be conducted using the basis of screening tools under the NIDA screening protocol, 
06-DA-N415. Candidate participants will be screened for participation based on the 
Inclusion/Exclusion criteria listed above. Informed consent will be obtained from prospective 
participants prior to the commencement of any screening procedures in a private area where 
participants are free to ask questions.  During screening, participants will be given some initial 
information regarding the study (see Appendix 3 “Fact Sheets”) to determine if they are interested 
in possible participation. Results of screening evaluations will be reviewed by the Medical 
Advisory Investigator (MAI) of the protocol who will determine if the individual meets the 
inclusion /exclusion criteria and qualifies for the study. 
D) Study procedures  
 
Before each study session, a nursing assessment will be done which includes vital signs, 
assessment of recent medical history, medications, drug use, breathalyzer, urine toxicology screen, 
MRI safety form (if the study session includes MRI scanning), TMS safety questionnaire and for 
females, a urine pregnancy test. Participant will also be asked when they last had TMS, and 
whether this was at NIDA or elsewhere. If breathalyzer is positive for alcohol or if urine is positive 
for THC, subjects will be rescheduled. Other positives will be evaluated by the MAI against known 
reasons for false positives.   In case of a suspected false positive and if there are no safety concerns, 
the subject may be allowed to participate at the discretion of the MAI. Otherwise, the subject will 
be rescheduled. Urine samples of suspected false positives will be sent to the laboratory for 
analysis.  
 
RTMS procedures have been used for over 10 years in a wide variety of settings and there are no 
published data to suggest that the procedure would have adverse effects on the cardiovascular 
system. Nevertheless, vital signs will be taken again prior to daily discharge.  
 
In general, participants will partake in one baseline session (orientation visit) and up to 10 rTMS 
visits. We may invite participants back for additional behavioral training if required. This may be 
the case if an alternative behavioral task is introduced or if several months have passed between 
sessions. If for some reason a session is not completed (such as equipment failure) we may bring 
a participant back to repeat or complete a session. We will not exceed 10 rTMS sessions. 
1. Baseline session:  
 
After signing informed consent, there will be a baseline session involving the following: 
 Structural MRI scan. This scan will be used to locate the stimulation target for TMS on the 
participant’s individual anatomy.. If a structural scan for the subject has been obtained 
under Protocol 10-DA-N457, this structural will be used, and no structural scan will be 
acquired during the baseline session. 
 A single pulse TMS session will be performed where motor hotspot is determined and motor 
threshold will be taken. This initial TMS session will provide the subject with the 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 19 of 72 
 
opportunity to experience TMS pulses and withdraw from the study if he or she is 
uncomfortable with the sensation of TMS pulses. If the motor hotspot cannot be determined 
within 1 hour, or if the leg active motor threshold is higher than 83% (therefore, if 120% 
of AMT exceeds the maximum stimulator output of the TMS apparatus), the participant 
may be discharged at the discretion of the lead investigator. Motor threshold determination 
is performed using single pulse TMS, which has no effect lasting beyond the pulse itself.  
 Habituation session: Following the determination of motor threshold, the TMS coil will be 
placed over the ACC region and a number of test stimuli will be administered. Intensity 
will be gradually increased according to the subjects’ subjective discomfort levels as 
assessed with  a verbal pain rating scale (“Please rate your discomfort level using a number 
from 0 to 10, with 0 being no pain, 5 being moderate pain and 10 worst possible pain”) . 
The total time stimulated will be 10 minutes or less. Scalp pain due to TMS pulses has been 
documented to decrease over sessions (Conca et al., 2002; O’Reardon et al., 2007), and 
similar habituation procedures have been used for ACC rTMS (Downar et al., 2013b). This 
session does not count towards the number of rTMS sessions.  
Depending on the design and phase of the pilot, the baseline session may also include the 
following: 
 A behavioral task may be practiced in the TMS chair or in the Mock scanner to assess 
baseline performance. 
 A simple fMRI task may be performed to functionally define a stimulation region of 
interest (for example a functional localizer for dorsal anterior cingulate cortex, or a 
functional localizer for leg motor cortex).  
 In Phase B of the pilots, other MRI measures may be taken in the baseline session. These 
will include resting-state fMRI and task-related fMRI, which may be supplemented with 
Magnetic Resonance Spectroscopy (MRS), and arterial spin labeling (ASL).  
2. rTMS sessions 1-10 
 
A typical experimental session will entail a pre-test on a relevant outcome measure, a TMS session 
and a post-test on the measure used (see Figure 3). We may explore small variations on the 
structure of the TMS sessions, such as have the participant perform the task during TMS to probe 
for immediate effects, or ask the subject to perform more than one behavioral task if the timeframe 
allows. Pilots will use a within-subject design, whereby performance on a task or a neural response 
is compared before and after real rTMS or sham rTMS. To enable a direct comparison of different 
stimulation parameters, the same subjects will partake in several sessions, whereby the task or 
stimulation parameters will be varied. Under these conditions, it is unlikely that any long-term 
changes will be induced. Typically, an rTMS session will produce an aftereffect proportional to 
the length of the session. For example, an rTMS stimulation protocol which lasts 15 minutes is 
expected to produce an aftereffect for 15 minutes (Chen et al., 2003). Aftereffects lasting over 24 
hours have been reported from 5 consecutive real rTMS days onwards (Polley et al., 2011). Here, 
we limit consecutive testing days to three, of which at least one is a sham session. Subjects will 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 20 of 72 
 
partake in a minimum of three sessions to be deemed completers, and will participate in up to 10 
TMS sessions. 
 
Figure 3. The simplified structure of an rTMS session for Phase A (top) and Phase B (bottom). 
The behavioral task (Phase A) or type of scan (Phase B) is always the same at all time points. 
 Pre-TMS questionnaires: Participants are asked to fill in a questionnaire about possible 
side-effects since the last rTMS session (the TMS monitoring questionnaire), and a 
questionnaire about their affect (the PANAS) See Appendix 5).  
 TMS calibration: The subject will be comfortably seated. Motor threshold of the TA 
muscle will be measured with the H-coil. Motor threshold is defined as the lowest intensity 
needed to evoke a visible muscle twitch. 
 Pre-stimulation measure (1): The participant will be assessed on a pre-stimulation 
measure. Depending on the design and session, this could be a computer-based behavioral 
task or an fMRI scanner session which could include resting state fMRI, task fMRI, ASL 
or MRS. In Phase A of the pilot, the subject will perform the task in the TMS room or the 
Mock scanner room at NIDA. In Phase B, the subject will perform the pre-stimulation 
measures in the MRI scanner at NIDA. 
 rTMS: The subject will be comfortable seated. The H-coil will be placed over the 
participants ACC. A brief habituation procedure will take place, whereby a small number 
of test stimuli1 will be administered to allow the subject to get used to the sensation of 
rTMS. Intensity will be ramped up according to the subject’s discomfort level (as indicated 
with a verbal pain rating scale; “Please rate your discomfort level using a number from 0 
to 10, with 0 being no pain, 5 being moderate pain and 10 worst possible pain”) until the 
target intensity  for that session is reached (between 100-120% of motor threshold). The 
length of this procedure will depend on the individual’s responses, but will take no more 
than 5 minutes of stimulation. After the habituation procedure, there will be a rest period 
                                                 
1 The test stimulus will consist of 20 seconds of 1Hz TMS or 2 trains of 10hz TMS (with one train consisting of a 
maximum of 32 pulses, and the intertrain interval at least twice the duration of the train, according to safety guidelines 
(Rossi et al., 2009). Intensity will be started at motor threshold level and then adjusted upward or downwards 
dependent on the subject’s response. 
Behavioral 
task (1)
Behavioral 
task (2)
Real rTMS or 
sham rTMS
MRI scan (1)
MRI scan (2)
Real rTMS or 
sham rTMS
Phase A:
Phase B:
Behavioral 
task (3)
Pre
Post  + 2min
Post  + 1hour

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
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of approximately 1 minute for every minute of the stimulation to any possible TMS effects 
to wear off. After this pause, rTMS will be administered. Precise stimulus parameters are 
to be determined in Phase A, but will remain within the clear boundaries set out in the 
Study overview section.  
 Post-stimulation measure (2). The post-stimulation measure will be identical to the pre-
stimulation measure.  
 Post-stimulation measure (3). In Phase A of the pilot, a second post-stimulation measure 
may be taken to assess whether the behavioral effects have returned to baseline. This will 
be one hour after the stimulation. 
 Post-TMS questionnaires: At the end of the visit, participants are asked to fill in a 
questionnaire about possible side-effects (the TMS monitoring questionnaire) and a 
questionnaire about their affect (the PANAS; See Appendix 5). Vital signs will be taken 
before daily discharge.   
 
3. Task 
 
The task used to capture ACC function will be the Eriksen Flanker task (Eriksen & Eriksen, 1974). 
This task engages areas thought to be involved in error monitoring or conflict, robustly activates 
the anterior cingulate (Bunge, Hazeltine, Scanlon, Rosen, & Gabrieli, 2002), and has been shown 
to be dysfunctional in drug abusers (Sokhadze, Stewart, Hollifield, & Tasman, 2009). It is one of 
the most sensitive ACC-related tasks known and is easily taught to subjects. It can be repeated 
almost indefinitely and continues to activate the region so that there are no expected habituation 
effects of the task. 
 
In a flanker task, participants respond according to the central item/letter (e.g., H or S) of a 
congruent (HHHHH or SSSSS) or incongruent (HHSHH or SSHSS) stimulus array.  On 
incongruent trials, the participant is required to suppress the response associated with the flankers 
and select the response associated with the central item. Participants are presented with a fixation 
mark on the screen, after which the stimulus array appears.  Participants are instructed to respond 
as fast as possible to avoid feedback indicating that their response was too slow according to a 
preset reaction time (RT) deadline.  Whenever participants respond too slowly, feedback (e.g., “!”) 
is presented indicating that they need to respond faster on future trials. 
In Phase A, the aim is to detect increases and decreases in performance in the flanker task due to 
rTMS. We therefore need as sensitive a performance measure as possible. The flanker task can be 
made easier of more difficult by varying the number of flankers (with more flankers a more 
difficult), and by adjusting the timing of the task. We will titrate the level of difficulty to a level at 
which the subject reaches a certain level of performance. Titrating the difficulty will have the 
added advantage that the task will be optimally challenging for every subject. 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
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In Phase B, the aim is to find BOLD differences in the ACC when subjects perform a flanker task. 
The task will be adjusted to be an effective and efficient MRI design. Due to the delayed nature of 
the BOLD response and the noisy nature of the signal, the timing of the task will be adjusted and 
the number of trials will be changed to allow proper estimation of the BOLD responses.   
  In the event that ACC stimulation does not result in behavioral differences with the flanker task, 
other behavioral tasks that have been found to recruit ACC will be employed (See Figure 2). These 
tasks are a Stroop task, a multiple source interference task (MSIT), and a Stop Signal Reaction 
Time (SSRT) task. If performance on none of these tasks is modulated by TMS, we will request 
an amendment to this protocol before using other tasks. 
 
The Flanker task, Stroop task, MSIT and SSRT task are simple computer-based tasks whereby the 
subject looks at letters and/or symbols on a screen and responds by means of a button press on a 
response keypad. Performance is not linked to any monetary gains and the subject is not exposed 
to any affective stimuli.  
 
4. rTMS procedures 
 
Apparatus and tests: A bilateral HAC-coil (Brainsway Inc, Israel) and a Magstim Rapid2 
magnetic stimulator (Magstim, Whitland, Dyfed, UK) will be used to apply rTMS. Each study 
visit day will start with a nursing assessment that includes urine drug screen, vital signs, and urine 
pregnancy test for females.  If breathalyzer is positive for alcohol or if urine is positive for THC, 
subjects will be rescheduled. If urine is positive for other illicit drugs, these positives will be 
evaluated by the MAI against known reasons for false positives. In case of a suspected false 
positive and if there are no safety concerns, the participants may be allowed to participate at the 
discretion of the MAI. Otherwise, subjects will be rescheduled.  Pregnant females will not be 
allowed to participate in the study.  Vital signs will be assessed again before daily discharge. All 
study visits will be done at National Institute on Drug Abuse Intramural Research Program (NIDA 
IRP) 
 
Localization of stimulation area: Structural MRI data will be acquired and the location of the 
stimulation will be determined using the structural image.  
Motor threshold determination:   
In determining motor threshold, first the scalp position closest to the motor representation (the 
“motor hot spot”) is sought. Then the motor threshold (MT) at this location is determined. The 
hotspot is located during the baseline session, whereas the motor threshold is measured every 
session. In accordance with the manufacturer’s instructions and other studies that have stimulated 
the anterior cingulate cortex (Downar et al., 2013b; Salomons et al., 2013), we stimulate leg motor 
cortex to obtain motor threshold. 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 23 of 72 
 
Determination of the optimal site (hot spot) for motor cortex stimulation and active motor 
threshold (AMT): Subjects will be seated in a recliner in a comfortable resting position and fitted 
with earplugs. The TMS H-coil connected to a magnetic stimulator (Magstim Rapid 2; Magstim 
Co. Ltd., Whitland, Wales, UK) will be placed over the leg-associated primary motor cortex. While 
suprathreshold stimuli will be  applied, the coil will be moved to determine the optimal scalp 
position for producing motor evoked potentials (MEP) of maximal amplitude (lowest threshold) 
in the contralateral target leg muscle.  
 
Subsequently motor threshold will be taken with the H-coil. This is done by using the single pulse 
mode and applying a series of 10 pulses at least 3 seconds apart. Stimulus intensities start at the 
level with which the motor hotspot was determined and will then be reduced in steps of 2% of 
maximal stimulator output. AMT is defined as the lowest stimulus intensity (in percentage of 
maximum stimulator output) that elicited at least five visible twitches out of 10 consecutive 
stimulations.  
This entire procedure (hotspot determination and threshold determination) can take 30 minutes to 
1.5 hour. If the hotspot is difficult to determine using the H-coil, a figure-of-eight coil may be used 
to find the hotspot location. If no motor hotspot can be determined within 1 hour or if the motor 
threshold exceeds 83% of maximal stimulator output, the participant may be discharged at the 
discretion of the lead investigator. The 83% of maximal output is used to allow for stimulation 
intensities as proscribed to reach 120% of MT.  Motor threshold will be measured at the beginning 
of each rTMS session.  
 
Sham Stimulation:  
The selection of the operation mode (active or sham) is done using a magnetic treatment card 
individually assigned to each subject. Each card is pre-programmed to activate either the active or 
sham TMS pulse mode when inserted into the card reader attached to the device.  Study personnel 
will not know which mode is being activated by any particular card, thus preserving the double-
blind. The H sham coil setting is designed to mimic the auditory artifact and the scalp sensations 
evoked by the real H coil, and to produce activation of facial muscles similar to the effect of a real 
H coil, without stimulating the brain itself. However, in experienced subjects, the difference 
between real and sham TMS, as well as the difference between different intensities of TMS is 
likely to be noticeable. In an attempt to avoid placebo effects, it is emphasized to the subject that 
the sensation is related to the stimulation of scalp nerves and muscles, and brain stimulation itself 
cannot be felt.  
 
Noticeable effects of the stimulation such as facial twitches could give away real TMS to the 
experimenter. Therefore, while efforts are taken to preserve the double-blind, it is possible that 
subject or the experimenter can become unblinded to the treatment condition. 
 
Session video recording: If a potential adverse event occurs during TMS stimulation, video 
footage of the session can help determine the nature of the incident. Thus, video will be recorded 
during threshold determination and during rTMS, barring any technical difficulties with recording 
instrumentation. If the session progresses without incident, this footage will be deleted within a 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 24 of 72 
 
week of the session. Should a possible adverse event occur, the footage may be used by the MAI, 
the ISM, and any experts they wish to consult to determine the nature of the event. Participants 
will not be given the option to opt out of the video recordings. If they do not wish to be recorded, 
the alternative is to not participate in the study. 
5. Relationship to other protocols  
 
All participants in this protocol will first enter the NIDA IRP screening protocol 06-DA-N415.  
Data from the screening protocol will be used by investigators in this study to determine eligibility. 
In line with current NIDA-IRP practice, every subject that is in a NIDA-IRP protocol will be 
invited to participate in protocol 10-DA-N457. Data obtained under 10-DA-N457 may be shared 
with this protocol.   The anatomic localization scans needed for this protocol may be served by 
those obtained under10-DA-N457.  
E) End of participation 
Participation in the study will be terminated once a subject has completed 10 sessions (per this 
protocol), or if their participation is no longer required. Tonic effects of rTMS can be expected 
from 2-3 weeks of daily treatment (10-15 sessions) onwards (Wassermann & Zimmermann, 
2012). Therefore no lasting effects should be expected from the herein proposed 10 sessions 
spaced over several weeks; with no more than three sessions on consecutive days and with 33%-
50% of sessions not involving real rTMS (sham sessions).  
 
Re-entry into the protocol will be allowed after two weeks following discharge. No published 
data indicate that there should be an upper limit to the number of TMS sessions in a lifetime; 
indeed a recent report noted no adverse effects of daily TMS over 40 and up to 80 sessions 
(Hadley et al., 2011). Nevertheless, we will maintain a period of two weeks where no TMS is 
undergone before re-entry into the protocol is allowed.  
 
Participants can withdraw from the study at any time should they no longer wish to participate. 
Typically, no data obtained during the course of this study will be shared with the individual 
participant or their health care providers. 
 
VI. Inclusion and Exclusion Criteria 
A) Description of the study population 
We will enroll up to 140 healthy adults who meet the exclusion/inclusion criteria in order to 
complete 50 subjects. Screening will be conducted using the basis of screening tools under the 
NIDA screening protocol, 06-DA-N415. 
B) Inclusion criteria 
Subjects must: 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
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1. Be able to give valid informed consent  
2. Be 18 – 55 years of age.  
a. Justification: Many neural processes change with age, and these changes 
could introduce unwanted variability in both behavioral and MRI signals. 
In addition, the risk of difficult-to-detect medical abnormalities such as 
silent cerebral infarcts increases with age. 
b.  Screening tool: History. Government-issued forms of identification (e.g. 
driver’s license, birth certificate) will be required when participant appears 
to be out of age range. 
3. Be in good health.  
a. Justification: Many illnesses may alter neural functioning as well as fMRI 
signals.   
b. Screening tools: Medical Assessment, Medical History and Physical 
Examination. Medical assessments include: Vital Signs, EKG, oral HIV 
test, height/weight measurements, urinalysis and blood sample. Tests on the 
blood sample include CBC, complete metabolic profile, TSH, ESR, STS 
and HIV (if needed to confirm a positive salivary test for HIV). The 
following individual laboratory results will independently disqualify 
individuals:  Cholesterol >250 mg/dl, Hemoglobin < 10.5 g/dl, WBC < 
2400/µl, LFTs > 3Xnormal, HCG positive, Casual serum glucose > 200 
mg/dl, Urine protein > 1+. The MAI will retain discretion to exclude at less 
extreme values, depending on the clinical presentation. (Serum glucose over 
140 mg/dl will be followed up with a fasting serum glucose assessment. 
Those with fasting glucose below 100 mg/dl may be considered for the 
protocol. Others will be rejected and referred for work-up.) MAI will make 
the final judgment on any questionable lab results.  
4. Right-handed.  
a. Justification: Using right-handed individuals will reduce variability in 
BOLD MRI data.  
b. Screening tool: Edinburgh Handedness Inventory.  
5.  Estimated IQ ≥ 85  
a.  Justification: Subjects must be able to perform a cognitively challenging 
task to a high standard.  
b. Screening tool: Wechsler Abbreviated Scale of Intelligence. 
 
C) Exclusion criteria 
1. Personal history of stroke, brain lesions, previous neurosurgery, any personal history of seizure 
or fainting episode of unknown cause, or head trauma resulting in loss of consciousness, lasting 
over 30 minutes or with sequela lasting longer than two days. 
a. Justification: Stroke or head trauma can lower the seizure threshold, and are therefore 
contra-indications for TMS. Fainting episodes or syncope of unknown cause could 
indicate an undiagnosed condition associated with seizures. 
b. Screening tool: TMS safety questionnaire, Medical History. 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
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2. First-degree family history of any neurological disorder with a potentially hereditary basis, 
including migraines, epilepsy, or multiple sclerosis.  
a. Justification: Neurological disorders can lower the seizure threshold, and are therefore 
contra-indications for TMS. First-degree family history of certain neurological 
disorders with a hereditary component increases the risk of the subject having an 
undiagnosed condition that is associated with lowered seizure threshold. 
b. Screening tool: TMS safety screening, Medical History. 
3. Cardiac pacemakers, neural stimulators, implantable defibrillator, implanted medication 
pumps, intracardiac lines, or acute, unstable cardiac disease, with intracranial implants (e.g. 
aneurysm clips, shunts, stimulators, cochlear implants, or electrodes) or any other metal object 
within or near the head that precludes MRI scanning. 
a. Justification: Any metal around the head is a contraindication for both MRI and TMS, 
as both methods involve exposure to a relatively strong magnetic field.  
b. Screening tool: TMS safety screening, MRI safety screening, Medical History. 
4.  Noise-induced hearing loss or tinnitus.  
a. Justification: individuals with noise-induced hearing problems may be particularly 
vulnerable to the acoustic noise generated by TMS and MRI equipment.  
b. Screening tools: TMS safety screening. 
5. Current use (any use in the past 4 weeks, chronic use within 6 past six months) of any 
investigational drug or of any medications with psychotropic, anti or pro-convulsive action. 
a. Justification: The use of certain medications or drugs can lower seizure threshold and 
is therefore contra-indicated for TMS.  
b. Screening tools: MRI safety screening questionnaire, Medical history, Medical 
Assessments: Urine toxicology analyzes for presence of a broad range of prescription 
and nonprescription drugs.  
6. Lifetime history of major depressive disorder, schizophrenia, bipolar disorder, mania, or 
hypomania. 
a.  Justification: The population of interest here is a healthy control population with no 
psychiatric disorders. In subjects with depression, bipolar disorder, mania or 
hypomania, there is a small chance that TMS can trigger (hypo)manic symptoms.   
b. Screening tools: SCID Screen Patient Questionnaire. Potential diagnoses will be further 
evaluated by a counsellor.  
7. Meet current DSM V criteria for moderate to severe substance use disorder (excluding 
nicotine), smoke daily, or urine toxicology positive for any illicit substance inconsistent with 
history given.  
a. Justification: The population of interest here is a healthy control population with no 
substance use disorder. Current use of illicit substances could impact on seizure 
threshold and is therefore contra-indicated for TMS. 
b. Screening tools: SCID Screen Patient Questionnaire. Potential diagnoses will be further 
evaluated by a counsellor, Drug Use Survey (DUS), Substance Use Disorder 
Evaluation, Medical Assessments: urine qualitative drug screen is performed for 
methadone, benzodiazepines, cocaine, amphetamine/methamphetamine, opiates, 
barbiturates, and tetrahydrocannabinol. 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 27 of 72 
 
8. Have met DSM V criteria for moderate to severe substance use disorder (excluding nicotine, 
alcohol and cannabis) in the past, or have met DSM V criteria for moderate to severe substance 
use disorder for cannabis or alcohol in the past 5 years. 
a. Justification: the population of interest here is a healthy control population with no 
present or past substance use disorder. 
b. Screening tools: SCID Screen Patient Questionnaire. Potential diagnoses will be further 
evaluated by a counsellor. Drug Use Survey (DUS), Substance Use Disorder 
Evaluation. 
9. History of myocardial infarction, angina, congestive heart failure, cardiomyopathy, stroke or 
transient ischemic attack, or any heart condition currently under medical care.  
a. Justifications: the risk of TMS for individuals with a heart condition is unknown.  
b. Screening tool: physical assessment (EKG), medical history. 
10. Pregnant women or women with reproductive potential who are sexually active and not using 
an acceptable form of contraception.  
a. Justification: it is unknown whether TMS poses a risk to fetuses.  
b. Screening tool: Medical assessments (urine pregnancy test) at the beginning of each 
visit that involves TMS or MRI.   
11. History of learning disability or current ADHD 
a. Justification: Subjects should be able to perform cognitive tasks to a high degree of 
accuracy, both in the MRI scanner and outside the scanner. Subjects with ADHD/LD 
may engage different neural circuitry even if they can perform the tasks. 
b. Screening tool: Wechsler Abbreviated Scale of Intelligence, Medical history, Adult 
ADHD Self-Report Scale. 
12. Participation in an rTMS session less than two weeks ago.  
a. Justification: in order to limit exposure to TMS, we will not enroll subjects who have 
received TMS less than two weeks ago.  
b. Screening tool: TMS safety screening questionnaire. 
 
VII. Clinical and Laboratory Methods  
Screening samples will be collected and processed as indicated in protocols 06-DA-N415. No 
other samples are collected for this protocol.   

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 28 of 72 
 
VIII. Collections and Storage of Human Specimens or Data 
Clinical data will be stored in the Clinical Data Warehouse (CDW) and in clinical research charts.  
Research charts will be stored in locked filing cabinet, in a locked room at the NIDA-IRP.  Imaging 
data are stored on a password protected drive on a UNIX server, which is maintained by the NRB. 
One copy of the consent form is kept in the participant’s NIDA-IRP medical chart, the other is 
kept in a limited access, locked cabinet with other consent forms from the same protocol.  
Summaries of data analyses (e.g. demographics, laboratory results, consent audit) are stored on a 
password protected shared NRB data drive.  Participant data contained within files on the NRB 
data drive are identified by ARC number, and not by other personal identifiers such as name. No 
samples are stored as part of this protocol. 
IX. Statistical Analysis 
Statistical methods will be chosen as most appropriate to the type of data collected for each phase 
of the protocol and for each task individually. We propose to test 50 individuals, each of which 
will partake in up to 10 conditions. Participants should complete at least three sessions in order to 
be deemed completers (a sham session and two levels of real TMS using the same behavioral task 
would constitute a useable piece of data). 
 
At a minimum, we plan to test (against a Sham TMS baseline) the efficacy of rTMS at 1 and 10Hz, 
using intensities of 100% and 110% of motor threshold (and 120% if the former are ineffective) 
on the Flanker (or Stroop or SSRT) task and on a number of MRI measures (see Study overview, 
Table 1). Planned group sizes are 10 subjects per condition, but an interim futility analysis will be 
undertaken when data for 6 subjects are available. A condition will be considered ineffective if 
fewer than 4 out of 6 subjects show a positive effect. A positive effect is defined as a 6% 2 change 
in error rate on the Flanker task. In the group of 10 subjects, a condition will be aborted of fewer 
than 6 out of 10 subjects show an effect. A group size of 10 will allow us to detect large effects 
(Cohen’s d of 1.4) at an alpha level of 0.05. We will employ a within-subjects design to minimize 
interindividual variability. If the true effect size is smaller than a Cohen’s d of 1.4, we should still 
be able to observe trends.  
 
Accrual Request:  
Due to the nature of this pilot protocol, the number of participants needed will depend greatly on 
the results of the initial tests. To go through the intensity range with one stimulus frequency and 
                                                 
2 We derive this estimate from a two-drug double-blind, placebo-controlled study performed at NIDA in which 
smokers and non-smokers performed a Flanker task on nicotine, varenicline or neither (Carroll, Sutherland, 
Salmeron, Ross, & Stein, 2013). In this study, the administration of nicotine led to a 9% change in performance 
(increase in errors on incongruent relative to congruent trials). We use this as an indication of how an intervention 
(here nicotine) can affect performance on a Flanker task. We take 2/3 of this change (6%) as indicative of an effect 
of TMS. 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 29 of 72 
 
one task (see Figure 5), a minimum of 16 subjects are required (if all subjects perform 10 sessions 
and all tests indicate a positive effect). To assess the proposed range of conditions (see Study 
overview, Table 1) for one behavioral task, 32 to 40 subjects will be needed if all subjects perform 
10 sessions.  To accommodate the likelihood that some subjects may not be able to complete 10 
sessions, we estimate that we will need 50 subjects to complete this pilot.  
Thus, we will enroll 140 subjects to arrive at a number of 50 completers. Participants should 
complete at least three sessions in order to be deemed completers (a sham session and two levels 
of rTMS using the same behavioral task. In accordance with NIH guidelines, a person who is 
readmitted into the protocol (a minimum of 6 month after the participant is discharged, see the 
parameter boundaries outlined in V.A), he or she will be considered as the same individual for the 
enrollee count. Official enrollment reports will therefore reflect the number of unique individuals 
enrolled in the study. However, to retain transparency we will also report the number of re-enrolled 
subjects along with the number of TMS sessions to the IRB.  
 
If more than 50 subjects are required (for example this is likely to occur if performance on the 
Flanker task appears not to be modulated by medial prefrontal TMS) we will seek permission from 
the IRB to recruit additional subjects. 
 
For conditions that show positive trends using a group of 10, a power analysis will be performed, 
and we will seek IRB approval to recruit an appropriate number of subjects to gain the statistical 
power needed to assess the effects of the stimulation paradigm with sufficient sensitivity and 
specificity. 
 
In the event that TMS stimulation appears entirely ineffective (that is, if none of the intensities at 
1Hz or 10 Hz elicit effects on the Flanker task or MRI measures), we will amend the protocol and 
seek permission from the IRB before continuing. 
 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 30 of 72 
 
 
Figure 5. Example flowchart for 1Hz stimulation with the Flanker task. Letters and asterisks 
represent conditions outlined in Table 1 (Study overview section). Cr 1: Criterion 1; 4 out of 6 
subjects show an effect. Cr 2: Criterion 2; 6 out of 10 subjects show an effect. Cr 3: Criterion 3; 
difference in ACC against sham significant at p<0.001 uncorrected in 2/3 of subjects. Blue: 
behavioral sessions. Green: MRI sessions. Green arrow: criterion is met. Red arrow: criterion is 
not met. 
X. Additional considerations 
This protocol does not intend to determine the safety or efficacy of the HAC coil.  Rather, it seeks 
to establish optimal stimulation parameters for and appropriate behavioral markers and biomarkers 
of anterior cingulate rTMS. This protocol is therefore exempt from CRF Title 21, part 812, and 
6 subjects
ABC
Cr1 
+ 4 subjects
ABC
6 new subjects
AD
Cr1 
Cr2 
6 subjects
A*B*C*
A**B**C**
A***B***C***
Cr3 
6 subjects
A*D*
A***D***
(rsMRI, ASL)
+ 4 subjects
AD
Cr2 
6 subjects
A*D*
A**D**
A***D***
Cr3 
Cr3 
1Hz with 
new task 
and/or 10Hz 
Effective at 1Hz, 120%
START 10 Hz
ACC rTMS seems  
ineffective. Go 
back to IRB.
6 subjects
E*H*
E***H***
(rsMRI, ASL)
Cr3 
1Hz
10Hz or 10Hz 
with new task  
Effective at 1Hz, 
100% or 110%.
START 10 Hz
Task false 
positive? 1Hz 
with new task 
and/or 10Hz 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 31 of 72 
 
does not require an IDE. A previously approved protocol (Protocol 479) also uses the HAC coil 
and has received an exemption from CRF Title 21, part 812, for the same reason.  
 
XI. Subject Safety monitoring 
A) Parameters to be monitored 
Seizure monitoring procedures: At screening and on each study day involving a TMS session, 
subjects will fill out the TMS safety form to ensure that there is no change in the subject’s 
suitability for TMS.  They will also have a urine drug screen and pregnancy test (females). If urine 
drug screen is positive, they will be rescheduled; if pregnant, females will be notified, referred if 
necessary for care, and discontinued from participation in the study. Subjects will be monitored 
throughout each rTMS session by trained staff.  Study staff will be trained in TMS safety using 
the most recent TMS practice and safety guidelines (Rossi et al., 2009).  Study staff will visually 
monitor subjects at all times during rTMS application for possible signs of seizures, such as 
involuntary muscle movements, generalized tonic stiffing of muscles, salivary frothing, or loss of 
consciousness.  In the event of a seizure, staff will have immediate access to life support equipment 
and antiepileptic drugs. 
Seizure management procedure: In the event of a seizure, the following procedure (Towne & 
DeLorenzo, 1999) will be followed by staff in order to minimize additional trauma:   
1. Protect patient’s head and limbs from injury. 
2. Ensure an adequate airway.  
 When jaws are clenched do not attempt to pry open the mouth to insert a mouth gag.  At 
no time should anything be placed in the patient’s mouth. 
 When safely able, turn the patient to the side to prevent aspiration and promote drainage of 
mucus and saliva. Do not force any part of the patient’s body during the seizure. 
 Loosen any constrictive clothing. 
3. Immediately call the on-call study physician or approved covering clinician (available in the 
building during TMS sessions).  When appropriate, call for medical assistance by dialing 911 
in order to have the patient transferred to Johns Hopkins Bayview emergency room 
4. Observe patient for:   
 Initial movements/ sensations 
 Progression of movements. 
 Change in respiratory status. 
 Skin color. 
 Incontinence. 
 Level of consciousness: 
 Ability to communicate. 
 Level of orientation. 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 32 of 72 
 
 Duration of seizure activity. If after two minutes, the seizure has not resolved, physician or 
approved covering clinician will order and physician/approved covering clinician or nurse 
will administer, midazolam IM, 10 mg that is contained in a lock box in the TMS suite. 
 Provide supportive care after the seizure resolves.  
 Orient patient to time and place.                       
Investigators will provide to any subject experiencing a seizure a letter documenting that the 
seizure was experimentally produced. 
The investigators, counselors and medical staff will be prepared to address psychological or 
medical issues that may arise during the study.  A physician or approved covering clinician 
knowledgeable about TMS will be immediately available in the building whenever rTMS is being 
administered and will be available by telephone or pager 24 hours a day for consultation.  NIDA 
health personnel will be available 24 hours a day in the event of a medical emergency.  If 
immediate medical assessment or intervention is required, the subject will be referred to the 
appropriate medical facility. Information on all adverse events will be cumulated and reported to 
the Addiction Institutional Review Board (IRB) with each continuing review application.  
Unexpected or serious adverse events (defined in accordance with NIH and NIDA policy) will be 
promptly reported to the NIDA Clinical Director and Addictions IRB in accordance with National 
Institutes of Health (NIH), and NIDA policy. 
fMRI: At screening and on each study day involving an fMRI scan, subjects will fill out an fMRI 
safety form to ensure that there is no change in the subject’s suitability for fMRI scanning.  They 
will also have a urine drug screen and pregnancy test (females). If urine drug screen is positive, 
they will be rescheduled; if pregnant, females will be notified, referred if necessary for care, and 
discontinued from participation in the study. At all times during fMRI scanning study clinician 
and scan operator will be present in the control room and subjects will be able to communicate 
with them via intercom. Subjects will also have a device they can squeeze to alert the operator in 
case of an urgent issue. 
B) Criteria for individual subject withdrawal from the study: 
 
A participant will be withdrawn from the study if he or she: 
- 
so requests, or withdraws consent. 
- 
requires study visits to be rescheduled more than twice for positive urine triage.  
- 
develops an exclusionary medical condition or medical problem, for which, in the Medical 
Advisory Investigator’s (MAI’s) judgment, it is in the participant’s best interest to be 
withdrawn from the study. 
- 
becomes or is found to be pregnant  
Participants withdrawn from the study for any medical reason will be referred for appropriate 
medical follow-up. 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 33 of 72 
 
XII. Outcome measures: 
The sensitivity of several outcome measures will be compared and assessed. These measures will 
include behavioral tasks and MRI measures. Not all MRI outcome measures mentioned in this 
section will necessarily be investigated for reasons outlined above (see Figure 2). 
Behavioral tasks: A flanker task, with the difficulty level adjusted to the individual’s capacity will 
be used. If the flanker task proves ineffective in showing rTMS effects, other tasks which have 
been shown to recruit ACC will be used. Performance before TMS will be compared with 
performance after TMS.  
Task fMRI: In Phase B, the task will be performed in the scanner. The recruitment of a stimulated 
area in a task is expected to change under conditions where that area is used. For example, after 
stimulation, the ACC may be more or less engaged in the incongruent conditions of the flanker 
task than before stimulation. 
Resting-state fMRI: rTMS could be effective in changing connectivity between the targeted tissue 
and connected regions in networks relevant to addiction. Resting-state connectivity analysis can 
be used to detect these differences. In depression, there is evidence that rTMS may influence 
resting-state functional connectivity between a targeted region and brain areas it is connected with 
(Salomons et al., 2013; Speer et al., 2003).  
Other MRI measures: additional MRI measures may be used to further characterize the effects of 
TMS. These include MR spectroscopy, which is able to measure changes in glutamate and other 
neurometabolite levels, and arterial spin labeling (ASL) which is able to indirectly capture absolute 
metabolic changes, and used as surrogate for neuronal activity. Both of these measures have 
previously been used to capture effects of TMS (Luborzewski et al., 2007; Michael et al., 2003; 
Moisa et al., 2010; Stagg et al., 2013)  
 
XIII. Human Subjects Protection 
A) Regulatory and ethical consideration 
The study will be conducted in accordance with Good Clinical Practice (GCP), 21CFR Parts 50 
and 56, and all applicable regulatory requirements. 
B) Subject Selection 
Applicants who fulfill study criteria will be included regardless of race, ethnicity, socioeconomic 
status, religious and political affiliations, and similar factors.  We will base recruitment 
demographics similar to that of prior recruitment of a healthy control population in Baltimore. The 
expected demographic composition is approximately 64% White, 32% Black or African American, 
3% Asian, 0.3% American Indian and Alaska Native, 0.04% Native Hawaiian and Other Pacific 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 34 of 72 
 
Islander and 0.8% some other race (http://www.census.gov/). Of this population (any race), 2% 
are Hispanic or Latino.  
APPROVED STUDY POPULATION 
  
FEMALE 
MALE 
TOTAL 
FEMALE 
MALE 
TOTAL 
ENROLLMENT 
ENROLLMENT 
ENROLLMENT 
COMPLETERS 
COMPLETERS 
COMPLETERS 
APPROVED 
CEILING 
70 
70 
140 
25 
25 
50 
 
NIH TARGETED/PLANNED ENROLLMENT 
  
Sex/Gender 
ETHNIC CATEGORY 
Females 
Males 
Total 
Hispanic or Latino 
2 
 2 
4 
Not Hispanic or Latino 
68 
68 
136 
Ethnic Category: Total of All Subjects* 
70 
70 
140 
RACIAL CATEGORIES 
  
  
  
American Indian/Alaska Native 
  
  
  
Asian 
2 
2 
4 
Native Hawaiian or Other Pacific Islander 
  
  
  
Black or African American 
23 
23 
46 
White 
45 
45 
90 
Racial Categories: Total of All Subjects* 
70 
70 
140 
*The “Ethnic Category: Total of All Subjects” must be equal to the “Racial Categories: total of All 
Subjects.” 
 
C) Exclusion of children 
Children under the age of 18 are excluded from this study because safety of rTMS in children has 
not been studied. In addition, this study is more than minimal risk and presents no direct benefit.  
Minors can therefore, not be enrolled. 
D) Exclusion of other vulnerable populations 
Pregnant women will be excluded as it is not known if TMS or fMRI have deleterious effects to 
pregnant mother or fetus.  Those who are unable to understand and provide their own consent will 
also be excluded, as compliance with study procedures is essential to the integrity of the study.  

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 35 of 72 
 
E) Justification of sensitive procedures 
The use of sham (placebo) stimulation is necessary to evaluate the effects of rTMS.  This is 
necessary to evaluate the action of rTMS with respect to study hypotheses.  
F) Safeguards for vulnerable populations 
No vulnerable populations are recruited into this study. Pregnancy testing is used to prevent fetal 
drug exposure.  
G) Qualifications of investigators 
Elliot A. Stein, Ph.D., (PI) is a behavioral neuroscientist and the Chief of the Neuroimaging 
Research Branch, NIDA/IRP.  His background in motivation and reinforcement began as a NIDA 
postdoctoral fellow with Dr. James Olds at the California Institute of Technology.  His laboratory 
at the Medical College of Wisconsin was one of the first to apply fMRI to the study of human drug 
abuse.  He will share responsibility for the design and implementation of experimental paradigms 
and procedures and will assist in interpreting and presenting findings and preparing manuscripts.  
He will not obtain consent.  
Osama Abulseoud, M.D. (MAI), is a staff clinician in the Neuroimaging Research Branch. He 
received his MD degree from Cairo University in Egypt then went through an extensive series of 
clinical and research training in eminent institutes. He was the sole psychiatrist at Mayo Clinic that 
established and successfully treated patients with refractory mental illness with deep brain 
stimulation. He will be responsible for the medical aspects of the protocol, is ACLS certified and 
will share responsibility for the implementation of experimental paradigms and procedures as well 
as the interpreting and presenting of findings and preparing of manuscripts. He will obtain 
informed consent for this protocol. 
Betty Jo Salmeron, M.D., is Board-Certified in psychiatry and is a Staff Clinician in the 
Neuroimaging Research Branch, NIDA/IRP.  She trained at the Massachusetts General Hospital, 
where she was a chief resident. She will be responsible for the medical aspects of the protocol and 
is ACLS certified. She will share responsibility for the design and implementation of experimental 
paradigms and procedures as well as the interpreting and presenting of findings and preparing of 
manuscripts. She will oversee all medical aspects of the protocol and obtain informed consent. 
Elise Lesage, PhD, (Guest Researcher at NIDA) is a FWO/Marie Curie Postdoctoral Fellow in the 
Department of Experimental Psychology at Gent University, Belgium. Prior to her current 
position, she was a post-doctoral visiting fellow at the Neuroimaging Research Branch at NIDA-
IRP. She has extensive experience using neurostimulation techniques (TMS, tDCS), neuroimaging 
techniques (fMRI), and various cognitive tasks to investigate the neural basis of cognitive 
processing, and has worked with both clinical and non-clinical groups. She has been trained in 
TMS procedures, has over 3 years’ experience administering TMS. Dr. Lesage will assist in data 
analysis and manuscript preparation for data from this protocol. Dr. Lesage is fully credentialed 
with clinical access and her required trainings are kept up-to-date. As such, she is currently able 
to access and analyze identifiable data directly on NIH systems via VPN. No data is transferred 

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directly to her and she does not store data offsite. These activities are covered by a signed FWA 
agreement. Dr. Lesage has also been given a copy of SOP 16 - Reporting Requirements for 
Unanticipated Problems, Adverse Events and Protocol Deviations. 
Thomas Ross, Ph.D., earned his doctorate in Experimental Plasma Physics and holds the position 
of Staff Scientist at NIDA-IRP.   He has spent the last 20 years involved in the acquisition and 
modeling of noisy signals. He also spent 2 years as a professional computer programmer and has 
extensive hardware and instrumentation experience.  He will hold primary responsibility in all 
aspects of the acquired fMRI data including the development and application of novel analysis 
techniques. He serves as systems administrator on this computationally demanding project and is 
responsible for the integrity of all data storage and backup, hardware and software 
implementations and will program and assist in the development of new scanner-compatible 
cognitive tasks. He will not obtain informed consent. 
Yihong Yang, Ph.D. is an Investigator and Chief of the MRI Physics Unit, Neuroimaging Research 
Branch.  Dr. Yang has extensive experiences in the development of functional and structural MRI 
techniques. He, with his colleagues, has developed fast spiral BOLD imaging, multislice arterial 
spin labeling perfusion imaging, event-related ASL perfusion imaging, silent fMRI for auditory 
studies, a novel diffusion tensor imaging, and methods for reduction of susceptibility artifacts. Dr. 
Yang will be responsible for the development and implementation of functional and structural MRI 
techniques employed in this protocol. He will not obtain informed consent. 
Karen McCullough, B.S., is a research associate at NIDA IRP, with 26 years’ experience in clinical 
research.  She has been trained in TMS procedures, is BLS certified and has experience conducting 
TMS sessions.  She will be conducting rTMS sessions in this protocol. She will not obtain informed 
consent. 
 
H) Consent documents and process 
Designation of those obtaining consent 
Study investigators designated as able to obtain consent in Qualifications of Investigators section 
above, will obtain informed consent.  In addition to completion of all required NIH and 
institutional required clinical access and consent trainings (per NIH SOP 25) there will be protocol-
specific consent training. In general that involves demonstrated knowledge of protocol procedures 
and consent material, observing a minimum number of consents and being observed a minimum 
number of times by the MAI, PI, or other senior staff (as determined by PI or MAI). The MAI or 
PI will determine when an associate investigator has completed training and is deemed ready to 
obtain consent. The observation process is usually 3 – 5, but again, is determined by the MAI or 
PI. 
Consent procedure  
Written informed consent will be obtained from each subject at entry into the study and will be 
conducted in a private setting.  The consent document will include details regarding all study 

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procedures (e.g. TMS and fMRI). Informed consent is obtained by the following process: Subject 
reviews the study consent form; a designated investigator3 then meets with the subject in a private 
area to review the consent, confirm subject understanding, and to answer any questions.  This 
process will include reviewing the entire document with the participant in order to further ensure 
participant understanding. Once the subject verbally demonstrates understanding to the 
investigator and agrees to the process, a consent quiz is administered. Provided the participant 
answers at least 80% of the questions correctly, the participant is invited to sign the consent form. 
If the score on the consent quiz is less than 80% correct, the investigator reviews the incorrect 
answers and re-administers the consent quiz.  Failure to obtain 80% correct on the second 
administration of the quiz excludes the subject from participating in the study. If the participant 
does score  80% on the consent quiz, they are asked to sign and date the consent form.  
Participants will be required to correctly answer questions #5 and #7 of the quiz in order to be in 
the study (#5 states “I cannot be in this study if I have certain types of metal in your body (T/F)” 
and #7 states “I cannot withdraw from the study once I sign the consent form (T/F).”   The 
investigator co-signs the consent form and, the consent is also signed by a third-party witness to 
the subject’s signature.  Two copies are made of the consent. The original is attached to the 
participant’s medical record, the participant is given a copy of the consent form for his/her own 
records and the second copy is stored with other protocol consents in a binder which is located in 
a locked filing cabinet. The consent quiz is attached to and stored with this latter copy. Once the 
signed consent has been obtained, the investigator will note the participant’s enrollment in the 
study in the CDW database.  Only after this last step has been completed will study procedures 
begin.   
Consent documents 
The consent form contains all required elements. The consent document for healthy volunteers is 
submitted with this protocol. 
 
XIV. Evaluation of Risks/Discomforts and Benefits ratio 
A) Anticipated Benefit 
There is no prospect of direct health benefits to subjects in this study, but the study is likely to 
yield generalizable knowledge about the potential therapeutic use of TMS as a treatment in drug 
abuse. Moreover, the study may also yield generalizable knowledge about the local and brain 
circuit effects of rTMS delivered by the H-coil.  
                                                 
3 Please see ‘Investigator Qualifications’ for details of investigators designated to obtain consent.  

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B) Risks and discomforts 
1. Tasks completed inside and outside of the scanner: 
 Participants may find the tasks that they are asked to perform during, before and after scanning 
sessions boring, difficult, and/or frustrating.  
Risk Minimization.  In order to reduce discomforts associated with performing the 
emotional and cognitive tasks, scanning sessions and task sessions outside of the scanner 
are organized in such a way that participants will not perform tasks for extended periods 
of time and will be given a chance to rest between tasks.  In addition, the tasks are 
designed to make performance neither too difficult nor too easy.  Ideally, individual 
adjustments of task difficulty enable participants to remain actively engaged in the task.  
2. rTMS  
 
Magnetic stimulation 
 
TMS uses magnetic pulses, and could therefore interfere with the function of pacemakers, 
implanted pumps or stimulators. Moreover, the use of magnetic pulses over the head could affect 
metallic objects inside the eye or skull. The effects of magnetic stimulation on fetal development 
are unknown.  
Risk minimization: Subjects will undergo TMS safety screening and will be excluded from 
participation if they have pacemakers, implanted pumps or stimulators, and metal objects 
inside the eye or skull. If they have a question about any metal objects being present in 
their body, they will be prompted to inform the physician or approved covering clinician.  
In addition, all magnetic objects (for example, watches, coins, jewelry, and credit cards) 
must be removed.  Women of childbearing potential will have a pregnancy test before each 
rTMS session and pregnant women will be excluded. 
Seizure   
 
The greatest concern with rTMS treatment is the possibility of inducing a seizure. The 1996 
and 2008 International Consensus Safety Guidelines describe the maximum safe duration of an 
rTMS train based on intensity and frequency of the stimulation (Rossi et al., 2009; Wassermann, 
1998). Since the issuance of these guidelines, the incidence of TMS-induced seizures worldwide 
is very low, estimated as “rare” with low-frequency (< 1 Hz) rTMS and < 1% with high-frequency 
(> 1 Hz) rTMS (Rossi et al.,  2009).  There have been no reports of any subject developing epilepsy 
or repeated spontaneous seizures after rTMS. All rTMS-induced seizures to date have been 
transient and self-limiting, without long-term sequela (Loo, McFarquhar, & Mitchell, 2008; Rossi 
et al., 2009).  Concurrent medication has been implicated as a risk factor in some of the seizures 
reported with rTMS. Some have suggested that certain medications, e.g. tricyclic antidepressants 
and neuroleptics, should be contraindicated in those receiving rTMS (Rossi et al., 2009; 
Wassermann, 1998).   

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Risk Minimization: There is a small risk of seizures from rTMS which is usually 
associated with high frequency stimulation (20 Hz) and in the context of subjects taking 
medications that can affect seizure threshold.  Neither will be the case in this study.  
Subjects will undergo TMS screening which will exclude subjects with a family history 
of epilepsy, subjects who take medication that can affect the seizure threshold, and 
subjects with recurring fainting spells. Psychotropic medications and use of illicit drugs 
associated with a reduction in the seizure threshold will also be exclusionary in this 
study.  All staff administering TMS will be trained in BLS.  An ACLS certified 
physician or approved covering clinician will be available in the building while TMS 
sessions are in progress and will be called in the event of any medical issue.    
 
Vasovagal syncope  
 
A small number of vasovagal syncopes have been reported following rTMS stimulation. In a 
number of the reports on TMS-induced seizures, it is unclear whether the event was a seizure or a 
syncope (Rossi et al., 2009).  
 
Risk minimization: Subjects undergo screening and are not admitted to the protocol if 
they have a history of fainting from an unknown cause. All staff administering TMS 
will be trained in BLS.  An ACLS certified physician or approved covering clinician 
will be available in the building while TMS sessions are in progress and will be called 
in the event of any medical issue. 
Scalp pain, headache and other minor symptoms  
 
Mild headache responding readily to non-opioid analgesics is the most common side-effect of 
rTMS reported in depression treatment trials. It may result from direct stimulation of superficial 
facial muscles or nerves, as rTMS may cause an uncomfortable facial twitch (Loo et al., 2003). 
However, discomfort levels are quickly habituated to and painful sensations over the scalp 
decrease over sessions (Anderson et al., 2009; George et al., 2010; O’Reardon et al., 2007).  In 
sham-controlled studies that reported rates of side-effects, about 28% of subjects experienced 
headache and 39% experienced pain or discomfort during stimulation with active rTMS, compared 
with rates of 16% and 15%, respectively, after sham rTMS (Loo et al., 2008).  There is one report 
of nausea in two subjects from rTMS over the cerebellum at an intensity of 90% of MT with a 
frequency of 0.9 Hz for 15 min (Satow et al., 2002). A small number of reports described focal 
pain, discomfort, and other minor symptoms. 
The rTMS coil may heat up with prolonged use, raising the risk of scalp burns (Pascual-Leone 
et al., 1991).  
In a single case report, a 57-year-old women being treated for major depressive disorder 
reported a pulsating, localized dental twinge in the region of the upper left jaw associated with the 
rTMS treatment (Ropohl, Hiller, Elstner, Sperling, & Kornhuber, 2004).  The pain disappeared 

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during the inter-train interval but emerged again during the next train of stimuli. The pain was 
dependent on the stimulus intensity and remained despite repositioning of the coil. The cause of 
the pain is unclear, but may be due to stimulation of the trigeminal nerve by the rTMS magnetic 
field (Ropohl et al., 2004).  
 
Risk Minimization:  The sensation of TMS over the scalp becomes better tolerated with 
experience, and habituation procedures can exploit this effect to minimize scalp pain. 
We will therefore include brief habituation procedures during the orientation visit and 
during rTMS visits. Similar procedures have been used in medial prefrontal cortex 
stimulation paradigms (Downar et al., 2013b). Headaches and scalp pain usually go 
away promptly with nonprescription medication, such as acetaminophen, which will 
be offered to subjects as needed.  
Coil heating will be avoided in the present study by using an air-cooled coil and by 
allowing the coil to cool off between treatment sessions. Moreover, the HAC coil is 
designed to shut down immediately if the coil temperature exceeds 38° C (100.4° F).   
If a participant reports dental pain, rTMS will be stopped. Acetaminophen or other 
medications may be provided for treatment of pain, if necessary. 
 
Acoustic noise:  
 
Rapid excitation of the stimulation coil produces clicks that have resulted in transient increase 
in the auditory threshold of human subjects (Wassermann, 1998).  This should not occur if earplugs 
are used. Loo et al., (2001) assessed the auditory threshold before and after 30 sessions of rTMS 
given over 6 weeks in a depression treatment trial. All subjects wore earplugs during stimulation. 
No significant mean changes in hearing threshold were detected. Two subjects showed small 
bilateral increases in threshold at mid to high frequencies, which returned to previous levels when 
retested 1 month later. Personnel in the rTMS room will also wear hearing protection during the 
delivery of stimulation. FDA guidelines require testing of auditory threshold only if subjects 
receive rTMS at a frequency higher than 1 Hz for four or more weeks. Auditory threshold will not 
be monitored in the current proposed study. 
 
Risk Minimization: The subjects will be fitted with earplugs to wear during the study 
to protect their hearing from the noise of the magnet.  Subjects with known hearing loss 
will be excluded. Investigators will ask each subject to report immediately any 
loosening or detachment of a subject’s earplug during application of rTMS.  If a subject 
reports or if an investigator observes that a subject’s earplug has loosened or fallen out, 
investigators will immediately stop applying rTMS. 
rTMS-Induced Manic Effects and other psychiatric complications  
 
rTMS over dorsolateral prefrontal cortex has induced manic and hypomanic symptoms in a 
very small number of healthy and depressed subjects.  

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Nedjat and Folkerts (1999) reported hypomanic symptoms after a single session of rTMS in 
three female subjects without a prior history of mood disorder. Stimulation parameters were 
comparable to those used in depression treatment studies and studies of mood changes in healthy 
subjects. 
Two subjects with unipolar depression have shown manic changes with rTMS treatment. 
George et al. (1995) reported mild hypomania in a patient with refractory recurrent unipolar 
depression. This female patient had responded well to previous shorter courses of rTMS, but 
became hypomanic after nine treatment sessions in the third course. The hypomanic symptoms 
resolved when rTMS was reduced to treatment every second day. Sakkas et al. (2003) reported on 
a 55-yr-old depressed male who became hypomanic for the first time after 3 weeks of twice daily 
rTMS to the left dorsolateral prefrontal cortex and concomitant citalopram. Over the following 
week, medication was stopped, but rTMS continued. His symptoms deteriorated into mania and 
rTMS was also stopped. The patient gradually became depressed again and five months later, a 
second course of 2 weeks of twice-daily rTMS also resulted in hypomania. Treatment intensity 
was decreased to once-a-day TMS treatment, and the patient returned to a normothymic state. 
rTMS may also have a therapeutic effect in mania, with high-frequency application to the right 
prefrontal cortex (Praharaj, Ram, & Arora, 2009) 
We are aware of six reports of mania induced by rTMS in patients with bipolar disorder 
(Dolberg, Schreiber, & Grunhaus, 2001; Garcia-Toro, 1999; Hausmann et al., 2001; Huang, Su, & 
Shan, 2004; Sakkas et al., 2003), in some cases while taking mood-stabilizing medications. In a 
trial of right prefrontal rTMS for post-traumatic stress disorder, two patients developed a manic 
episode after the third session (Cohen et al.,  2004). One patient was randomized to 1 Hz rTMS 
and one to 10 Hz. Another subject in this trial developed a ‘mild rage attack, probably related to 
the stimulation’. Apart from manic symptoms, there is a single case report of high-frequency left 
prefrontal rTMS inducing transient persecutory delusions in a depressed, non-psychotic subject 
(Zwanzger et al., 2002). 
In all the above cases, the psychiatric side-effects induced by rTMS were transient, resolving 
with the cessation of rTMS or rapidly responding to pharmacological treatment.   
 
Risk Minimization: Reports of manic symptoms occurred exclusively after unilateral or 
bilateral DLPFC stimulation, whereas the site stimulated in this section is medial PFC 
(ACC). The risk of side-effects associated with DLPFC stimulation is therefore 
minimal. Moreover, the risk for psychiatric complications appears to exist 
predominantly in subjects with pre-existing psychiatric morbidity (all except one 
report), and in patients who are on antidepressants or antipsychotics. An important 
means of minimizing risk in the current proposed study is therefore to exclude this 
population. In addition, rTMS sessions will not occur on more than 3 consecutive days 
of which 1 or 2 will be sham sessions. Finally, subjects will be informed of the small 
risk of transient mania or hypomania, informed of early symptoms to look out for, and 
instructed to contact the study physician if they believe they are experiencing any such 
symptoms. 
 

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Date of Submission: November 30, 2018  
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3. MRI scanning 
Magnetic field 
When used on appropriately qualified individuals, MRI presents virtually no risk as long 
as technical scan parameters remain within FDA guidelines. There is no exposure to x-rays or 
radioactivity.  The radio waves used have produced burns (most of these minor) in about one in a 
million exams.  The field of the 3T scanner is higher than that of most clinical magnets and there 
is a remote chance of other risks associated with the stronger magnetic field that might include 
temporary dizziness with nausea and flickering light sensations. The magnet may move metal 
implants in the body, the motion of which could be painful and harmful.  Metal implants may also 
cause burns from the radio frequency energy used.  While inside the magnet, subjects may 
experience an acute panic attack due to claustrophobia. Subjects may also experience mild, 
remittable discomfort from lying in the scanner. 
 
Risk Minimization.  To ensure adherence to FDA guidelines for MRI, a trained MRI 
operator who has been instructed in these guidelines performs all machine 
manipulations.  Other preventative measures include assuring that all equipment to be used 
during imaging sessions is MR compatible, that participants are familiar with the MRI 
environment (using the mock scanner), and that participants are aware of how to signal the 
MR operator if they need to do so during the session.  Furthermore, participants are 
screened prior to each MRI session for any MR contraindications, including metal 
implants, pregnancy, fear of small, enclosed spaces, and inability to lie still for prolonged 
periods of time.    
  
Acoustic Noise   
 
The sound generated by an MR system usually consists of a series of repetitive pulses. Acoustic 
noise is a result of the mechanical vibration produced by the gradient coils when the large 
currents are applied to them to create time varying imaging gradient fields. Some subjects may 
experience temporary, reversible shifts in hearing threshold after MRI. 
 
Risk Minimization: MRI compatible headphones and earplugs will be used for hearing 
protection. The use of these two devices in combination reduces the noise level to levels 
much lower than those required by the Occupational Safety and Health Administration 
(OSHA) regulations (Occupational Noise Exposure – 1910.95, www.osha.gov) regulations 
for lifetime exposure, and provides effective hearing protection for the participants. 
Nevertheless, some subjects may experience temporary, reversible shifts in hearing 
threshold after MRI. 
4. Mock Scanner 
 

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Potential side effects associated with the mock scanner include mild backache from having to lie 
still for a prolonged period of time, temporary difficulty hearing soft sounds after the exam, and 
being uncomfortable being in a small enclosed space.  
 
Risk Minimization.  Pre-study screening for history of back problems or claustrophobia will 
minimize the likelihood of side effect from mock scanning.  In addition, participants will be 
given adequate hearing protection to minimize hearing difficulties resulting from Classification 
of risk (for the study as a whole) 
C) Overall Risk Determination 
More than Minimal Risk: Overall risk and discomfort in this study are more than minimal due to 
the use of rTMS. This level of risk is justified because it may facilitate understanding of the 
therapeutic uses of TMS in addiction, thereby addressing unmet medical needs. 
XV. Protection of participants’ Privacy and Confidentiality 
Great care is taken to protect participants’ privacy and strict participant confidentiality will be 
maintained throughout. Participants will be consented in a private setting. Participants will be 
assigned a code number without personally-identifying information following their first contact in 
the protocol. This number will be used throughout the experiment and will be the only identifier 
on specimen samples, behavioral and physiological archival data, fMRI/MRI and TMS data.  The 
identity of participants will not be revealed at scientific meetings, in publications or other vehicles 
of public communication. The PI and co-investigators will have access to the ID code, which will 
be maintained in a separate electronic file from the study data. Medical and questionnaire data will 
be gathered in a secure database on a closed network. Access to records is protected by a system 
of password-protected accounts and monitored by the Clinical Director (CD). Data downloaded 
for analysis will be identified only by participant number. A Certificate of Confidentiality will be 
obtained for this protocol. 
A) Medical records:  
All medical history information is stored in the CDW database, which is password protected and 
has limited access.  In addition, each participant is assigned a medical records folder during the 
screening process, which is used to store source documents collected on paper rather than 
electronically.  This record is kept in locked cabinet and access to these files is limited to study 
personnel, including study investigators, nursing staff and clinicians.    
B) Research Records/Data.  
Participant records will be kept in a research record folder upon entry to the first NRB study that 
they enroll in.  This folder is kept in a locked cabinet, in a locked room, which has limited access.  
Participant folders remain in this room at all times, apart from when required for study sessions.  
At the completion of each session the folder will be returned to the locked cabinet by the 
investigator or research associate responsible for the experimental session.  

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C) Stored Samples.  
No biological samples will be stored for future use.  
XVI. Study Agents/Interventions 
This protocol uses a TMS intervention. We will use an HAC coil from Brainsway Inc., (Jerusalem, 
Israel). This protocol does not intend to determine the safety or efficacy of the HAC coil and should 
therefore be exempt from CRF Title 21, part 812. An IDE is not necessary for this protocol. A 
previously approved protocol (Protocol 10-DA-N479) also uses the HAC coil and has received an 
exemption from CRF Title 21, part 812, for the same reason.   
XVII. Event Characterization and reporting to the IRB, Clinical Director 
(CD) and Sponsor 
Adverse events, protocol deviations, unanticipated problems (UP), Unanticipated Adverse Device 
Effects (UADEs), serious adverse events, sponsor and serious, are defined as described in NIH 
HRPP SOP 16 (“Reporting Requirements for Unanticipated Problems, Adverse Events and 
Protocol Deviations.”). All adverse events occurring during the study, including those observed 
by or reported to the research team, will be recorded. Serious unanticipated problems, 
Unanticipated Adverse Device Effects and serious protocol deviations will be reported to the IRB 
and CD as soon as possible but not more than 7 days after the PI first learns of the event. Not 
serious unanticipated problems will be reported to the IRB and CD as soon as possible but not 
more than 14 days after the PI first learns of the event. Not serious protocol deviations will be 
reported to the IRB as soon as possible but not more than 14 days after the PI first learns of the 
event. Deaths and other serious events will be reported to the Clinical Director and IRB within 7 
days after the PI first learns of the event. 
XVIII. Data and Safety monitoring Plan 
a. Selection of a Data and Safety Monitoring Mechanism -  
1. Daily Study Monitoring: Data and safety for this protocol will be monitored by the 
Principal Investigator and MAI.   
2. Overall Study Monitoring: Data and safety will be monitored by an Independent Safety 
Monitor, Dr. Mark Hallett, M.D., a neurologist and TMS expert.   
b. Frequency of the monitoring – Dr. Mark Hallett will review data every 10 participants who 
complete the protocol. 
c. Stop or change rules - The study will be put on hold pending investigation to determine 
appropriate adjustments to the stimulus parameters by the Principal Investigator if repeated (more 
than 2) serious adverse events that are related to the protocol interventions are encountered. 
d. Advanced plans for any interim analyses and/or futility analyses - There are no current plans 
for interim analyses and/or futility analyses.   
e. Information to be monitored - 

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Date of Submission: November 30, 2018  
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1. Progress of the study, including assessment of participant recruitment and accrual and 
adverse events will be reviewed to determine whether there is any change to the risk/benefit 
ratio of the study. This information will be reported to the IRB at the time of continuing 
review. 
2. Subjects will be monitored for adverse events by study staff. Significant as well as mild 
adverse effects of rTMS stimulation will be monitored through questionnaires (see 
Appendix 6; TMS monitoring questionnaire) before and after each rTMS session. At the 
start of the first session, the baseline occurrence of the events in the checklist will be asked 
for (i.e. how often do you experience these symptoms per week, per month?)  Moreover, 
participants will be contacted telephonically two to three weeks after the rTMS session and 
will again be asked the questions from the TMS monitoring questionnaire. The ISM will 
review unblinded data for all participants, confirm that AE’s have been appropriately 
reported, and determine whether the risk to benefit ratio has changed.   
3. There are no external factors (e.g., developments in the literature, results of related 
studies, etc.) that may have an impact on the safety of participants or on the ethics of the 
research study. 
f. Communication - Adverse events will be recorded by staff in the subjects’ medical record and 
reported to the Clinical Director and NIDA IRB in accordance with all NIH and NIDA 
requirements for adverse event reporting. Additionally, a summary of study progress, including 
assessment of participant recruitment and accrual and adverse events will be reported to the IRB 
at the time of continuing review. If any of the responses to the TMS monitoring questionnaire are 
positive, the MAI will evaluate the responses and contact the participant further as necessary.  
The NIDA PI will report adverse events according to established NIH IRB guidelines. ISM 
reports will be forwarded to the IRB at the time of continuing review or within a separate 
submission. 
XIX. Data/Records Management 
Medical and questionnaire data will be gathered in the CDW, a secure database on a closed 
network. Access to records in the CDW is protected by a system of password-protected accounts 
and monitored by the Clinical Director (CD). Data downloaded from the CDW for analysis will 
be identified only by participant number.  
Data (physiological, behavioral) obtained during experimental sessions is stored on password 
protected, network drives, which have limited access.  Data stored on these drives is identified by 
study number, participant code number and/or task. Some files may also include age, race and 
gender. No personal identifiers are stored with the data. Imaging data is stored on a password-
protected LINUX computer with limited access. Data on this server is identified by participant 
number only with no other identifying information. These data are backed up nightly to a second 
secure server. 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
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XX. Compensation 
All participants will be compensated for their participation following the NIDA-IRP remuneration 
guidelines. Participants will be compensated for those parts of the study completed. Remuneration 
rates are summarized in Table 1.   In addition to the hourly rate ($20/hr), subjects will receive the 
following remuneration: $15 per TMS session will be given as compensation for inconvenience. 
$15 will be given per visit that includes MRI scanning. A completion incentive of $25 will be 
given at the end of each set of rTMS visits, since the within-subject comparison between several 
conditions on different days is critical for this protocol.  
Remuneration rates will vary according to the phase of the protocol (Phase A does not include 
MRI scanning), and the amount of times the subjects is invited back (3 to 10 rTMS sessions).   
 
Table 2. Remuneration rates. 
  
Rate 
Time/frequency 
Hourly rate 
$20/hour 
3-4 hours per visit 
Compensation in addition to hourly rate: 
TMS 
$15/visit 
Up to 11 visits (10 rTMS) 
MRI scan (if appropriate) 
$15/visit  
up to 10 visits  
Travel 
$15/visit 
Up to 11 visits 
Compliance Incentive 
$25/set of visits 
Up to 4 sets of rTMS visits 
Total (max) per visit  
$125 
Total (min) per visit 
$90
Total (max) overall 
$1,465
 
 
XXI. Quality Assurance  
A) Quality Assurance Monitor:   
The Principal Investigator and the MAI will be monitoring data collection and the study on an 
ongoing basis.  Quality assurance will monitored by the NIDA Quality-Assurance Team on a 
schedule to be determined by the Clinical Director. 
B) Quality Assurance Plan  
We will use the quality-assurance plan that is being developed by the NIDA IRP Clinical Director. 
 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
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XXII. Alternatives to participation or Alternative therapies 
Participants do not receive any treatment in this study or forgo any treatment in order to join it.   
The alternative, therefore, is simply not to participate.  
 
XXIII. Conflict of Interest 
A) Distribution of NIH Guidelines 
NIH guidelines on conflict of interest have been distributed to all investigators. There are no 
conflicts of interest to report.  
 
B) Conflict of interest 
There are no conflicts of interest to report. 
 
C) Role of a commercial company or sponsor  
This study is investigator-initiated and investigator-sponsored.  
XXIV. Technology Transfer 
There are no confidential disclosure agreements necessary for this protocol. There is a Data 
Transfer Agreement (DTA) in place with the University of Illinois at Urbana-Champaign (UIUC) 
to analyze the MRS data. Specifically, Drs. Zhi-Pei Liang and Fan Lam will receive de-identified 
magnetic resonance imaging data to conduct data analyses specific to measuring glutamate levels 
using MRS. UIUC will set up a secured ftp server for NIDA to upload the de-identified data. The 
code to the data will not be shared with investigators at UIUC. 
 
 
 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
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Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
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Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
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Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
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Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
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Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
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Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
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Neuroscience, 33(28), 11425–31. 

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Sutherland, M. T., McHugh, M. J., Pariyadath, V., & Stein, E. a. (2012). Resting state functional 
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XXVI. Appendices 
A) Appendix 1: Eligibility checklist 
 
186 Inclusion/Exclusion Criteria for CDW 
 
To be considered for participation, individuals must meet the following eligibility criteria: 
 
Note: There may be stricter medical and screening criteria depending on the task or experiment. 
 
Screening 
 
General Participants 
 
 
 
 
 
 
 
 
 
Yes 
No 
N/A 
MAI 
1. Age 18 – 55 years  
 
 
 
 
 
 
 
 
2. Right-handed.  
 
 
 
 
 
 
 
 
 
3. Estimated IQ ≥ 85  
 
 
 
 
 
 
 
 
4. Free from learning disability or current ADHD  
 
 
 
 
 
 
5. Free from present or past moderate to severe  
 
 
 
 
 
substance use  disorder (as defined by DSM-V)   
 
for alcohol or cannabis in the last 5 years 
6. Free from present or past moderate to severe  
 
 
 
 
 
substance use disorder (as defined by DSM-V)  
for any other substance except nicotine. 
7. Free from any past or current DSM-V axis I disorder  
 
 
 
  
 
8. Two weeks or more since last rTMS session, or   
 
 
 
 
no previous TMS 
9. Free from daily smoking   
 
 
 
 
 
 
 
 
Medical 
 
General Participants 
 
 
 
 
 
 
 
 
 
Yes 
No 
N/A 
MAI 
10. MRI compatible    
 
 
 
 
 
 
 
 
11. TMS compatible  
 
 
 
 
 
 
 
 
12. Free of medication that may alter seizure threshold 
 
 
 
 
13. Free of current or history of any heart condition.  
 
 
 
 
14. Free from personal history of any neurological   
 
 
 
 
disorder, stroke, brain lesions, previous neurosurgery,  
any personal history of seizure or fainting episode  
of unknown cause, or head trauma resulting in loss of  
consciousness, lasting over 30 minutes or with sequela  

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 57 of 72 
 
lasting longer than two days. 
 
 
 
 
 
 
15. Pregnancy/breastfeeding-free and not planning to  
 
 
 
 
become pregnant.  
16. Generally healthy (based on physical exam,  
 
 
 
 
 
vital signs, EKG, height/weight, blood work,  
urinalysis, HIV and Syphilis screen) 
HIV negative 
 
 
 
 
 
 
 
 
 
Syphilis-free 
 
 
 
 
 
 
 
 
 
Cholesterol < 251 mg/dl  
 
 
 
 
 
 
 
Hemoglobin > 10.4 g/dl  
 
 
 
 
 
 
 
WBC > 2399/µl  
 
 
 
 
 
 
 
 
LFTs < 3Xnormal  
 
 
 
 
 
 
 
 
Casual serum glucose < 201 mg/dl 
 
 
 
 
 
 
Urine protein < 2+ 
 
 
 
 
 
 
 
 
17. Free from first-degree family history of any  
 
 
 
 
 
neurological disorder with a potentially  
hereditary basis, including migraines, epilepsy,  
or multiple sclerosis. 
 
 
 
 
 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 58 of 72 
 
B) Appendix 2: Recruitment materials 
 
 
PTMS  
Statu
s 
Material 
Participant 
Type 
 
Uses 
12-DA-N888 
 
Amend (FF) 
In use
 
 
Healthy 
volunteers 
 
Print Ad 
Bus Ad 
Flyer 
 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 59 of 72 
 
PTMS  
Statu
s 
Material 
Participant 
Type 
 
Uses 
10-DA-999 
Amend (YY) 
In 
use 
 
 
 
 
 
 
All 
participants 
 
Card 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 60 of 72 
 
PTMS  
Statu
s 
Material 
Participant 
Type 
 
Uses 
10-DA-999 
Amend (X) 
In 
use 
 
 
 
All 
participants 
Website 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 61 of 72 
 
PTMS  
Statu
s 
Material 
Participant 
Type 
 
Uses 
 
12-DA-N888 
Amend (W) 
In 
use 
 
 
 
All 
participants 
 
Flyer. 
 
 
PTMS  
  
Status 
Material
Participant Type 
  
On line Posting 
Healthy Volunteer 
In use 
888(I) 
Research opportunities available for volunteers who DO NOT smoke cigarettes or use drugs of any kind. 
The National Institute on Drug Abuse (NIDA) conducts research studies to find out how various drugs, 
including nicotine, affect the body, the brain, and behavior. 
Your part in a NIDA research study could help us better understand how the healthy brain works and how to 
prevent and treat drug abuse and addiction. 
The studies take place in East Baltimore area. All volunteers will receive money for their participation in a 
study. 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: November 30, 2018  
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 62 of 72 
 
If you are interested in being a healthy control in a NIDA research study, please call 1-800-535-8254 or 443-
740-2295 or visit www.ResearchStudies.DrugAbuse.gov for a confidential screening.
 
Craigslist Posting 
In use 
888 (B) 
1.      Are You Drug Free? Join a Research Study at NIDA 
w/titles 
  
2.      Healthy Participants: We Need You for a Research Study! 
Healthy Volunteer 
3.      Healthy Volunteers Needed to Help Scientists Learn About the Body and Brain 
  
4.      Don’t Smoke or Use Drugs? Participate in a Confidential Research Study 
5.      Don’t Smoke or Use Drugs? Join a Research Study as a Healthy Volunteer 
6.      NIDA Seeks Healthy Participants for a Research Study 
7.      Help Advance Science — Join a Research Study 
Research opportunities available for volunteers who DO NOT smoke cigarettes or use drugs of any kind.  
The National Institute on Drug Abuse (NIDA) conducts research studies to find out how various drugs, 
including nicotine, affect the body, the brain, and behavior.  
Your part in a NIDA research study could help us better understand how the healthy brain works and how 
to prevent and treat drug abuse and addiction.  
The studies take place in East Baltimore area. All volunteers will receive money for their participation in a 
study.  
If you are interested in being a healthy control in a NIDA research study, please call 1-800-535-8254 or visit 
www.ResearchStudies.DrugAbuse.gov for a confidential screening.
 
 
 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: 
November 30, 2018 
 
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions  IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 63 of 72 
C) Appendix 3: Fact Sheet 
STUDY T-DA-1042 FACT SHEET 
T-DA-1042: “rTMS equipment testing and pilot” 
All visits will take place at the NIH/NIDA research facility on the Johns Hopkins Bayview 
Medical Campus. This study will use a type of brain stimulation called “repetitive 
transcranial magnetic stimulation” (rTMS) to stimulate a part of the brain that is thought 
to play a role in decision making and in addiction. This study is looking at how stimulating 
this area affects brain function, thinking and decision making.   
 
rTMS stimulation: 
TMS uses a magnet to stimulate parts of the brain and is not an invasive procedure.  We 
place a coil on the scalp and deliver magnetic pulses. Similar types of brain stimulation are 
used to understand brain function in healthy participants, and this type of brain stimulation 
is also used to treat depression. It is now being studied for other mental problems.  We will 
measure brain function after rTMS stimulation using a cognitive task and/or magnetic 
resonance imaging (MRI).  MRI uses a magnet and radio waves to measure brain function.  
The procedures conducted in this study will help us design future studies in people who 
are suffering from addiction. Participation in this study will consist of 4 to 11 visits. At 
each visit (except the first) you will have an rTMS session. During some of the visits you 
may also have two MRI scans. 
 
rTMS has been used on thousands of people throughout the world.  Most people do not 
find the stimulation painful.  Common side effects can include contractions of scalp 
muscles, headache and hearing disturbance.  These usually go away promptly without 
treatment.  Rare side effects include seizures but this has occurred largely in persons taking 
certain medications and in people with past seizure disorders.  Persons on such medications 
or those that have past or family history of seizures will not be able to participate.  
 
Study commitment: 
 4 to 11 total sessions 
 First visit includes consent, orientation, and a baseline assessment, and can 
take up to 5 hours. This session will include a TMS session and may also 
include an MRI scan. 
 Visits 2-11 will take 3-4 hours.  
o There will be a brief medical assessment at each visit 
o There will be an rTMS session at each visit. 
o Most visits will include two or three thinking tasks.  
o Some or all visits can include two short MRI scans (30-45 min). 
During these scans you may be asked to perform a thinking task, or 
just to relax. The MRI scans will take 30-45 minutes each. 
 
Compensation:  

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: 
November 30, 2018 
 
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions  IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 64 of 72 
Compensation will be $20 per hour during each study visit which will last from 3-4 
hours; $15 per visit if this visit has MRI scans, and an additional $15 for each TMS 
session. Fifteen dollars compensation for travel costs will also be given per visit, and 
$25 per set of studies will be given as a completion incentive. 
 
 
 
 
 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: 
November 30, 2018 
 
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions  IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 65 of 72 
D) Appendix 4: TMS information sheet 
TMS INFORMATION SHEET 
What is TMS? 
TMS (transcranial magnetic stimulation) is a method to non-invasively stimulate regions 
of the brain. To deliver TMS, a wire coil is placed on the head. A brief electrical current is 
passed through the coil to create a magnetic pulse that stimulates the brain. When a long 
series of pulses is delivered in short succession, this is called repetitive TMS or rTMS. The 
effects of rTMS depend on what part of the brain the coil is placed over. The duration of 
the effect depends on how long the part of the brain was stimulated for. For example, if 
the rTMS is delivered for 30 minutes, the effects will last about 30 minutes after the 
stimulation is over. In this study we will deliver no more than 30 minutes of rTMS. 
Therefore, the effects are expected to wear off by the time you leave NIDA. 
 
This is the TMS helmet that will be used in this study. You will also be fitted with a cap 
like the one displayed.  
 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: 
November 30, 2018 
 
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions  IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 66 of 72 
What does TMS feel like? 
Scalp sensation and muscle twitches: Your brain does not actually feel the TMS pulses, 
because there are no pain receptors or other sensory receptors in the brain. What you 
feel during TMS is stimulation of the muscles and nerves around your head and scalp. We 
will use different types of TMS and these are likely to differ in the way they stimulate the 
overlying nerves and muscles and in how they feel. Many people describe the sensation 
of these muscle contractions as a series of taps on the head. Depending on which muscles 
and nerves get stimulated, these taps can feel quite hard and uncomfortable, but usually 
the discomfort decreases as you get used to the sensation. In addition to the tapping 
sensation, it is possible that you will blink involuntarily and it as also possible that you will 
feel a twitching or ticklish sensation on other parts of the head (for example a tickling 
sensation over the nose).  These side effects stop after the rTMS pulses stop. Any 
remaining scalp pain from TMS is easily treated with over-the-counter pain medication, 
which we will provide to you if requested.   
 
During the first visit, you will receive TMS pulses at a number of different strengths. 
During this procedure, we will we slowly increase the strength of the pulses, to allow you 
to get used to the sensation. We will ask you how uncomfortable the stimulation is and 
will only increase the strength of the stimulation if you agree to this.  Before every rTMS 
session, we will repeat this procedure briefly.  
 
Sound: TMS makes a clicking sound, which can be rather loud. You be fitted with earplugs 
during the rTMS stimulation session. 
 
Screening precautions: 
 
Metal: TMS works with magnetic pulses and can therefore have an impact on metal. All 
metal around the head must be removed before the stimulation. If you have metal 
objects inside the eye or skull you cannot participate in this study. You will be screened 
for the presence of metal and if you have any, you will not receive TMS. 
 
Implanted medical devices: Because of the magnetic pulses, TMS can interfere with 
implanted medical devices and will not be done in people who have pacemakers, 
implanted pumps or stimulators (like cochlear implants). You will be screened for 
implanted devices and if you have any, you will not receive TMS.  
 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: 
November 30, 2018 
 
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions  IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 67 of 72 
Noise: TMS makes a clicking sound, which can be rather loud and can lead to hearing 
damage if no ear protection is worn. You be fitted with earplugs during the rTMS session. 
If you already have some hearing loss or a persistent ringing in your ear (tinnitus), you 
may be particularly vulnerable to hearing damage from the sounds. You will be screened 
for these conditions and if you have any, you will not receive TMS.  
 
SIDE-EFFECTS 
Common side-effects  
Most people who receive TMS do not report any side-effects. However, it is estimated 
that about 5 out of every 100 people who receive TMS report mild, transient side-effects 
after the stimulation.  
 
Headache: In about 2 out of every 100 sessions, individuals develop a headache after the 
stimulation. These headaches can be treated with over-the-counter pain-killers, which 
will be provided to you if necessary.  
 
Nausea: In about 1 out of every 100 sessions, participants report nausea after the 
stimulation. This has only been reported after stimulation of a different part of the brain 
than the one we stimulate, so it is unlikely that it will happen in this study. However, there 
will be medically trained staff available to respond appropriately if this should happen.  
 
Muscle pain: About 1 in 200 people report muscle aches after TMS, and these tend to be 
muscles around the area stimulated. Muscle pains tend to occur after stimulation of areas 
different than the one we stimulate in this study.  
 
Uncommon side-effects 
Seizure: There have been a very small number of reports of people getting a seizure 
during or after TMS stimulation. These seizures were single, non-recurring events, which 
did not lead to the development of a seizure disorder. In most cases, seizures have 
happened with people who already had an elevated risk of seizures or after they received 
TMS with a very high stimulation rate. The stimulation rates in this experiment are much 
lower. If you have higher risk of seizure, you cannot participate in this study. For example, 
if you have a family history of epilepsy, or if you are on any medication that makes you 
more vulnerable to seizures. You will be screened for these conditions and if you have 
any, you will not receive TMS. It is therefore extremely unlikely a seizure will be induced. 
However, we will have medically trained staff available to respond appropriately if this 
should happen.  

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: 
November 30, 2018 
 
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions  IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 68 of 72 
 
Vasovagal syncope (fainting): There have been a small number of reports of people 
fainting during or immediately after TMS. It is very unlikely that this would happen. 
However, medically trained staff will be available to respond appropriately if this should 
happen.    
 
Manic symptoms: There have been a very small number of reports of people developing 
manic symptoms (excited or euphoric mood) after TMS stimulation. This has only 
happened after stimulation of a part of the brain that will not be stimulated in this study. 
In addition, most of the people who showed manic symptoms already had a psychiatric 
disorder like bipolar disorder or post-traumatic stress disorder. This is a why if you have 
ever been diagnosed with a psychiatric disorder you cannot participate in this study. 
 
Feelings of detachment: There have been a very small number of reports of people 
feeling “detached” after TMS stimulation. This has only ever happened after the use of a 
piece of equipment that we will not use in this study and after stimulation of a different 
part of the brain than the area we will stimulate in this study. In cases where it this has 
been reported, it was gone in the first hours or days following stimulation. 
 
MONITORING OF SIDE-EFECTS 
To monitor possible side effects of stimulation, we will use questionnaires at each visit. 
Please fill these in truthfully. Two to three weeks after your participation, we will also 
contact you telephonically to ask you whether you have had any side-effects of the rTMS. 
Like all information gathered during the study, your answers are always confidential. 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: 
November 30, 2018 
 
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions  IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 69 of 72 
E) Appendix 5: rTMS questionnaires 
TRANSCRANIAL 
MAGNETIC 
STIMULATION 
(TMS) 
MONITORING QUESTIONNAIRE 
 
Please answer the questions listed below. The information you provide will be treated as 
confidential and will be held in secure conditions. Group results of this survey may be 
published, but no information will be disclosed that can identify any individual person. If 
you have any questions, please ask the researcher who gave you this form. 
 
 
 
Please tell us if you experienced any of the following symptoms following your most 
recent TMS session.  
     
Seizure 
 
Yes 
No 
Details: 
 
 
     
 Fainting or Collapse 
 
Yes 
No 
Details: 
 
 
Dizziness 
 
Yes 
No 
Details: 
 
 
 
Nausea or vomiting 
 
Yes 
No 
Details: 
 
 
 
Headache 
 
Yes 
No 
Details: 
 
 
Muscular aches 
 
Yes 
No 
Details: 
 
Muscle spasm or twitch 
 
Yes 
No 
Details: 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: 
November 30, 2018 
 
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions  IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 70 of 72 
Insomnia 
 
Yes 
No 
Details: 
 
 
Sensory Problems 
 
Yes 
No 
Details: 
 
 
 
Difficulties speaking or understanding speech 
 
Yes 
No 
Details: 
 
 
Lack of coordination 
 
Yes 
No 
Details: 
 
 
 
Slowness or impairment of thought 
 
Yes 
No 
Details: 
 
 
Other (please specify) 
 
Yes 
No 
Details: 
 
 
 
Any other comments 
 
 
 
 
 
 
 
 
 
 
 
 
Do not write below this line (for staff use only) 
 
Details of protocol undertaken TODAY: to be completed by researcher following session 
 
Researcher
Participant 
ARC 
Sham/Active 
(cardno) 
TMS Frequency
TMS
Intensity 
No. Pulses
 
 
 
 
 
 
 

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: 
November 30, 2018 
 
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions  IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 71 of 72 
POSITIVE AND NEGATIVE AFFECT SCALE (PANAS) 
This scale consists of a number of words that describe different feelings and emotions. 
Read each item and then list the number from the scale below next to each word. Indicate 
to what extent you feel this way right now. 
Right now I feel… 
very 
slightly 
a little 
moderately 
quite a bit 
extremely 
or not at all
interested
1
2
3
4
5
excited
1
2
3
4
5
upset
1
2
3
4
5
strong
1
2
3
4
5
guilty
1
2
3
4
5
scared
1
2
3
4
5
scared
1
2
3
4
5
hostile
1
2
3
4
5
enthusiastic
1
2
3
4
5
proud
1
2
3
4
5
irritable
1
2
3
4
5
alert
1
2
3
4
5
detached
1
2
3
4
5
inspired
1
2
3
4
5
nervous
1
2
3
4
5

Protocol: Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study 
PI : Elliot A. Stein, Ph.D. 
 
Date of Submission: 
November 30, 2018 
 
Protocol Number: 14-DA-N186 
Version: 7.0 
Addictions  IRB Protocol Template (rev 10-23-12) 
 
 
 
 
 
 
page 72 of 72 
Right now I feel… 
very 
slightly 
a little 
moderately 
quite a bit 
extremely 
or not at all
determined
1
2
3
4
5
attentive
1
2
3
4
5
jittery
1
2
3
4
5
active
1
2
3
4
5
afraid
1
2
3
4
5
ashamed
1
2
3
4
5