Examining the Mechanisms of Anxiety Regulation Using a Novel, Sham-controlled, fMRI-guided rTMS Protocol and a Translational Laboratory Model of Anxiety
Phase: NA
Conditions: Anxiety, Fear, Anxiety and Fear
Sponsor: University of Pennsylvania

  
Examining the mechanisms of anxiety regulation using a novel, sham-controlled, 
fMRI-guided rTMS protocol and a translational laboratory model of anxiety. 
 
Principal Investigator 
Nicholas Balderston 
3700 Hamilton Walk 
3rd Floor 
Philadelphia, PA 19104    ׀
215-746-3058 
Nicholas.Balderston@pennmedicine.upenn.edu 
NIH Grant Number               1K01MH121777-01 
IRB Number: 
833320 
 
 
 
ClinicalTrials.gov Number  
 
 
 
NCT03993509 
 
 
Current version 
 
06/21/2022 V-1.1 
Previous Versions  
10/28/2021 V-1.0 
 
 
 
03/24/2021 V-0.9 
 
 
 
10/05/2020 V-0.8 
 
 
 
03/19/2020 V-0.7 
 
 
 
10/11/2019 V-0.5 
 
 
 
09/12/2019 V-0.4 
 
 
 
06/12/2019 V-0.3 
 
 
 
02/18/2020 V-0.6 
 
 

CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
Table of Contents 
 
Contents 
LIST OF ABBREVIATIONS......................................................................................................................... IV 
STUDY SUMMARY ...................................................................................................................................... 1 
BACKGROUND AND STUDY RATIONALE ................................................................................................ 3 
INTRODUCTION ............................................................................................................................................ 3 
1.1 
BACKGROUND AND RELEVANT LITERATURE ..................................................................................... 3 
2 
STUDY OBJECTIVES ......................................................................................................................... 5 
3 
INVESTIGATIONAL PLAN .................................................................................................................. 5 
3.1 
GENERAL DESIGN .......................................................................................................................... 5 
3.1.1 
Screening Phase ..................................................................................................................... 6 
3.2 
STUDY ENDPOINTS......................................................................................................................... 6 
4 
STUDY POPULATION AND DURATION OF PARTICIPATION ........................................................ 7 
4.1 
INCLUSION CRITERIA ...................................................................................................................... 7 
4.2 
EXCLUSION CRITERIA ..................................................................................................................... 7 
4.3 
SUBJECT RECRUITMENT ................................................................................................................. 8 
4.4 
DURATION OF STUDY PARTICIPATION .............................................................................................. 8 
4.5 
TOTAL NUMBER OF SUBJECTS AND SITES........................................................................................ 8 
4.6 
VULNERABLE POPULATIONS: .......................................................................................................... 8 
5 
STUDY PROCEDURES ....................................................................................................................... 9 
5.1 
STUDY INTERVENTION PHASE ....................................................................................................... 10 
5.1.1 
WEEK 1 TEST VISIT ...................................................................... ERROR! BOOKMARK NOT DEFINED. 
5.1.2 
WEEK 1 SCAN .............................................................................. ERROR! BOOKMARK NOT DEFINED. 
5.1.3 
WEEK 2 TMS SESSIONS (X4) ........................................................................................................ 10 
5.1.4 
WEEK 2 TEST VISIT ...................................................................... ERROR! BOOKMARK NOT DEFINED. 
5.1.5 
WEEK 4 TMS SESSIONS (X4) ........................................................ ERROR! BOOKMARK NOT DEFINED. 
5.1.6 
WEEK 4 TEST VISIT ...................................................................................................................... 10 
5.1.7 
PROCEDURES .............................................................................................................................. 10 
5.2 
SUBJECT WITHDRAWAL ................................................................................................................ 13 
5.3 
EARLY TERMINATION VISITS ......................................................................................................... 13 
6 
STATISTICAL PLAN ......................................................................................................................... 14 
6.1 
PRIMARY ENDPOINTS ................................................................................................................... 14 
6.2 
SAMPLE SIZE AND POWER DETERMINATION ................................................................................... 15 
7 
SAFETY AND ADVERSE EVENTS ................................................................................................... 15 
7.1 
DEFINITIONS ................................................................................................................................ 15 
7.1.1 
Adverse Event ....................................................................................................................... 15 
7.1.2 
Serious Adverse Event .......................................................................................................... 15 
7.2 
RECORDING OF ADVERSE EVENTS ................................................................................................ 16 
7.3 
RELATIONSHIP OF AE TO STUDY ................................................................................................... 16 
7.4 
REPORTING OF ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND UNANTICIPATED PROBLEMS ..... 16 
7.4.1 
Follow-up report..................................................................................................................... 16 
7.4.2 
Investigator Reporting: Notifying the Penn IRB ..................................................................... 16 
7.5 
STOPPING RULES ......................................................................................................................... 16 
7.5.1 
Data and Safety Monitoring Plan........................................................................................... 16 
8 
STUDY ADMINISTRATION, DATA HANDLING AND RECORD KEEPING .................................... 17 
8.1 
CONFIDENTIALITY ......................................................................................................................... 17 
8.2 
DATA COLLECTION AND MANAGEMENT .......................................................................................... 18 
8.3 
RECORDS RETENTION .................................................................. ERROR! BOOKMARK NOT DEFINED. 

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9 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 18 
9.1 
AUDITING AND INSPECTING ........................................................................................................... 18 
10 
ETHICAL CONSIDERATIONS .......................................................................................................... 19 
10.1 
RISKS .......................................................................................................................................... 19 
10.2 
BENEFITS .................................................................................................................................... 22 
10.3 
RISK BENEFIT ASSESSMENT ......................................................................................................... 22 
10.4 
INFORMED CONSENT PROCESS / HIPAA AUTHORIZATION .............................................................. 23 
11 
STUDY FINANCES ............................................................................................................................ 23 
11.1 
FUNDING SOURCE ........................................................................................................................ 23 
11.2 
CONFLICT OF INTEREST ................................................................................................................ 23 
11.3 
SUBJECT STIPENDS OR PAYMENTS ............................................................................................... 23 
12 
REFERENCES ................................................................................................................................... 24 
13 
ATTACHMENTS ................................................................................................................................ 29 
 
 
 
 

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List of Abbreviations 
 
 
adverse event (AE)  
analysis of functional neuroimages AFNI  
anxiety potentiated startle (APS)  
anxiety-potentiated-BOLD AP-BOLD  
bed nucleus of the stria terminalis (BNST) 
case report form (CRF)  
central nervous system (CNS) 
cognitive paired-associate stimulation (C-PAS)  
continuous theta-burst stimulation (cTBS) 
dorsolateral prefrontal cortex (dlPFC) 
electromyographic (EMG) 
echo planar imaging (EPI) 
Ethics Committee (EC) 
Food and Drug Administration (FDA) 
Fear potentiated startle (FPS) 
first dorsal interosseus (FDI) 
fear-potentiated-BOLD (FP-BOLD) 
Health Insurance Portability and Accountability Act of 1996 (HIPAA) 
high-frequency rTMS (HF-rTMS) 
independent components analysis (ICA) 
intermittent theta-burst stimulation (iTBS) 
intertrial interval (ITI) 
low-frequency rTMS (LF-rTMS) 
motor evoked potential (MEP) 
motor threshold (MT) 
magnetic resonance imaging (MRI) 
National Institute for Neurological Disorders and Stroke (NINDS) 
neutral (N) 
neutral predictable unpredictable threat task (NPU) 
principle investigator (PI) 
predictable shock (P) 
protected health information (PHI) 
repetitive TMS (rTMS) 
serious adverse event (SAE) 
echo time (TE) 
Beck Anxiety Inventory (BAI) 
State Anxiety Scale (S-Anxiety)  
transcranial magnetic stimulation (TMS) 
TMS adult safety screen (TASS) 
Theta-burst stimulation TBS 
unanticipated problem (UP) 
unpredictable shock (U) 
working memory (WM) 
 
 
 

Effect of TBS on anxiety 
 
page 1 
03/24/2021 V-0.9 
Study Summary 
Title 
Examining the mechanisms of anxiety regulation using a novel, 
sham-controlled, fMRI-guided rTMS protocol and a translational 
laboratory model of anxiety. 
 
Short Title 
Effect of rTMS on anxiety 
IRB Number 
833320 
Phase 
Pilot Study 
Methodology 
Randomized, double-blinded, sham-controlled, cross-over 
design 
Study Duration 
4 years 
Study Center(s) 
Single-center 
Objectives 
Aim 1: Determine the effect of a 1-week course of TBS 
treatment (Continuous vs. Intermittent; right dlPFC target) on 
anxiety using the unpredictable shock-threat paradigm.  
 
Aim 2: Determine the effect of a 1-week course of TBS 
treatment (Continuous vs. Intermittent; right dlPFC target) on 
anxiety-related WM-deficits using the Sternberg WM paradigm 
during threat of shock.  
 
Aim 3: Demonstrate target engagement by measuring BOLD 
responses evoked by TMS pulses to the right dlPFC during 
threat of shock.  
Number of 
Subjects 
75 

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Main Inclusion 
and Exclusion 
Criteria 
Healthy volunteers, between 18 – 50 years old, free of 
psychological and neurological conditions, free of contra-
indications for TMS and MRI 
Statistical 
Methodology 
Aim 1: Outcome measures. Fear potentiated startle (FPS) and 
Anxiety potentiated startle (APS) Statistical Analysis. The main 
analysis will be a 3 [stimulation: pre-stimulation vs. post-active 
vs. post-sham] by 2 [protocol: cTBS vs. iTBS] repeated-
measures ANOVA.  
 
Aim 2: Outcome measures. Accuracy and reaction time during 
the Sternberg Working memory paradigm. Statistical Analysis. 
The main analysis will be a 3 [stimulation: pre-stimulation vs. 
post-active vs. post-sham] by 2 [protocol: cTBS vs. iTBS] 
repeated-measures ANOVA.  
 
Aim 3: Outcome measures. TMS-evoked BOLD activity during 
periods of acute fear and sustained anxiety. Statistical Analysis. 
BOLD maps will then be analyzed using a paired-sample t-test 
to compare BOLD responses evoked by active TMS and those 
evoked sham scalp stimulation. 
 
Data and Safety 
Monitoring Plan  
The Principal Investigator is responsible for detecting, 
documenting, and reporting unanticipated problems (UPs), 
adverse events (AEs), including serious adverse events (SAEs), 
and deviations in accordance with IRB requirements and federal 
regulations. 
 
 
 

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BACKGROUND AND STUDY RATIONALE 
This study will be conducted in full accordance all applicable University of Pennsylvania 
Research Policies and Procedures and all applicable Federal and state laws and 
regulations including [as applicable include the following regulations as they apply 45 
CFR 46, 21 CFR Parts 50, 54, 56, 312, 314 and 812 and Good Clinical Practice. All 
episodes of noncompliance will be documented. 
Introduction 
1.1 Background and Relevant Literature  
 
Although anxiety disorders are the most commonly diagnosed class of disorders, with 
1 in 5 individuals diagnosed annually, less than 50% of these patients receive treatment, 
and less than 15% receive minimally adequate treatment (Kessler & Chiu, 2005). 
Although extensive research has linked subcortical structures like the amygdala and bed 
nucleus of the stria terminalis (BNST) to the hyperarousal symptoms experienced by 
anxiety patients, hyperarousal is only one facet of the symptom profile shared across 
anxiety disorders. Much less is known about the cognitive symptoms (i.e. difficulty 
concentrating) experienced by anxiety patients. Given the low level of understanding of 
basic anxiety mechanisms, it is understandable that the most commonly used 
pharmacological treatments (e.g. benzodiazepines and SSRIs) for anxiety were 
developed more than 20 years ago, with little advancement since. Accordingly, there is a 
critical need for mechanistic research into the CNS mechanisms that mediate the 
cognitive symptoms experienced by anxiety patients. Without such research, treatment 
development for these disorders will continue to be slow.   
TMS is approved by the FDA as a second-line treatment for depression (Horvath, 
Mathews, Demitrack, & Pascual-Leone, 2010; O’Reardon et al., 2007; Shajahan et al., 
2002; Stern, Tormos, Press, Pearlman, & Pascual-Leone, 2007), and some studies have 
shown that TMS can reduce comorbid symptoms of anxiety in depressed individuals 
(Mantovani, Aly, Dagan, Allart, & Lisanby, 2013; O’Reardon et al., 2007; White & 
Tavakoli, 2015). TMS uses a strong and alternating magnetic field at the scalp to induce 
electrical currents in neurons just below the TMS coil. Theta-burst stimulation (TBS), 
where high frequency bursts (50 hz triplets) are delivered at the theta frequency (5 Hz), 
is capable of altering the resting membrane potentials of local neurons (Lefaucheur et al., 
2014). Continuous TBS (cTBS) tends to decrease local excitability, while intermittent TBS 
(iTBS) tends to increase local excitability (Lefaucheur et al., 2014). TMS treatment 
protocols for depression are based on the hypothesis that the left dlPFC is associated 
with positive thoughts, and is hypoactive in depression (Berman, Doran, Pickar, & 
Weinberger, 1993; Galynker et al., 1998; Miller, Crocker, Spielberg, Infantolino, & Heller, 
2013), while the right dlPFC is associated with negative thoughts and is hyperactive in 
depression (valence model) (Davidson, 2004). Thus, successful rTMS treatments for 
depression typically involve either excitatory rTMS to the left dlPFC or inhibitory rTMS to 
the right dlPFC (Chen et al., 2013; Concerto et al., 2015; Fox, Buckner, White, Greicius, 
& Pascual-Leone, 2012; Horvath et al., 2010; Lefaucheur et al., 2014; Miniussi et al., 
2005; Nauczyciel et al., 2011; O’Reardon et al., 2007; Shajahan et al., 2002; Stern et al., 
2007) (or both), however other paradigms have also shown benefit (e.g. excitatory of both 
right and left dlPFC).  
There is evidence that rTMS treatment protocols (based on the valence model) may 
be effective at treating anxiety symptoms comorbid with depression. For instance, 
excitatory stimulation to the left dlPFC (O’Reardon et al., 2007), inhibitory stimulation to 
the right dlPFC (Mantovani et al., 2013), and combined right inhibitory rTMS and left 

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excitatory rTMS to the dlPFC (White & Tavakoli, 2015) can reduce anxiety or panic in 
depressed individuals. However, several recent meta-analyses have concluded that there 
is little support for the efficacy of these treatments for anxiety reduction in non-depressed 
individuals (Lefaucheur et al., 2014; Pallanti & Bernardi, 2009; Pigot, Loo, & Sachdev, 
2008; Zwanzger, Fallgatter, Zavorotnyy, & Padberg, 2009). One possible reason for this 
lack of support is that the underlying neuropathology mediating generalized anxiety and 
depression-related anxiety is fundamentally different (Baeken et al., 2010; Moulier et al., 
2016; Zwanzger et al., 2014), suggesting a need for the development of novel, anxiety-
specific rTMS treatment parameters. For instance, although excitatory stimulation to the 
left dlPFC facilitates retrieval of positive information in high anxious individuals (Balconi 
& Ferrari, 2012, 2013a, 2013b), excitatory stimulation to the left dlPFC does not reduce 
anxiety in non-depressed individuals (Moulier et al., 2016). Similarly, treatment with 
inhibitory stimulation to the right dlPFC enhances rather than suppresses subsequent 
visual processing of fearful stimuli (Zwanzger et al., 2014), while excitatory stimulation to 
the right dlPFC reduces subsequent amygdala activity to negative faces (Baeken et al., 
2010). Taken together, these results suggest that the valence model may not be sufficient 
to explain the symptoms of anxiety in non-depressed individuals.  
Instead, we propose a novel hypothesis based on the frontoparietal attention network 
(FPN; Figure 1) (Cole, Repovš, & Anticevic, 2014). According 
to our model, 1) elevated state anxiety enhances bottom-up 
attentional processes, and 2) top-down cognitive control 
processes, mediated by the right dlPFC, counteract this 
enhancement, reducing anxiety. This model is an extension of 
the attention control theory, which states that anxious 
individuals cannot efficiently engage goal-directed attention 
(Eysenck, Derakshan, Santos, & Calvo, 2007). Support for this 
model comes from the observations that 1) the right dlPFC 
plays a key role in attention control (Basten, Stelzel, & 
Fiebach, 2012; Cieslik et al., 2013; Fales et al., 2008; Harding, 
Yücel, Harrison, Pantelis, & Breakspear, 2015; Peers, Simons, 
& Lawrence, 2013), and 2) anxiety patients are impaired in 
their ability to recruit this structure for cognitive control 
(Armstrong, Zald, & Olatunji, 2011; Berggren & Derakshan, 
2013a, 2013b; Braver, Cole, & Yarkoni, 2010; Coombes, 
Higgins, Gamble, Cauraugh, & Janelle, 2009; Derryberry & 
Reed, 2002; Eysenck et al., 2007; Grillon, Robinson, Mathur, 
& Ernst, 2015; Morrison & Heimberg, 2013; Najmi, Kuckertz, 
& Amir, 2012; Najmi, Amir, Frosio, & Ayers, 2014; Price, 
Eldreth, & Mohlman, 2011; Reinholdt-Dunne, Mogg, & 
Bradley, 2009, 2012). This model is also supported by recent 
studies and preliminary data from our lab that suggest, 1) cognitive tasks that occur during 
periods of elevated state anxiety recruit the right dlPFC, 2) tasks that engage the right 
dlPFC reduce state anxiety (Balderston, Quispe-Escudero, et al., 2016; Vytal, Cornwell, 
Arkin, & Grillon, 2012; Vytal, Cornwell, Letkiewicz, Arkin, & Grillon, 2013), 3) anxiety 
patients are less able to recruit the right dlPFC during demanding cognitive tasks 
(Balderston, Vytal, et al., 2016). Therefore, according to our model, we expect that 
enhancing activity in the right dlPFC with excitatory iTBS should facilitate top-down 
cognitive control processes associated with anxiety reduction. In addition, data suggest 
that activating the stimulation site via task engagement can facilitate the effect of rTMS 
(Luber et al., 2007, 2008, 2013), suggesting that rTMS during a challenging cognitive task 
may be more effective at anxiety reduction than rTMS alone.  
This research is significant because upon completion, we expect to have direct 
evidence for a causal role of the right dlPFC in anxiety regulation, complete with evidence 

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of target engagement through simultaneous TMS/fMRI, and a novel application to anxiety. 
This research will lay the groundwork for my long-term career objective, which is to 
develop an independent, NIH-funded research program employing psychophysiology, 
neuroimaging, and neuromodulation in healthy and anxious participants aimed at 
developing a circuit-level understanding of the neurobiological mechanisms underlying 
anxiety. 
2 
Study Objectives 
 
Aim 1: Determine the effect of a 1-week course of TBS treatment (Continuous vs. 
Intermittent; right dlPFC target) on anxiety using the unpredictable shock-threat 
paradigm. Our hypothesis, consistent with our pilot data, is that strengthening circuits 
in the right dlPFC will facilitate anxiety regulation. Accordingly, we expect excitatory 
but not inhibitory TBS (compared to sham) to reduce induced anxiety. 
 
Aim 2: Determine the effect of a 1-week course of TBS treatment (Continuous vs. 
Intermittent; right dlPFC target) on anxiety-related WM-deficits using the Sternberg 
WM paradigm during threat of shock. Our hypothesis is that the rTMS will strengthen 
right dlPFC circuits, which will rescue the anxiety-related WM deficits. Accordingly, we 
expect that 10 Hz rTMS (compared to sham) will improve accuracy on the Sternberg 
WM task during threat. 
 
Aim 3: Demonstrate target engagement by measuring BOLD responses evoked by 
TMS pulses to the right dlPFC during threat of shock. Our hypothesis is that direct 
stimulation of the right dlPFC will reduce ongoing anxiety-related activity. Accordingly, 
we expect active but not sham TMS pulses to the right dlPFC to evoke BOLD 
deactivations in regions of the fear/anxiety network (i.e. amygdala, BNST, anterior 
insula). 
 
3 
Investigational Plan  
3.1 General Design 
 
Aims 1 and 2 of this project will be tested using a between-subjects design where 1 
group of healthy volunteers will receive 4-day courses of active and sham cTBS 
stimulation to the right dlPFC, while the other group will receive 4-day courses of active 
and sham iTBS stimulation to the right dlPFC. In Aim 1, we will test the effects of this 
stimulation on anxiety during the NPU threat task. In Aim 2, we will test the effects of this 
stimulation on anxiety-related WM deficits using the Sternberg WM paradigm. In addition, 
we will also administer several self-report questionnaires to assess their baseline (pre-
stimulation) anxiety. Subjects will be randomly assigned to groups, and the order of 
stimulation (active vs. sham) will be counterbalanced across subjects. Aim 3 will be tested 
using a within-subjects design where this same group of subjects will receive single-pulse 
active and sham stimulation to the right dlPFC during the NPU threat task while in the 
MRI scanner. BOLD activity to the TMS pulses will be the primary outcome measure. 
 
Subjects will undergo 12 study visits spaced over a 4-week period (Figure 3). Subjects 
may also be offered an optional 13th visit where TMS/fMRI is conducted. On Week 1, 

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subjects will undergo a pre-stimulation behavioral visit where they complete the NPU 
threat task and the Sternberg WM paradigm, and a pre-stimulation MRI visit where they 
undergo all the structural and functional imaging needed to identify the optimal target of 
stimulation for the course of TMS used in Aims 1 and 2. This information will be used to 
perform neuronavigation during the study visits to ensure accurate target stimulation. 
Subjects will complete the TMS/fMRI scans needed for Aim 3 during the optional visit. On 
Weeks 2 and 4, subjects will undergo 5 visits. The first 4 visits will be stimulation visits 
where they receive either active or sham stimulation while doing the Sternberg WM task. 
On the 5th visit, they will return for the post-stimulation test visit, where they will complete 
the NPU threat task and the Sternberg WM paradigm.  
 
3.1.1 Screening Phase 
 
Participants will be recruited from the community via paper or web ads, flyers, and 
listserv announcements. Participants will be recruited without any preference based on 
gender, race, religion, or other social variables. All recruitment materials (paper or web 
ads, flyers and listserv announcements) will be IRB approved prior to use. 
Study members authorized by the IRB will obtain informed consent from the 
participant. All study investigators obtaining informed consent complete formal informed 
consent training. All participants will receive a verbal explanation in terms suited to their 
comprehension of the purposes, procedures and potential risks of the study and of their 
rights as research participants. Participants will have the opportunity to carefully review 
the written consent form and ask questions regarding this study prior to signing. Consent 
forms will be signed in the presence of a witness. 
Subjects will be informed that they can withdraw from the study whenever they wish. 
The experiment will also be stopped for any subject who exhibits signs of distress during 
any phase of the study. Subjects will be constantly monitored by the study staff. The 
subject will be withdrawn at any time if unable to follow the rules for participation in this 
study. In the event of unanticipated problems or serious side effects, the principal 
investigator will consider whether the study should continue. 
3.2 Study Endpoints  
 
Aim 1: Determine the effect of a 1-week course of rTMS TBS treatment (Continuous vs. 
Intermittent; right dlPFC target) on anxiety using the unpredictable shock-threat paradigm. 
Our hypothesis, consistent with our pilot data, is that strengthening circuits in the right 

CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
dlPFC will facilitate anxiety regulation. Accordingly, we expect excitatory but not inhibitory 
TBS (compared to sham) to reduce induced anxiety. 
 
Aim 2: Determine the effect of a 1-week course of rTMS TBS treatment (Continuous vs. 
Intermittent; right dlPFC target) on anxiety-related WM-deficits using the Sternberg WM 
paradigm during threat of shock. Our hypothesis is that the rTMS will strengthen right 
dlPFC circuits, which will rescue the anxiety-related WM deficits. Accordingly, we expect 
that iTBS (compared to sham) will improve accuracy on the Sternberg WM task during 
threat. 
 
Aim 3: Demonstrate target engagement by measuring BOLD responses evoked by TMS 
pulses to the right dlPFC during threat of shock. Our hypothesis is that direct stimulation 
of the right dlPFC will reduce ongoing anxiety-related activity. Accordingly, we expect 
active but not sham TMS pulses to the right dlPFC to evoke BOLD deactivations in 
regions of the fear/anxiety network (i.e. amygdala, BNST, anterior insula). 
4 
Study Population and Duration of Participation  
 
Participants will be recruited without any preference based on gender, race, religion, 
or other social variables, and participants will not be excluded on the basis of sex/gender, 
racial, or ethnic affiliation. We exclude pregnant women because of the unknown effects 
of the TMS pulses, shocks, and fMRI on the developing fetus. We exclude non-English 
speakers since not all the instruments and tests we use are translated and validated in 
Spanish or other languages.  
4.1 Inclusion Criteria 
 
o Subjects must be 18-50 years old 
o Able to give their consent 
o Right-handed 
 
4.2 Exclusion Criteria 
 
o Non-english speaking 
o Any significant medical problems 
o Current or past Axis I psychiatric disorder(s),  
o Active or history of active suicidal ideation 
o Alcohol/drug problems in the past year or lifetime alcohol or drug dependence 
o Medications that act on the central nervous system 
o History of seizure 
o History of epilepsy or other neurological problems 
o Increased risk of seizure for any reason 
o Pregnancy 
o Any medical condition that increases risk for fMRI or TMS 
o Any metal in their body which would make having an MRI scan unsafe 
o Any sort of medical implants 
o Hearing loss 

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o Claustrophobia 
 
4.3 Subject Recruitment  
 
Participants will be recruited from the community via paper or web ads, flyers, and listserv 
announcements. Participants will be recruited without any preference based on gender, 
race, religion, or other social variables. All recruitment materials (paper or web ads, flyers 
and listserv announcements) will be IRB approved prior to use. 
 
In order to facilitate the enrollment of interested subjects in multiple studies at the Center 
for Neuromodulation in Depression and Stress (CNDS), we utilize a general pre-
screening form (either administered by phone or self-report depending on participant 
preference) center-wide as the majority of our projects closely relate, in both purpose and 
eligibility criteria.  
 
4.4 Duration of Study Participation 
 
The study will consist of 12 study visits and take place over a period of approximately 4 
weeks depending upon subject availability. Subjects may also be offered 3 optional visits. 
TMS/fMRI will be conducted during the first optional visit. The NPU will be administered 
before and after cTBS during the second and third optional visits. If subjects choose to 
participate in the optional visits. Their study participation will be extended approximately 
1 week, according to their schedule. Each session will last approximately 2-3 hours.  
4.5 Total Number of Subjects and Sites  
 
The target number of completers will be N=56. We anticipate that about 20% of subjects 
(N=11) will terminate the study during the task because of discomfort and another 10% 
(N = 5) to withdraw due to scheduling issues. An additional 3 subjects per experiment 
(n=3) will be included for piloting. 
4.6 Vulnerable Populations:  
 
All subjects must be able to provide their own consent. This study is above minimal risk 
and we do not want to enroll participants who do not understand the risk/benefit ratio of 
the study, particularly when there is no benefit to the participants. For this reason we 
exclude people with IQ lower than 80. We exclude and rule out pregnant women because 
of the unknown effects of the shocks and of the fMRI on the developing fetus. We exclude 
non-English speakers since not all the instruments and test we use are translated and 
validated in Spanish or other languages. Based on our experience, we made the decision 
that 50 would be the upper age limit to prevent age-related changes in brain structure and 
function from confounding our analyses. Patients will not be taken off medications for the 
purpose of the study. 

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5 
Study Procedures 
Does your study use MRI? (CAMRIS is the appropriate contact for all studies involving 
MRIs) 
 Yes 
 
 
 No 
 
 
Check of all that apply: 
 1.5T MRI 
 3T MRI 
 7TMRI 
 
Does the MRI use investigational sequences and/or coils? 
(See Experimental Device Clause) 
  
 Yes 
 
 
 No              
 Unsure (if unsure you need to 
contact CAMRIS)  
 
Experimental Device Clause -- Some of the pulse sequences and/or RF coils are not 
FDA approved but are considered to pose no more than minimal risk. 
 
Does your study include pregnant women? 
(See Pregnancy Clause and Justification) 
 
 Yes 
 
 
 No 
 
Pregnancy Clause -- Although there are no known risks related to MRI on pregnant 
women or a fetus, there is a possibility of yet undiscovered pregnancy related risks. Since 
there is no possible benefit from participating in this protocol for a pregnant woman, we 
will exclude pregnant women.  
 
Does the MRI require the use of Contrast Agents?  
(See Contrast Risks) 
 
 Yes 
 
 
 No 
 
Does your study involve the exposure to radiation, radiotracers and/or radiological 
imaging modalities?  
 
 Yes 
 
 
 No (If No, no RRSC review is needed)  
 
 
Will any of the radiation exposure result from procedures that are or could be performed 
solely as a result of a subject’s participation in the research protocol? 
 Yes 
 
 
 No 
 

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Ultrasound  
 Yes 
 
 
 No 
Will your study be using CT Scans? (CACTIS is the appropriate contact for studies 
involving CT scans)  
 Yes 
 
 
 No 
 
5.1 Study Intervention Phase 
The following procedures will be carried out on each study visit. See section 5.1.7 for a 
detailed description of each procedure.  
5.1.1 Lab Visit 1 
 
Consent 
Motor threshold testing 
White noise habituation 
Shock workup 
NPU 
Sternberg working memory task 
5.1.2 MRI visit 
 
Basic MRI scans 
5.1.3 TMS visits (1-4) 
 
Either cTBS or iTBS  
5.1.4 Lab Visit 2 
 
White noise habituation 
Shock workup 
NPU 
Sternberg working memory task 
5.1.5 TMS visits (5-8) 
 
Either cTBS or iTBS  
5.1.6 Lab Visit 3 
 
White noise habituation 
Shock workup 
NPU 
Sternberg working memory task 

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5.1.7 Optional MRI visit 
 
NPU TMS/fMRI 
5.1.8 Optional Pilot visits 
 
NPU (1 run) 
cTBS 
NPU (1 run) 
5.1.9 Procedures  
 
TMS motor threshold testing: The resting motor threshold (MT) will be determined in 
order to find the safe TMS dosing level.  MT is defined as the minimum magnetic flux 
needed to elicit a threshold EMG response in a target muscle in 5 out of 10 trials.  MT is 
the standard in the field for measuring cortical excitability and to reduce seizure risk. 
MEPs for the contralateral first dorsal interosseus (FDI) muscle will be measured with 
EMG.  The scalp region producing the largest amplitude MEP will be identified.  At that 
scalp location, the lowest TMS intensity able to elicit 5 MEP's of ≥50µV in peak-to-peak 
amplitude in 10 trials at this site will be determined using a descending method of limits 
procedure.  
 
Sternberg working memory task: On each WM trial, subjects will see a series of 4 
letters presented singularly (encoding period) that will be followed by a brief interval where 
subjects are required to maintain these letters (maintenance period). At the end of the 
maintenance period, subjects will be prompted to make a response based on the task 
instructions (response period; Sternberg, 1966). The response prompt will consist of a 
letter and a number. The letter will be chosen from the study series, and the number will 
correspond to a position in the series. The subjects will indicate whether the position of 
the letter in the series matches the number.  
 
There will be 2, 14 min runs of the experiment. Within each run, there will be 4 blocks (2 
threat, 2 safe). Within each block, there will be 2 types of trials based on the delivery of 
startle probes. On each trial a startle probe will be presented either during the 
maintenance period or the ITI. There will be 6 trials per condition per block. There will be 
a total of 3 shocks per run presented at random points during the threat blocks.  
 
NPU Task: The instructed fear paradigm that will be implemented uses administration of 
predictable and unpredictable shocks to generate phasic and sustained forms of 
potentiated startle. We will use the NPU threat procedure as described in (Schmitz & 
Grillon, 2012). The experiment consists of three different conditions: no shock (N), 
predictable shock (P), and unpredictable shock (U), each lasting approximately 150 sec. 
In the N condition, no shocks will be delivered. In the P condition, shocks will be 
administered predictably, that is, only in the presence of a threat cue. In the U condition, 
the shocks will be unpredictable. In each 150-sec condition, an 8-sec cue will be 
presented four times. The cues will be different geometric colored shapes in each 

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condition (e.g., a blue square for N, a red circle for P, and a green star for U) presented 
on a computer monitor in front of the subjects. The cue will signal the possibility of 
receiving a shock only in the P condition. It has no signal value in the N and U conditions. 
Instructions will also be displayed on a computer monitor to inform subjects of the nature 
of current condition by showing the following information throughout the testing 
procedure: “no shock” (N), “shock only during shape” (P), or “shock at any time” (U). 
During each predictable and unpredictable condition, one shock will be administered 
during the cue in the predictable condition and in the absence of a cue in the unpredictable 
condition.  
 
There will be 2, 12 min runs during each test visit. Within each run, there will be 8 blocks 
(2 predictable, 2 unpredictable, 4 neutral). There are twice the number of neutral blocks 
to ensure that safe blocks alternate with threat (predictable or unpredictable) blocks. 
Startle probes will be presented either during the cue period, or the ITI. During the 
predictable and unpredictable blocks, there will be 2 trials per condition. Given that there 
will be twice as many neutral blocks, during these blocks there will only be 1 trial per 
condition. There will be a total of 3 shocks per run presented during either the ITI 
(unpredictable) or cue (predictable) periods.  
 
White noise habituation: The acoustic startle stimuli will be a 40-ms burst of white noise 
(103 dB) with instantaneous rise time. Auditory stimuli will be delivered binaurally via 
headphones. The eyeblink component of the startle response will be measured by 
recording electromyographic (EMG) activity of the left orbicularis oculi muscle. The 
session will begin with a startle habituation phase with 9 startle stimuli presented alone 
to reduce startle reactivity. 
 
Shock workup: Electric shocks will be delivered through two tin disk electrodes located 
on the median nerve of the right wrist with a current constant stimulator. During each test 
visit prior to the experiment, the subject will undergo a shock workup procedure to identify 
an appropriate shock level. During the workup, subjects will receive brief (100 ms) 
presentations of the shock starting at a low level (2 mA), which will be increased in 
intensity gradually, until it reaches a level that they rate as uncomfortable but tolerable. 
Shocks will be administered at that level during the visit. The subject will also be informed 
that they are free to withdraw from the experiment if they later determine that the shock 
level is too high.  
 
Self-report Questionnaires: Subjects will be asked to fill out self-report questionnaires 
during the experiments (i.e. TMS adult safety screen (Keel, Smith, & Wassermann, 2000), 
the State Anxiety Scale (S-Anxiety)(Spielberger, 1987), the Beck Anxiety Inventory (Beck, 
Epstein, Brown, & Steer, 1988), Retrospective Threat Questionnaire). During the test 
visits, subjects will be asked to retrospectively rate their fear and anxiety levels using an 
analog scale during each condition (Retrospective Threat Questionnaire). Retrospective 
measures of fear and anxiety will be collected on an analog scale ranging from 0 (not at 
all anxious) to 10 (extremely anxious).  This analog scale has been a reliable measure of 
anxiety in our past studies. The State Anxiety Scale (S-Anxiety) (Spielberger, 1987) a 20-
item self-administered rating scale with measures of mood.  

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cTBS: Subjects will receive a continuous train of triplet 50 Hz bursts, repeated at 5 Hz. 
They will receive a total of 600 pulses per session. Consistent with the iTBS condition, 
TMS will occur during the Sternberg WM paradigm.  
 
iTBS. Subjects will receive 20 trains of triplet 50 Hz bursts, repeated at 5 Hz; 2 s on and 
8 s off for a total of 600 pulses per session and a total duration of 3 min. and 9 s). 
Stimulation will occur while subjects are doing the Sternberg WM paradigm, which should 
facilitate the efficacy of the stimulation by taking advantage of the cognitive paired-
associate stimulation (C-PAS) principle (Luber et al., 2017). The timing of the Sternberg 
task will be jittered so that each rTMS train will be administered during the maintenance 
interval of a WM trial.  
 
Basic scans: During the MRI visit, we will collect at T1, a T2, and a diffusion-weighted 
echo-planar image using an available 3T scanner. Next subjects will undergo a two runs 
of the Sternberg task, without shocks, probes, or TMS pulses to serve as functional 
localizers to identify a dlPFC. Subjects may also undergo a resting state scan.  
 
NPU TMS/fMRI. A Magventure MagPro 100X stimulator with a MRi-B91 figure-8 coil will 
be used. The TMS coil will be placed on the head over the target. TMS intensity will be 
100% of the motor threshold (MT). For sham stimulation, a 4 cm spacer will be placed 
between the subject’s scalp and the TMS coil. As with the study visits, subjects will have 
Neutral, Predictable, and Unpredictable periods. During the neutral periods, they will be 
safe from shocks. During the predictable periods, they can receive shocks but only when 
there is a cue present. During the unpredictable periods, they will be at risk for shock 
during the entire duration of the block. Rather than probing their ongoing fear and anxiety 
with the startle probes, we will replace the startle probes with single TMS pulses to the 
right dlPFC. This will allow us to causally examine the effect of right dlPFC activity 
(induced by the TMS pulse) on the neural activity that mediates fear (during the 
predictable cue) and anxiety (during the unpredictable cue and ITI). Importantly, by 
replacing the startle probes with TMS pulses, it will be possible to directly compare the 
TMS-evoked BOLD responses to the pattern of startle responses collected during the 
MRI/pre-stimulation visit. Subjects will have 1 run of active stimulation and one run of 
sham stimulation. Subjects may receive an additional 1 run of active stimulation at a 
control site in over the parietal cortex.  
5.2 Subject Withdrawal  
 
Subjects will be informed that they can withdraw from the study whenever they wish. 
Sample shocks will be administered prior to the study. At this point, subjects will be 
explicitly asked if they wish to continue. The experiment will also be stopped for any 
subject who exhibits signs of distress during any phase of the study. The subject will be 
withdrawn at any time if unable to follow the rules for participation in this study. 
5.3 Early Termination Visits   
 

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If a subject is withdrawn from the study or decides to discontinue, they will be 
compensated for the visits they completed, and a note will be placed in their CRF.  
6 
Statistical Plan 
6.1 Primary Endpoints 
 Aim 1: Determine the effect of a 1-week course of TBS treatment (Continuous 
vs. Intermittent; right dlPFC target) on anxiety using the Neutral, Predictable, and 
Unpredictable (NPU) shock-threat paradigm.  
Outcome measures. Fear potentiated startle (FPS) will be calculated by subtracting 
the blink magnitude during the predictable inter-trial interval (ITI) from the predictable cue. 
Anxiety potentiated startle (APS) will be calculated by subtracting the blink magnitude 
during the neutral ITI from the unpredictable ITI. Online anxiety ratings will be processed 
similarly. 
Statistical Analysis. The main analysis will be a 3 [stimulation: pre-stimulation vs. 
post-active vs. post-sham] by 2 [protocol: cTBS vs. iTBS] repeated-measures ANOVA. In 
addition to the main factors considered, we may also co-vary out several individual 
difference measures (e.g. baseline anxiety via self-report questionnaires, counterbalance 
order, overall stimulation accuracy, and Sternberg working memory (WM) performance 
to assess target engagement).  
 
Aim 2: Determine the effect of a 1-week course of TBS treatment (Continuous 
vs. Intermittent; right dlPFC target) on anxiety-related WM-deficits using the 
Sternberg WM paradigm during threat of shock.  
Outcome measures. During each Sternberg trial, subjects will see a series of 5 or 8 
letters presented singularly (encoding period) that will be followed by a brief interval where 
subjects are required to maintain these letters (maintenance period). At the end of the 
maintenance period, subjects will indicate whether the position of the letter in the series 
matches the number. Accuracy will be scored as the percent correct for each trial type.  
Statistical Analysis. The main analysis will be a 3 [stimulation: pre-stimulation vs. 
post-active vs. post-sham] by 2 [protocol: cTBS vs. iTBS] repeated-measures ANOVA. 
As with Aim 1, we may also include several other individual difference measures as 
covariates in this analysis.  
 
Aim 3: Demonstrate target engagement by measuring BOLD responses evoked 
by TMS pulses to the right dlPFC during threat of shock.  
Outcome measures. Standard Multi-echo fMRI preprocessing will be conducted 
using the AFNI software package. Steps include: slice-time correction, despiking, volume 
registration, TE-dependent ICA denoising (to remove non-BOLD artifacts), masking, 
blurring, scaling, motion scrubbing, T1-EPI alignment, normalization (using MNI 
template). At the first level, variable duration mini-blocks will be used to model BOLD 
activity during the maintenance interval of the Sternberg trials. Motion parameters and all 
other events will be included in the model as regressors of no interest.  
Statistical Analysis. Whole-brain maps will be created for contrasts mirroring those 
used to create FPS and APS in Aim 1. FP-BOLD and AP-BOLD maps will then be 
analyzed using a paired-sample t-test to compare BOLD responses evoked by active 
TMS and those evoked sham scalp stimulation. Monte Carlo simulations will be 
conducted to cluster-correct the results using a voxelwise p-value threshold of 0.001, a 
cluster alpha of 0.05, and a realistic spatial autocorrelation function to model the noise. 
This is the standard approach implemented in AFNI following the influential Eklund et al. 
2016 paper. As with Aim 1, we may also include several other individual difference 
measures as covariates in this analysis.  

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6.2 Sample Size and Power Determination 
 
Because we have several outcome measures, and because there is little known about 
how TMS will affect these outcome measures, we are conducting a single power analysis 
to determine sample size, based on a moderate effect size of (f=0.5). If we set power at 
0.8 and use a corrected two-tailed alpha of 0.025 we would need 26 subjects per group 
to detect a main effect. Assuming a 15% unusable data rate and 3 pilot subjects, we will 
need 63 total subjects. However, this will be updated prior to enrollment based on the 
best available information at the time. To ensure that we are adequately powered across 
the study arms, and to account for additional dropout due to scheduling issues, we plan 
to recruit up to 75 participants.   
7 
Safety and Adverse Events 
7.1 Definitions 
7.1.1 Adverse Event 
 
An adverse event (AE) is any symptom, sign, illness or experience that develops or 
worsens in severity during the course of the study.  Intercurrent illnesses or injuries should 
be regarded as adverse events.  Abnormal results of diagnostic procedures are 
considered to be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
7.1.2 Serious Adverse Event 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is 
any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are 
clearly of major clinical significance.   They may jeopardize the subject, and may require 
intervention to prevent one of the other serious outcomes noted above.  For example, 
drug overdose or abuse, a seizure that did not result in in-patient hospitalization, or 
intensive treatment of bronchospasm in an emergency department would typically be 
considered serious.  
 

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All adverse events that do not meet any of the criteria for serious should be regarded as 
non-serious adverse events.  
 
7.2 Recording of Adverse Events 
 
All adverse events will be recorded by the study team via the adverse event source 
document, and summarized in the enrollment log. All adverse events will be reported by 
the study staff to the PI within 4 days. 
 
7.3 Relationship of AE to Study  
 
Relatedness to the research of all serious adverse events will be determined by the 
medical advisor.  
7.4 Reporting of Adverse Events, Adverse Device Effects and Unanticipated 
Problems 
 
7.4.1 Follow-up report 
 
If an SAE has not resolved at the time of the initial report and new information arises that 
changes the investigator’s assessment of the event, a follow-up report including all 
relevant new or reassessed information (e.g., concomitant medication, medical history) 
will be submitted to the IRB. The PI is responsible for ensuring that all SAE are followed 
until either resolved or stable.  
 
7.4.2 Investigator Reporting 
 
The medical advisor will determine whether the event represents a severe adverse event 
(SAE) or an unanticipated problem (UP). SAEs and UPs will be reported to the IRB and 
DSMB within 7 days. Mild and Moderate adverse events will be logged and reported to 
the IRB annually and the DSMB quarterly. 
7.5 Stopping Rules 
 
The study will be suspended if there is any UP or SAE until IRB reviews the event and 
approves continuation. 
 
7.5.1 Data and Safety Monitoring Plan 
 
The Principal Investigator is responsible for detecting, documenting, and reporting 
unanticipated problems (UPs), adverse events (AEs), including serious adverse events 
(SAEs), and deviations in accordance with NIH policy, IRB requirements, and federal 
regulations. Relatedness to the research of all serious adverse events will be determined 
by the medical advisor. 

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In addition, the PI will maintain a full FDA regulatory binder tracking subject 
enrollment, qualifications of investigators, IRB correspondence, inclusion/exclusion 
criteria, and all source data. All essential data will be recorded in the electronic case report 
form by the study staff. Acknowledgement of incomplete data records will be noted in the 
screening and enrollment log. Pilot subjects, subjects who withdraw, or subjects who 
experience an adverse event are expected to have incomplete data records, and will be 
excluded from the final analysis. 
 
Site monitoring is conducted to ensure that the rights and well-being of trial 
participants are protected, that the reported trial data are accurate, complete, and 
verifiable, and that the conduct of the trial is in compliance with the currently approved 
protocol/amendment(s), with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), and with applicable regulatory requirement(s). 
• 
Monitoring for this study will be performed by an in-house individual trained by the 
office of clinical research. 
• 
The first subject will be monitored. Then 30% of all subsequent subjects will be 
monitored. 
• 
Monitored subjects will be selected randomly during the yearly monitoring visit 
conducted prior to continuing review.  
• 
The following data will be reviewed for all monitored subjects: 
o Informed consent and documentation of consent 
o Verification of eligibility 
o SAE (Serious Adverse Events) reported to IRB 
o Primary and secondary outcome measures  
• 
Details of clinical site monitoring are documented in a Monitoring Plan (MP). The 
MP describes in detail who will conduct the monitoring, at what frequency 
monitoring will be done, at what level of detail monitoring will be performed, and 
the distribution of monitoring reports. 
• 
Independent audits or compliance reviews may be conducted by the Office of 
clinical Research to ensure that monitors are following the MP. 
8 
Study Administration, Data Handling and Record Keeping 
8.1 Subject Confidentiality 
 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). 
Access to PHI will be limited to study staff, and allowed on an as needed basis. All 
protected health information (PHI) will be maintained using an institutionally secured and 
managed network drive. Transportation of any PHI will be conducted via either a Penn-
approved encrypted portable drive, or via a Penn-approved secure encrypted file transfer 
service. All PHI will be deleted upon study close.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization.  For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect at least vital status (i.e. that the 
subject is alive) at the end of their scheduled study period. 

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8.2 Data Collection and Management  
 
The study case report form (CRF) is the primary data collection instrument for the study.  
All data requested on the CRF must be recorded.  All missing data must be explained.  If 
a space on the CRF is left blank because the procedure was not done or the question 
was not asked, write “N/D”.  If the item is not applicable to the individual case, write “N/A”.  
All entries should be printed legibly in black ink.  If any entry error has been made, to 
correct such an error, draw a single straight line through the incorrect entry and enter the 
correct data above it.  All such changes must be initialed and dated.  DO NOT ERASE 
OR WHITE OUT ERRORS.  For clarification of illegible or uncertain entries, print the 
clarification above the item, then initial and date it. 
 
8.3 Subject Privacy 
 
All subject interactions including screening, consent discussion, and study procedures 
will occur in a private location with only the subject and necessary study staff present. All 
electronic records will be kept confidential according to standard policies. Participants’ 
names and other personal identifying information will be stored in electronically secured 
databases.  These databases will be password protected and only study personnel will 
be given a password.  Results will be published as group data without the use of 
characteristics that would identify individual subjects.  No biological samples will be 
collected.  
9 
Study Monitoring, Auditing, and Inspecting 
9.1 Auditing and Inspecting 
 
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) 
composed of individuals with the appropriate expertise, including expertise in affective 
neuroscience, transcranial magnetic stimulation, and biostatistics. Members of the DSMB 
should be independent from the study conduct and free of conflict of interest, or measures 
should be in place to minimize perceived conflict of interest. The DSMB will meet quarterly 
to assess safety and efficacy data on each arm of the study. The DSMB will operate under 
the rules of an approved charter that will be written and reviewed at the organizational 
meeting of the DSMB. At this time, each data element that the DSMB needs to assess 
will be clearly defined. The DSMB will provide its input to Dr. Balderston who is the 
Sponsor/Investigator 
 
The investigator will permit study-related monitoring, audits, and inspections by the 
EC/IRB, government regulatory bodies, and University compliance and quality assurance 
groups of all study related documents (e.g. source documents, regulatory documents, 
data collection instruments, study data etc.).  The investigator will ensure the capability 
for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, 
etc.). 
 

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Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality 
assurance offices. 
10 Ethical Considerations 
This study is to be conducted in accordance with applicable US government 
regulations and international standards of Good Clinical Practice, and applicable 
institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted 
independent Ethics Committee (EC) or Institutional Review Board (IRB), in agreement 
with local legal prescriptions, for formal approval of the study conduct.  The decision of 
the EC/IRB concerning the conduct of the study will be made in writing to the investigator 
and a copy of this decision will be provided to the sponsor before commencement of this 
study.  
10.1 Risks 
 
Clinical interview and assessments: There is minimal medical risk in completing the 
questionnaires. Some of the questions may make the participants feel uncomfortable or 
anxious. Participants may refuse to answer any question or to stop a test at any time and 
for any reason. 
 
Auditory startle stimulus (i.e. loud noises): The auditory stimuli that will be used in 
the startle studies are 40-ms duration 102 dB white noise. Auditory startling sounds of 
much higher intensities are frequently used in startle studies. Sounds of higher intensities 
and longer duration are also widely used in aversive conditioning in human subjects, 
where they serve as unconditioned stimuli. The short duration (40 ms) of these sounds 
makes them safe (i.e., there is no danger of hearing impairment). In addition, a white 
noise is safer than a pure tone. The PI has been involved in similar studies and 
collaborations involving over 200 subjects with no adverse reactions. The auditory 
stimulus may trigger a migraine. 
 
Psychophysiological (Blink) recording: The psychophysiological measures that will 
be obtained are non-invasive, requiring the administration of no needles, drugs, or dyes. 
Little discomfort is expected. During electrode placement, the possibility of skin irritation 
from contact with the saline electrode paste exists. However, this is unlikely as the salt 
concentration of the paste is similar to that of human sweat. 
 
Electric shock: The shocks will be delivered through two disk electrodes located on 
the subject’s left wrist. The PI has extensive experience with shocks. The shock is 
generally described by subjects as anxiogenic and uncomfortable. The mean rating of 
aversiveness on a scale of 1 (not painful at all) to 10 (extremely painful) is about 5. Over 
95% of subjects who experienced the shock chose to participate in the experiment. 
In very rare occasions, subjects have experienced symptoms that may be related to 
the shock. A participant with a condition called “cubital tunnel syndrome,” a repetitive 
motion injury similar to carpal tunnel syndrome, indicated worsening of his syndrome over 
the months subsequent to his participation. Another participant reported pain in her arms 
for several hours after testing. The pain was no longer present the next day. It is unclear 
whether these symptoms were due to the shocks. Nevertheless, subjects with 
neurological symptoms of the wrist and arms will be excluded from the study. 
 

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MRI: MRI is widely regarded as a safe, noninvasive procedure for visualization of brain 
tissue. The risks involved with fMRI are the same as those involved in standard anatomic 
MRI, since these three procedures rely on the same physical properties of brain tissue. 
This study will be performed on an FDA approved 3T scanner. MRI at 3 Tesla is a routine 
clinical procedure, and issues regarding radio frequency deposition, time varying 
magnetic fields, and the static field at 3 Tesla do not require detailed discussion.  
 
Likely/ Common:  
• Because the MRI scanner is a narrow space, subjects may experience claustrophobia, 
or a fear of enclosed spaces and/or anxious feelings accompanied by fast heart rate 
or shortness of breath.  
• Additionally, the scanner produces a loud repetitive knocking noise during the study 
that some people find bothersome. To lessen the noise, earplugs will be provided.  
 
Rare:  
• 
The MRI scanner has a strong magnet which attracts certain metals. As a result, 
the MRI will not be performed on anyone having these types of metal in their 
body. This includes metallic fragments and certain implanted medical devices, 
such as: Pacemakers, Internal Cardiac Defibrillators, Insulin Pumps, and other 
medical devices. Implanted medical devices and metallic foreign fragments 
inside the subject may pose a risk if they were to enter the MRI magnet room. 
Therefore, questions regarding medical and work history will be asked prior to 
the exam to ensure subjects do not have any of these metallic fragments in their 
body 
• 
Flying Objects: The known risks associated with this study are minimal. The 
greatest risk is a magnetic object flying through the air toward the magnet and 
hitting the subject. To reduce this risk we require that all people involved with the 
study remove all magnetic metal from their clothing and all magnetic metal 
objects from their pockets. No magnetic metal objects are allowed to be brought 
into the magnet room at any time except by approved personnel. To prevent any 
injury to patients and staff and any damage to the MRI scanner, subjects will be 
asked to remove all jewelry and clothing containing metal before they enter the 
MRI scan room. Also, since the MRI magnet will erase credit cards, they must 
not be taken into the scan room. In addition, once they are in the magnet, the 
door to the room will be closed so that no one inadvertently walks into the room. 
• 
Some dyes in tattoos and permanent eyeliner contain metals which may heat up 
during the MRI scan. This can cause the area with the tattoo to become irritated 
and swollen.    
• 
It is possible that during the course of the research study, the research staff may 
notice an unexpected finding. Should this occur, the finding will be considered by 
the appropriate personnel and the PI will inform the subject. These possible 
findings may or may not be significant, but could lead to anxiety about the 
condition and to further evaluation by their physician. 
• 
Although there are no known risks related to MRI on pregnant women or a fetus, 
there is a possibility of yet undiscovered pregnancy related risks. Since there is 
no possible benefit from participating in this protocol for a pregnant woman, we 
will exclude pregnant women. All women of childbearing potential will be asked to 

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confirm before entering the MRI scanner that they are not pregnant at the time. 
Implantable contraceptives are generally very safe for MRI, but the MRI 
technician may ask the subject additional questions before entering the MRI suite 
to ensure their safety. 
 
TMS: When used in accordance with the safety guidelines, there are no known long-
term risks associated with TMS (Rossi, Hallett, Rossini, & Pascual-Leone, 2009). A recent 
consensus safety report summarized the likelihood and factors contributing to the 
recorded occurrences of seizure (Rossi et al., 2009). As of 2008, there were only 16 cases 
of seizure reported in the preceding 20 years of research. Seven of these occurrences 
occurred prior to the development of rigorous safety guidelines implemented in 1997, 
which govern stimulator intensity, pulse frequency, train duration, inter-train intervals. 
According to the consensus report, when used according to the safety guidelines the 
occurrence of seizure is rare, and the few new cases involve “TMS protocols exceeding 
previous guidelines, often in patients under treatment with drugs which potentially lowered 
the seizure threshold” (Rossi et al., 2009). While there are no known long-term adverse 
effects reported with the use of this device, there may be unforeseen risks in the long-
term that are currently unknown.   
 
Likely/ Common:  
 
• The most common side effect of TMS is a mild headache, jaw pain, or other facial 
discomfort, which approximately 25% of patients experience. We will demonstrate 
TMS at the initial screening visit to make sure the subject is comfortable receiving this 
procedure. The TMS that will be used in this research is not expected to carry any 
more than the limited potential for these risks listed above. 
 
Rare: 
• Subjects may experience temporary and local bruising, swelling or pain from the 
swim cap and/ or muscle activation by TMS. 
• Although uncommon, some subjects have experienced nausea during the 
experiment. 
• In patients with epilepsy, TMS could result in a seizure.  Patients with stroke may 
also be at increased risk for a seizure due to brain scarring. Therefore, those with 
history of epilepsy or stroke will be excluded from TMS studies. For a typical healthy 
person, producing a seizure from TMS in this experiment is very unlikely. 
• The TMS device produces a clicking sound. Although studies have found no hearing 
impairments as a result of this sound, some subjects’ experience a mild temporary 
effect on their hearing. To minimize this possibility, you will be given protective 
earplugs.  
• Objects such as watches and credit cards should be removed as these could be 
damaged.  
• The effects of TMS on a fetus are unknown. Therefore, we require that females of 
child-bearing potential attest at the time of participation that they are not pregnant.  
 
Alternatives to participation: The studies proposed in this project do not involve an 
intervention, so the participants will not directly benefit from the research. Therefore, there 
are no alternatives to participation. However, participants will be free to withdraw from the 

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study without consequence. 
 
Protections against risk 
 
Electric Shock: Shock will be delivered at a level that is judged by the subject as 
unpleasant but not painful. Study shock levels will be determined before the test begins. 
The subject may stop the experiment at any time if they find the discomfort to be too great. 
 
TMS: To minimize the likelihood of seizures we will 1) conform to the guidelines set in 
the workshop convened by the National Institute for Neurological Disorders and Stroke 
(NINDS) in 1996 (Rossi et al., 2009), and 2) screen subjects for risk factors using the 
TMS adult safety screen questionnaire (Keel et al., 2000). In addition, we will train all 
personnel to recognize potential seizures, and administer appropriate care. In the event 
that the TMS operator observes symptoms of a seizure he or she will 1) stop the protocol 
and inquire about the subject’s well-being, 2) apply first-aid if the subject is unresponsive, 
3) ensure the subject is physically safe for the duration of the seizure, 4) call 911. If the 
subject develops a headache during or immediately after the stimulation, this will be 
managed with over-the-counter pain medication. To minimize the likelihood of hearing 
loss or tinnitus, subjects will wear hearing protection for the duration of the rTMS session. 
Risks to the unborn children of pregnant women receiving MRI and TMS are unknown. 
Pregnant women will be excluded as per IRB policy.  
MRI: The potential risks related to MRI will be minimized as follows: 1) Claustrophobia 
associated with MRI will be reduced by explaining the nature of the procedure in detail 
prior to subject enrollment; and 2) a possible history of any intraocular, intra-aural, 
intracranial, or intrathoracic metal will exclude the subject from the study. Earplugs will be 
given to each subject to wear during the scan to minimize discomfort and prevent any 
adverse effects on hearing resulting from the scanning procedure.  
A radiology technologist (or trained individual authorized to run the scanner) and a 
clinician will be present throughout the MRI study in case medical emergencies would 
arise. During MRI scanning, the subject can communicate with the control room personnel 
via an intercom at the operating console. Thus, the subject can be removed immediately 
from the MRI scanner, if necessary. 
10.2 Benefits 
 
Participants in the experiments proposed during the project will be compensated for 
their time and travel, but will not directly benefit from the proposed research.  
10.3 Risk Benefit Assessment 
 
Although anxiety disorders are the most commonly diagnosed class of disorders, 
with 1 in 5 individuals diagnosed annually, less than 50% of these patients receive 
treatment, and less than 15% receive minimally adequate treatment (Kessler & Chiu, 
2005). Although extensive research has linked subcortical structures like the amygdala 
and bed nucleus of the stria terminalis (BNST) to the hyperarousal symptoms 
experienced by anxiety patients, hyperarousal is only one facet of the symptom profile 
shared across anxiety disorders. Much less is known about the cognitive symptoms (i.e. 
difficulty concentrating) experienced by anxiety patients. Given the mismatch between 
the existing literature and the anxiety phenotype in patients, it is understandable that the 
most commonly used pharmacological treatments (e.g. benzodiazepines and SSRIs) for 

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This material is the property of the University of Pennsylvania.   
 
anxiety were developed more than 20 years ago, with little advancement since. 
Accordingly, there is a critical need for mechanistic research into the CNS mechanisms 
that mediate the cognitive symptoms experienced by anxiety patients. Without such 
research, treatment development for these disorders will continue its stunted progress.  
Once completed, we expect this research to yield direct evidence for a causal role of the 
right dlPFC in anxiety regulation, complete with evidence of target engagement through 
simultaneous TMS/fMRI, and a novel application to clinical anxiety. 
 
10.4 Informed Consent Process / HIPAA Authorization  
 
Consent will be obtained by research coordinators, postdoctoral fellows, a graduate 
student or the principal investigator. Because this study does not involve treatment, 
coercion is not a concern. Consent will be obtained in a private room where study staff 
members can explain the purpose of the fMRI and what it will add to our knowledge of 
TMS, neuroscience and cognitive processes. They will explain that participating is 
completely voluntary and that not participating will not change access to treatment in any 
way. The potential participant will be given the option to consider study enrollment and 
will not be forced to make a decision the same day. If they decide to participate, a 
combined consent and HIPAA form will be signed by research staff and the patient. The 
patient will be reminded before and after enrolling, and before any research procedure 
that their participation is optional and has no impact on the care they can expect. 
11 Study Finances 
11.1 Funding Source 
 
This study is financed through a grant from the US National Institute of Health.  
11.2 Conflict of Interest 
All University of Pennsylvania Investigators will follow the University of Pennsylvania 
Policy on Conflicts of Interest Related to Research.  
11.3 Subject Stipends or Payments 
 
Study compensation is based on the following schedule: 
• Week 1 
o Lab Visit 1 $25 
o MRI Visit $50 
• Week 2 
 
 
 
o TMS Visit 1 $25 
o TMS Visit 2 $25 
o TMS Visit 3 $25 
o TMS Visit 4 $25 
o Lab Visit 2 $25 
• Week 3 

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This material is the property of the University of Pennsylvania.   
 
o No Visits 
• Week 4 
o TMS Visit 5 $25 
o TMS Visit 6 $25 
o TMS Visit 7 $25 
o TMS Visit 8 $25 
o Lab Visit 3 $25 
• Completion Bonus 
o Upon Completion $175 
• Optional MRI visit $50 
• Optional Pilot visit 1 $75 
• Optional Pilot visit 2 $75 
 
Total Compensation $700 
12 References 
 
Armstrong, T., Zald, D. H., & Olatunji, B. O. (2011). Attentional control in OCD and GAD: 
specificity and associations with core cognitive symptoms. Behaviour Research and 
Therapy, 49(11), 756–762. https://doi.org/10.1016/j.brat.2011.08.003 
Baeken, C., De Raedt, R., Van Schuerbeek, P., Vanderhasselt, M. a, De Mey, J., Bossuyt,  
a, & Luypaert, R. (2010). Right prefrontal HF-rTMS attenuates right amygdala 
processing of negatively valenced emotional stimuli in healthy females. Behavioural 
Brain Research, 214(2), 450–455. https://doi.org/10.1016/j.bbr.2010.06.029 
Balconi, M., & Ferrari, C. (2012). RTMS stimulation on left dlpfc affects emotional cue 
retrieval as a function of anxiety level and gender. Depression and Anxiety, 29(11), 
976–982. https://doi.org/10.1002/da.21968 
Balconi, M., & Ferrari, C. (2013a). Left DLPFC rTMS stimulation reduced the anxiety bias 
effect or how to restore the positive memory processing in high-anxiety subjects. 
Psychiatry 
Research, 
209(3), 
554–559. 
https://doi.org/10.1016/j.psychres.2013.03.032 
Balconi, M., & Ferrari, C. (2013b). Repeated transcranial magnetic stimulation on 
dorsolateral prefrontal cortex improves performance in emotional memory retrieval 
as a function of level of anxiety and stimulus valence. Psychiatry and Clinical 
Neurosciences, 67(4), 210–218. https://doi.org/10.1111/pcn.12041 
Balderston, N. L., Quispe-Escudero, D., Hale, E., Davis, A., O’connell, K., Ernst, M., & 
Grillon, C. (2016). Working memory maintenance is sufficient to reduce state anxiety. 
Psychophysiology, 00. https://doi.org/10.1111/psyp.12726 
Balderston, N. L., Vytal, K. E., O’Connell, K., Torrisi, S., Letkiewicz, A., Ernst, M., & 
Grillon, C. (2016). Anxiety Patients Show Reduced Working Memory Related Dlpfc 
Activation During Safety and Threat. Depression and Anxiety, 12(April), 1–12. 
https://doi.org/10.1002/da.22518 
Basten, U., Stelzel, C., & Fiebach, C. J. (2012). Trait anxiety and the neural efficiency of 
manipulation in working memory. Cognitive, Affective & Behavioral Neuroscience, 
12(3), 571–588. https://doi.org/10.3758/s13415-012-0100-3 
Beck, A. T., Epstein, N., Brown, G., & Steer, R. a. (1988). An inventory for measuring 

CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
clinical anxiety: psychometric properties. Journal of Consulting and Clinical 
Psychology, 56(6), 893–897. https://doi.org/10.1037/0022-006X.56.6.893 
Berggren, N., & Derakshan, N. (2013a). Attentional control deficits in trait anxiety: Why 
you see them and why you don’t. Biological Psychology, 92(3), 440–446. 
https://doi.org/10.1016/j.biopsycho.2012.03.007 
Berggren, N., & Derakshan, N. (2013b). The role of consciousness in attentional control 
differences 
in 
trait 
anxiety. 
Cognition 
& 
Emotion, 
27(5), 
923–931. 
https://doi.org/10.1080/02699931.2012.750235 
Berman, K. F., Doran, A. R., Pickar, D., & Weinberger, D. R. (1993). Is the mechanism of 
prefrontal hypofunction in depression the same as in schizophrenia? Regional 
cerebral blood flow during cognitive activation. British Journal of Psychiatry, 
162(FEB.), 183–192. https://doi.org/10.1192/bjp.162.2.183 
Braver, T. S., Cole, M. W., & Yarkoni, T. (2010). Vive les differences! Individual variation 
in neural mechanisms of executive control. Current Opinion in Neurobiology, 20(2), 
242–250. https://doi.org/10.1016/j.conb.2010.03.002 
Chen, J., Zhou, C., Wu, B., Wang, Y., Li, Q., Wei, Y., … Xie, P. (2013). Left versus right 
repetitive transcranial magnetic stimulation in treating major depression: A meta-
analysis of randomised controlled trials. Psychiatry Research, 210(3), 1260–1264. 
https://doi.org/10.1016/j.psychres.2013.09.007 
Cieslik, E. C., Zilles, K., Caspers, S., Roski, C., Kellermann, T. S., Jakobs, O., … Eickhoff, 
S. B. (2013). Is there one DLPFC in cognitive action control? Evidence for 
heterogeneity from Co-activation-based parcellation. Cerebral Cortex, 23(11), 2677–
2689. https://doi.org/10.1093/cercor/bhs256 
Cole, M. W., Repovš, G., & Anticevic, A. (2014). The frontoparietal control system: a 
central role in mental health. The Neuroscientist : A Review Journal Bringing 
Neurobiology, 
Neurology 
and 
Psychiatry, 
20(6), 
652–664. 
https://doi.org/10.1177/1073858414525995 
Concerto, C., Lanza, G., Cantone, M., Ferri, R., Pennisi, G., Bella, R., & Aguglia, E. 
(2015). Repetitive transcranial magnetic stimulation in patients with drug-resistant 
major depression: A six-month clinical follow-up study. International Journal of 
Psychiatry 
in 
Clinical 
Practice, 
19(4), 
252–258. 
https://doi.org/10.3109/13651501.2015.1084329 
Coombes, S. A., Higgins, T., Gamble, K. M., Cauraugh, J. H., & Janelle, C. M. (2009). 
Attentional control theory: Anxiety, emotion, and motor planning. Journal of Anxiety 
Disorders, 23(8), 1072–1079. https://doi.org/10.1016/j.janxdis.2009.07.009 
Davidson, R. J. (2004). What does the prefrontal cortex “do” in affect: Perspectives on 
frontal EEG asymmetry research. Biological Psychology, 67(1–2), 219–233. 
https://doi.org/10.1016/j.biopsycho.2004.03.008 
Derryberry, D., & Reed, M. a. (2002). Anxiety-related attentional biases and their 
regulation by attentional control. Journal of Abnormal Psychology, 111(2), 225–236. 
https://doi.org/10.1037//0021-843X.111.2.225 
Eysenck, M. W., Derakshan, N., Santos, R., & Calvo, M. G. (2007). Anxiety and cognitive 
performance: attentional control theory. Emotion (Washington, D.C.), 7(2), 336–353. 
https://doi.org/10.1037/1528-3542.7.2.336 
Fales, C. L., Barch, D. M., Burgess, G. C., Schaefer,  a, Mennin, D. S., Gray, J. R., & 
Braver, T. S. (2008). Anxiety and cognitive efficiency: differential modulation of 

CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
transient and sustained neural activity during a working memory task. Cognitive, 
Affective 
& 
Behavioral 
Neuroscience, 
8(3), 
239–253. 
https://doi.org/10.3758/CABN.8.3.239 
Fox, M. D., Buckner, R. L., White, M. P., Greicius, M. D., & Pascual-Leone, A. (2012). 
Efficacy of transcranial magnetic stimulation targets for depression is related to 
intrinsic functional connectivity with the subgenual cingulate. Biological Psychiatry, 
72(7), 595–603. https://doi.org/10.1016/j.biopsych.2012.04.028 
Galynker, I. I., Cai, J., Ongseng, F., Finestone, H., Dutta, E., & Serseni, D. (1998). 
Hypofrontality and negative symptoms in major depressive disorder. Journal of 
Nuclear Medicine : Official Publication, Society of Nuclear Medicine, 39(4), 608–612. 
Grillon, C., Robinson, O., Mathur, A., & Ernst, M. (2015). Effect of attention control on 
sustained attention during induced anxiety. Cognition and Emotion, 9931(April), 1–
13. https://doi.org/10.1080/02699931.2015.1024614 
Harding, I. H., Yücel, M., Harrison, B. J., Pantelis, C., & Breakspear, M. (2015). Effective 
connectivity within the frontoparietal control network differentiates cognitive control 
and 
working 
memory. 
NeuroImage, 
106, 
144–153. 
https://doi.org/10.1016/j.neuroimage.2014.11.039 
Horvath, J. C., Mathews, J., Demitrack, M. a, & Pascual-Leone, A. (2010). The NeuroStar 
TMS device: conducting the FDA approved protocol for treatment of depression. 
Journal of Visualized Experiments : JoVE, (45), 9–11. https://doi.org/10.3791/2345 
Keel, J. C., Smith, M. J., & Wassermann, E. M. (2000). Letter to the Editor. A safety 
screening 
questionnaire 
for 
transcranial 
magnetic 
stimulation. 
Clinical 
Neurophysiology : Official Journal of the International Federation of Clinical 
Neurophysiology, 112, 720. https://doi.org/10.3111/13696998.2014.909438 
Kessler, R., & Chiu, W. (2005). Prevalence, severity, and comorbidity of 12-month DSM-
IV disorders in the National Comorbidity Survey Replication. Archives of General …, 
62(6), 617–627. https://doi.org/10.1001/archpsyc.62.6.617.Prevalence 
Lefaucheur, J. P., Andre-Obadia, N., Antal, A., Ayache, S. S., Baeken, C., Benninger, D. 
H., … Garcia-Larrea, L. (2014). Evidence-based guidelines on the therapeutic use of 
repetitive transcranial magnetic stimulation (rTMS). Clin Neurophysiol, 125(11), 
2150–2206. 
https://doi.org/S1388-2457(14)00296-X 
[pii]\r10.1016/j.clinph.2014.05.021 [doi] 
Luber, B. M., Davis, S., Bernhardt, E., Neacsiu, A., Kwapil, L., Lisanby, S. H., & Strauman, 
T. J. (2017). Using neuroimaging to individualize TMS treatment for depression: 
Toward a new paradigm for imaging-guided intervention. NeuroImage, 148(January), 
1–7. https://doi.org/10.1016/j.neuroimage.2016.12.083 
Luber, B. M., Kinnunen, L. H., Rakitin, B. C., Ellsasser, R., Stern, Y., & Lisanby, S. H. 
(2007). Facilitation of performance in a working memory task with rTMS stimulation 
of the precuneus: Frequency- and time-dependent effects. Brain Research, 1128(1), 
120–129. https://doi.org/10.1016/j.brainres.2006.10.011 
Luber, B. M., Stanford,  a. D., Bulow, P., Nguyen, T., Rakitin, B. C., Habeck, C., … 
Lisanby, S. H. (2008). Remediation of sleep-deprivation-induced working memory 
impairment with fMRI-guided transcranial magnetic stimulation. Cerebral Cortex, 
18(9), 2077–2085. https://doi.org/10.1093/cercor/bhm231 
Luber, B. M., Steffener, J., Tucker, A., Habeck, C., Peterchev, A. V, Deng, Z.-D., … 
Lisanby, S. H. (2013). Extended remediation of sleep deprived-induced working 

CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
memory deficits using fMRI-guided transcranial magnetic stimulation. Sleep, 36(6), 
857–871. https://doi.org/10.5665/sleep.2712 
Mantovani, A., Aly, M., Dagan, Y., Allart, A., & Lisanby, S. H. (2013). Randomized sham 
controlled trial of repetitive transcranial magnetic stimulation to the dorsolateral 
prefrontal cortex for the treatment of panic disorder with comorbid major depression. 
Journal 
of 
Affective 
Disorders, 
144(1–2), 
153–159. 
https://doi.org/10.1016/j.jad.2012.05.038 
Miller, G. a, Crocker, L. D., Spielberg, J. M., Infantolino, Z. P., & Heller, W. (2013). Issues 
in localization of brain function: The case of lateralized frontal cortex in cognition, 
emotion, and psychopathology. Frontiers in Integrative Neuroscience, 7(January), 2. 
https://doi.org/10.3389/fnint.2013.00002 
Miniussi, C., Bonato, C., Bignotti, S., Gazzoli, A., Gennarelli, M., Pasqualetti, P., … 
Rossini, P. M. (2005). Repetitive transcranial magnetic stimulation (rTMS) at high 
and low frequency: An efficacious therapy for major drug-resistant depression? 
Clinical 
Neurophysiology, 
116(5), 
1062–1071. 
https://doi.org/10.1016/j.clinph.2005.01.002 
Morrison, A. S., & Heimberg, R. G. (2013). Attentional control mediates the effect of social 
anxiety on positive affect. Journal of Anxiety Disorders, 27(1), 56–67. 
https://doi.org/10.1016/j.janxdis.2012.10.002 
Moulier, V., Gaudeau-Bosma, C., Isaac, C., Allard, A., Bouaziz, N., Sidhoumi, D., … 
Januel, D. (2016). Effect of repetitive transcranial magnetic stimulation on mood in 
healthy 
subjects. 
Socioaffective 
Neuroscience 
& 
Psychology, 
6, 
6–11. 
https://doi.org/10.3402/snp.v6.29672 
Najmi, S., Amir, N., Frosio, K. E., & Ayers, C. (2014). The effects of cognitive load on 
attention control in subclinical anxiety and generalised anxiety disorder. Cognition & 
Emotion, 
9931(December 
2014), 
1–14. 
https://doi.org/10.1080/02699931.2014.975188 
Najmi, S., Kuckertz, J. M., & Amir, N. (2012). Attentional impairment in anxiety: 
inefficiency in expanding the scope of attention. Depression and Anxiety, 29(3), 243–
249. https://doi.org/10.1002/da.20900 
Nauczyciel, C., Hellier, P., Morandi, X., Blestel, S., Drapier, D., Ferre, J. C., … Millet, B. 
(2011). Assessment of standard coil positioning in transcranial magnetic stimulation 
in 
depression. 
Psychiatry 
Research, 
186(2–3), 
232–238. 
https://doi.org/10.1016/j.psychres.2010.06.012 
O’Reardon, J. P., Solvason, H. B., Janicak, P. G., Sampson, S., Isenberg, K. E., Nahas, 
Z., … Sackeim, H. A. (2007). Efficacy and Safety of Transcranial Magnetic 
Stimulation in the Acute Treatment of Major Depression: A Multisite Randomized 
Controlled 
Trial. 
Biological 
Psychiatry, 
62(11), 
1208–1216. 
https://doi.org/10.1016/j.biopsych.2007.01.018 
Pallanti, S., & Bernardi, S. (2009). Neurobiology of repeated transcranial magnetic 
stimulation in the treatment of anxiety: a critical review. International Clinical 
Psychopharmacology, 
24(4), 
163–173. 
https://doi.org/10.1097/YIC.0b013e32832c2639 
Peers, P. V, Simons, J. S., & Lawrence, A. D. (2013). Prefrontal control of attention to 
threat. 
Frontiers 
in 
Human 
Neuroscience, 
7(February), 
24. 
https://doi.org/10.3389/fnhum.2013.00024 

CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
Pigot, M., Loo, C., & Sachdev, P. (2008). Repetitive transcranial magnetic stimulation as 
treatment for anxiety disorders. Expert Review of Neurotherapeutics, 8(10), 1449–
1455. https://doi.org/http://dx.doi.org/10.1586/14737175.8.10.1449 
Price, R. B., Eldreth, D. a, & Mohlman, J. (2011). Deficient prefrontal attentional control 
in late-life generalized anxiety disorder: an fMRI investigation. Translational 
Psychiatry, 1(10), e46. https://doi.org/10.1038/tp.2011.46 
Reinholdt-Dunne, M. L., Mogg, K., & Bradley, B. P. (2009). Effects of anxiety and attention 
control on processing pictorial and linguistic emotional information. Behaviour 
Research and Therapy, 47(5), 410–417. https://doi.org/10.1016/j.brat.2009.01.012 
Reinholdt-Dunne, M. L., Mogg, K., & Bradley, B. P. (2012). Attention control: 
Relationships between self-report and behavioural measures, and symptoms of 
anxiety and depression. Cognition & Emotion, 9931(June 2015), 1–11. 
https://doi.org/10.1080/02699931.2012.715081 
Rossi, S., Hallett, M., Rossini, P. M., & Pascual-Leone, A. (2009). Safety, ethical 
considerations, and application guidelines for the use of transcranial magnetic 
stimulation in clinical practice and research. Clin Neurophysiol, 120(12), 2008–2039. 
https://doi.org/S1388-2457(09)00519-7 [pii]\r10.1016/j.clinph.2009.08.016 [doi] 
Schmitz, A., & Grillon, C. (2012). Assessing fear and anxiety in humans using the threat 
of predictable and unpredictable aversive events (the NPU-threat test). Nature 
Protocols, 7(3), 527–532. https://doi.org/10.1038/nprot.2012.001 
Shajahan, P. M., Glabus, M. F., Steele, J. D., Doris, A. B., Anderson, K., Jenkins, J. A., 
… Ebmeier, K. P. (2002). Left dorso-lateral repetitive transcranial magnetic 
stimulation affects cortical excitability and functional connectivity, but does not impair 
cognition in major depression. Progress in Neuro-Psychopharmacology and 
Biological 
Psychiatry, 
26(5), 
945–954. 
https://doi.org/10.1016/S0278-
5846(02)00210-5 
Spielberger, C. D. (1987). State-Trait Anxiety Inventory. Anxiety, Vol. 19, p. 2009. 
https://doi.org/10.1037/t06496-000 
Stern, W. M., Tormos, J. M., Press, D. Z., Pearlman, C., & Pascual-Leone, A. (2007). 
Antidepressant effects of high and low frequency repetitive transcranial magnetic 
stimulation to the dorsolateral prefrontal cortex. The Journal of Neuropsychiatry and 
Clinical Neurosciences, 19(2), 179–186. https://doi.org/10.1176/jnp.2007.19.2.179 
Vytal, K. E., Cornwell, B. R., Arkin, N., & Grillon, C. (2012). Describing the interplay 
between anxiety and cognition: From impaired performance under low cognitive load 
to reduced anxiety under high load. Psychophysiology, 49(6), 842–852. 
https://doi.org/10.1111/j.1469-8986.2012.01358.x 
Vytal, K. E., Cornwell, B. R., Letkiewicz, A. M., Arkin, N. E., & Grillon, C. (2013). The 
complex interaction between anxiety and cognition: insight from spatial and verbal 
working 
memory. 
Frontiers 
in 
Human 
Neuroscience, 
7(March), 
93. 
https://doi.org/10.3389/fnhum.2013.00093 
White, D., & Tavakoli, S. (2015). Repetitive transcranial magnetic stimulation for 
treatment of major depressive disorder with comorbid generalized anxiety disorder. 
Annals 
of 
Clinical 
Psychiatry, 
27(3), 
192–196. 
Retrieved 
from 
http://login.ezproxy.lib.umn.edu/login?url=http://ovidsp.ovid.com/ovidweb.cgi?T=JS
&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=26247218%5Cnhttp://primo.lib.
umn.edu/openurl/TWINCITIES/TWINCITIES_SP?sid=OVID:medline&id=pmid:2624

CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
7218&id=doi:&issn=1040-1237&isbn=&vo 
Zwanzger, P., Fallgatter, A. J., Zavorotnyy, M., & Padberg, F. (2009). Anxiolytic effects of 
transcranial magnetic stimulation-an alternative treatment option in anxiety 
disorders? 
Journal 
of 
Neural 
Transmission, 
116(6), 
767–775. 
https://doi.org/10.1007/s00702-008-0162-0 
Zwanzger, P., Steinberg, C., Rehbein, M. A., Bröckelmann, A.-K., Dobel, C., Zavorotnyy, 
M., … Junghöfer, M. (2014). Inhibitory repetitive transcranial magnetic stimulation 
(rTMS) of the dorsolateral prefrontal cortex modulates early affective processing. 
NeuroImage, 101, 193–203. https://doi.org/10.1016/j.neuroimage.2014.07.003 
 
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