Causal Role of Frontostriatal Circuitry in Goal-directed Behavior
Phase: NA
Conditions: Executive Function
Sponsor: University of North Carolina, Chapel Hill

 
Causal Role of Frontostriatal Circuitry in Goal-directed 
Behavior 
 
 
 
NCT number NCT05593965 
Document Date 12/26/2022 
 

Causal role of frontostriatal circuitry in goal-directed 
behavior 
Protocol Number: 22-2430 
Principal Investigator: Flavio Frohlich, PhD 
Medical Monitor: Clio Rubinos, MD 
Study Coordinator: Justin Riddle, PhD 
Statistical Analyst: Justin Riddle, PhD 
Funded by: Foundation of Hope, National Institute of Mental Health 
Version Number:  V3 
26 December 2022 
 
 
Summary of Changes from Previous Version: 
Version 
Control 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
V2 
Adverse 
events 
reporting 
section. Side 
effects 
description. 
There is no plan for a follow-up 30 days 
following the completion of study 
participation. Side effects were 
expanded to include psychological 
discomfort from receiving stimulation 
and rare side effects to mood, 
concentrating, and sleepiness. 
This is now consistent with our 
previous work using transcranial 
magnetic stimulation. Side effects are 
now consistent between post-
stimulation questionnaire and 
description of risks. 
V3 
Adding EMG 
and session 1 
TMS for 
tolerability. 
An EMG recording is added for session 
1, 3, and 4. TMS is added to the end of 
the first session to screen participants 
with low tolerability. Inclusion criteria 
updated to be right-handed only. 
Recent findings suggest that recording 
electrical activity in the hand and 
forearm might contribute to the 
mechanistic understanding of our 
findings. To increase study feasibility, 
participants will receive two practice 
blocks of TMS on the first session to 
screen for tolerability. 

  
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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1. PROTOCOL SUMMARY ....................................................................................................................................... 2 
1.1 Synopsis ............................................................................................................................................................. 2 
1.2 Schema .............................................................................................................................................................. 4 
1.3 schedule of activities (soa) .............................................................................................................................. 5 
2. INTRODUCTION ..................................................................................................................................................... 6 
2.1 Study Rationale ................................................................................................................................................. 6 
2.2 Background ........................................................................................................................................................ 6 
2.3 Risk/Benefit Assessment ................................................................................................................................. 7 
2.3.1 Known Potential Risks 7 
2.3.2 Known Potential Benefits ..........................................................................................................................9 
2.3.3 Assessment of Potential Risks and Benefits .........................................................................................9 
2.3.4 Referrals for medical follow-up.................................................................................................................9 
3. Objective and Outcome Measures ..................................................................................................................... 11 
4. STUDY DESIGN ................................................................................................................................................... 12 
4.1 Overall Design ................................................................................................................................................. 12 
4.2 Scientific Rationale for Study Design .......................................................................................................... 14 
4.3 Justification for Dose ...................................................................................................................................... 15 
4.4 End of Study Definition .................................................................................................................................. 18 
5. STUDY POPULATION ......................................................................................................................................... 18 
5.1 Inclusion Criteria ............................................................................................................................................. 18 
5.2 Exclusion Criteria ............................................................................................................................................ 18 
5.3 Lifestyle Considerations ................................................................................................................................. 19 
5.4 Screen Failures ............................................................................................................................................... 19 
5.5 Strategies for Recruitment and Retention................................................................................................... 19 
6. STUDY INTERVENTION ..................................................................................................................................... 20 
6.1 Study Intervention(s) Administration ............................................................................................................ 20 
6.1.1 Study Intervention Description .............................................................................................................. 20 
6.1.2 Dosing and Administration ..................................................................................................................... 21 
6.3 Measures to Minimize Bias: control conditions and Randomization ...................................................... 21 
6.4 Study Intervention Compliance ..................................................................................................................... 22 
6.5 Concomitant Therapy ..................................................................................................................................... 22 
7. STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 22 
7.1 Discontinuation of Study Intervention .......................................................................................................... 22 
7.2 Participant Discontinuation/Withdrawal from the Study ............................................................................ 23 
7.3 Lost to Follow-Up ............................................................................................................................................ 23 
8. STUDY ASSESSMENTS AND PROCEDURES .............................................................................................. 24 
8.1 Efficacy Assessments .................................................................................................................................... 24 
8.1.1 
ELECTROPHYSIOLOGY 
24 
8.1.2 
task PERFORMANCE 
24 
8.1.3 
Self-Report Assessments 
25 
8.2 Safety and Other Assessments .................................................................................................................... 25 
8.3 Adverse Events and Serious Adverse Events ........................................................................................... 26 
8.3.1 Definition of Adverse Events (AE) ........................................................................................................ 26 
8.3.2 Definition of Serious Adverse Events (SAE) ....................................................................................... 26 

  
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8.3.3 Classification of an Adverse Event ....................................................................................................... 26 
8.3.4 Time Period and Frequency for Event Assessment and Follow-Up ............................................... 27 
8.3.5 Adverse Event Reporting ....................................................................................................................... 28 
8.3.6 Reporting of Pregnancy.......................................................................................................................... 28 
8.4 Unanticipated Problems ................................................................................................................................. 29 
8.4.1 Definition of Unanticipated Problems (UP).......................................................................................... 29 
8.4.2 Unanticipated Problem Reporting ......................................................................................................... 29 
8.4.3 Reporting Unanticipated Problems to Participants ............................................................................ 29 
9. STATISTICAL CONSIDERATIONS ................................................................................................................... 29 
9.1 Statistical Hypotheses .................................................................................................................................... 29 
9.2 Sample Size Determination ........................................................................................................................... 31 
9.3 Populations for Analyses ............................................................................................................................... 33 
9.4 Statistical Analyses ......................................................................................................................................... 33 
9.4.1 General Approach 
33 
9.4.2 Analysis of the Primary outcome (behavior) ....................................................................................... 34 
9.4.3 Analysis of the Secondary OUTCOME (electrophysiology) ............................................................. 34 
9.4.4 Analysis of the exploratory outcomes .................................................................................................. 35 
9.4.5 Safety Analyses 
36 
9.4.6 Baseline Descriptive Statistics .............................................................................................................. 36 
9.4.7 Planned Interim Analyses ...................................................................................................................... 36 
9.4.8 Sub-Group Analyses 
37 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ..................................... 37 
10.1 Regulatory, Ethical, and Study Oversight Considerations ..................................................................... 37 
10.1.1 Informed Consent Process .................................................................................................................. 37 
10.1.2 Study Discontinuation and Closure .................................................................................................... 37 
10.1.3 Confidentiality and Privacy .................................................................................................................. 38 
10.1.4 Future Use of Stored Specimens and Data ...................................................................................... 38 
10.1.5 Key Roles and Study Governance ..................................................................................................... 38 
10.1.6 Safety Oversight 
39 
10.1.7 Clinical Monitoring 
39 
10.1.8 Quality Assurance and Quality Control.............................................................................................. 40 
10.1.9 
Data Handling and Record Keeping ........................................................................... 40 
10.1.10 
Protocol Deviations 
41 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 41 
10.1.12 
Conflict of Interest Policy .............................................................................................. 41 
10.2 
Additional Considerations ................................................................................................................. 41 
10.3 
Abbreviations ...................................................................................................................................... 42 
10.4 
Protocol Amendment History ........................................................................................................... 44 
11 
REFERENCES .............................................................................................................................................. 45 
 

Causal role of frontostriatal circuitry in goal-directed behavior 
Version: V3 
Protocol: IRB#22-2430 
 
26 December 2022 
 
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
 
1 
STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP) and the following:    
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 
46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible 
for the conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects 
Protection and ICH GCP Training.  
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled.  Any amendment to 
the protocol will require review and approval by the IRB before the changes are implemented to the 
study.  In addition, all changes to the consent form will be IRB-approved; a determination will be made 
regarding whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 
 
 

Causal role of frontostriatal circuitry in goal-directed behavior 
Version: V3 
Protocol: IRB#22-2430 
 
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1. PROTOCOL SUMMARY 
1.1 SYNOPSIS  
Title: 
Causal role of frontrostriatal circuitry in goal-directed behavior  
Study Description: 
The purpose of this clinical trial is to investigate the causal role that 
frontrostriatal circuitry plays in goal-directed behavior. The participants 
will perform a reward-based decision-making task. During the task, cross-
frequency patterned rhythmic transcranial magnetic stimulation (rTMS) 
will be delivered at delta-beta frequency, a control-frequency, or an active 
sham to either the dorsolateral or medial prefrontal cortex (PFC). 
Electroencephalography will be collected concurrent with stimulation. 
Structural and functional magnetic resonance imaging (MRI) will be 
collected during performance of the reward-based decision-making task to 
localize the stimulation targets. 
Objectives: 
 
Primary Objective: To investigate whether delta-beta rTMS to anterior 
middle frontal gyrus will produce an increase in goal-directed behavior 
during reward-based decision-making. 
Secondary Objective: To investigate whether delta-beta rTMS to anterior 
middle frontal gyrus will result in a lasting increase in delta-beta coupling 
during the decision-period of reward-based decision-making. 
Exploratory Objective 1: To investigate whether personality traits of 
motivation explain individual differences in the primary outcome. 
Exploratory Objective 2: To investigate whether theta-gamma rTMS to 
medial prefrontal cortex will produce an increase in reward-evaluation 
during reward-based decision-making. 
Exploratory Objective 3: To investigate whether theta-gamma rTMS to 
medial prefrontal cortex will result in a lasting increase in theta-gamma 
coupling during the decision-period of reward-based decision-making. 
Exploratory Objective 4: To investigate whether the strength of functional 
connectivity between dorsal striatum and anterior middle frontal gyrus 
explains individual differences in the primary outcome. 
 
  
Outcomes: 
Primary Outcome: Behavioral metric, percentage of hard trials chosen, 
during the streamlined version of the Expenditure of Effort for Reward 
Task (S-EEfRT). 
Secondary Outcome: Neural metric, degree of phase-amplitude coupling 
between prefrontal delta oscillations and left motor beta oscillations, 
quantified during the decision epoch of the S-EEfRT. 
Exploratory Outcome 1: Personality metric, traits of motivation explain 
individual differences in the primary outcome. 
Exploratory Outcome 2: Behavioral metric, percentage of hard trials 
chosen as a function of incentive during the S-EEfRT. 
Exploratory Outcome 3: Neural metric, degree of phase-amplitude 
coupling between prefrontal theta oscillations and posterior gamma 
oscillations, quantified during the decision epoch of the S-EEfRT. 

Causal role of frontostriatal circuitry in goal-directed behavior 
Version: V3 
Protocol: IRB#22-2430 
 
26 December 2022 
 
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Exploratory Outcome 4: Connectivity metric, strength of task-based 
functional MRI connectivity between dorsal striatum and dorsolateral 
prefrontal cortex during the decision-epoch of the S-EEfRT. 
Study Population: 
We will recruit healthy men and non-pregnant women ages 18-65 without 
a neurological disorder, free of benzodiazepines and anticonvulsant 
medications. Participants must also be eligible to receive rTMS and MRI. 
Participants will be recruited from the Chapel Hill, Durham and Raleigh 
areas. 
Phase: 
Pilot Phase 
Description of 
Sites/Facilities Enrolling 
Participants: 
University of North Carolina at Chapel Hill 
 
 
Description of Study 
Intervention: 
We will use the MagPro X100 or R30 system (MagVenture Inc., Alpharetta, 
Georgia, USA) for transcranial magnetic stimulation. The MagPro X100 or 
R30 are an advanced, high performance magnetic stimulator designed 
primarily for research purposes. It is a high-quality tool for researchers 
with a large choice of stimulating parameters and has stimulation rates up 
to 100 pulses per second at high intensities and the possibility to combine 
waveforms and pulse modes. Patterned rhythmic TMS will be delivered in 
either cross-frequency delta-beta, cross-frequency theta-gamma, or an 
arrhythmic pattern that is matched for the number of pulses and duration.  
Stimulation will be delivered at 80% of motor threshold in the 2 seconds 
before the decision epoch with 5 triplets of 3 pulses per train per trial. 
Study Duration: 
2 years 
Participant Duration: 
Participation for each participant will be 4 weeks. Completion includes 
four sessions: an EEG session, an MRI session, and two EEG-TMS sessions. 
The EEG session will take approximately 1.5 hours. The MRI session will 
take approximated 1.5 hours. The two stimulation sessions will each take 
approximately 2 hours. We estimate that total participation to be 
approximately 7 hours. 
 
 

Causal role of frontostriatal circuitry in goal-directed behavior 
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1.2 SCHEMA 
 
Figure 1. Experimental design depicted as a flow-chart for this protocol. This study is four sessions with a full 
crossover design. After a phone screening to assess eligibility, an EEG baseline session is conducted to estimate 
baseline metrics of task performance and task-based neural metrics. Brief session of TMS is delivered to assess 
tolerability. Participants are then excluded based on task performance. In session 2, participant complete a 
functional MRI session that is used to localize the stimulation targets that are used in the 3rd and 4th session. In the 

Causal role of frontostriatal circuitry in goal-directed behavior 
Version: V3 
Protocol: IRB#22-2430 
 
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3rd & 4th session, stimulation is delivered to lateral prefrontal cortex (PFC) or medial PFC in a counterbalanced and 
randomized sequence. For each block of the task, rhythmic transcranial magnetic stimulation (TMS) is delivered in 
the target frequency delta-beta, an active control frequency (theta-gamma), or an arrhythmic pattern (active 
control condition). 
 
1.3 SCHEDULE OF ACTIVITIES (SOA) 
 
Procedures 
Phone Screening 
 
Session 1 EEG Only 
Session 2 - MRI 
Session 3 – EEG 
and TMS 
Session 4 – EEG 
and TMS 
Verbal informed consent 
X 
 
 
 
 
Written informed consent 
 
X 
 
 
 
Determine Eligibility 
X 
X 
 
 
 
MRI Screening 
X 
 
X 
 
 
TMS Screening 
X 
X 
 
X 
X 
Demographics 
X 
 
 
 
 
SHAPS 
 
X 
 
 
 
RRS 
 
X 
 
 
 
BIS/BAS 
 
X 
 
 
 
TEPS 
 
X 
 
 
 
STAI 
 
X 
 
 
 
Urine Pregnancy Test (if 
applicable) 
 
X 
 
 
 
Resting-state with EEG 
 
X 
 
X 
X 
S-EEfRT with EEG 
 
X 
 
X 
X 
EMG recorded 
 
X 
 
X 
X 
Structural MRI 
 
 
X 
 
 
S-EEfRT with functional MRI 
 
 
X 
 
 
Motor threshold using single 
pulse TMS 
 
X 
 
 
 
TMS tolerability test 
 
X 
 
 
 
S-EEfRT with patterned TMS 
 
 
 
X 
X 
Stimulation Questionnaire 
 
X 
 
X 
X 
AE Structured Interview 
 
* 
 
* 
* 
AE Review and Evaluation 
 
* 
 
* 
* 
* when applicable 
 

Causal role of frontostriatal circuitry in goal-directed behavior 
Version: V3 
Protocol: IRB#22-2430 
 
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2. INTRODUCTION 
 
2.1 STUDY RATIONALE  
 
Anhedonia, the inability to seek-out and experience pleasure, remains difficult to treat, with many pharmacological 
interventions occasionally increasing, or introducing, anhedonia (Husain and Roiser 2018; Lambert et al. 2018; 
Treadway and Zald 2011). Many proven treatments in psychiatry are less effective in patients with elevated 
symptoms of anhedonia (Hatzigiakoumis et al. 2011; Landén et al. 2005; McMakin et al. 2012; Nierenberg et al. 1999; 
Shelton and Tomarken 2001). In affective disorders such as major depressive disorder (MDD), anhedonia is positively 
correlated with suicidal behavior (Bonanni et al. 2019). Therefore, effective treatment for anhedonia is a critical 
factor in the ongoing mental health crisis. Symptoms of anhedonia fall within the “Positive Valence System” of the 
research domain criteria (RDoC) framework (Nusslock and Alloy 2017) and comprise two primary components: 
“liking” and “wanting” (Gard et al. 2006; Kring and Barch 2014). The “liking,” or consummatory, component reflects 
the experience of rewards as pleasurable. Collectively, reward evaluation is known to critically rely on the 
orbitofrontal cortex of the medial prefrontal cortex (mPFC) to process the value of the reward (O’Doherty 2004; 
Padoa-Schioppa and Cai 2011) and the nucleus accumbens of the ventral striatum (vSTR) to evaluate the effortful 
cost (Sugam et al. 2012). Correlational studies find reduced activation and decreased functional connectivity in 
mPFC-vSTR during reward-based decision-making tasks in patients with anhedonia (Epstein et al. 2006; Greenberg 
et al. 2015; Wacker et al. 2009). The second component is the “wanting,” or anticipatory, component that reflects 
the organization of behavior according to a cost-benefit computation – goal-directed behavior. The dorsal striatum 
(dSTR) processes the anticipation of receiving a future reward and orients behavior towards reward-seeking 
(Pizzagalli et al. 2009; Zhang et al. 2016). The dSTR (caudate and putamen) is guided by the dorsolateral prefrontal 
cortex (dlPFC; middle frontal gyrus) and together they play a critical role in planning and initiating goal-directed 
behavior (Badre and Nee 2018). Lesion to the dlPFC results in deficits in planning and initiating goal-directed behavior 
(Szczepanski and Knight 2014) and lesion to dSTR results in apathy and similar deficits as lesions to dlPFC (Mendez 
et al. 1989). Thus, the neuropsychological etiology of anhedonia presents two candidate neural circuits tied to two 
relevant cognitive constructs: mPFC-vSTR for reward-evaluation and dlPFC-dSTR for goal-directed behavior (Höflich 
et al. 2019; Kring and Barch 2014; Rizvi et al. 2016). Pathology of both circuits is correlated with anhedonia (Walsh 
et al. 2019), and causal investigation may differentiate the relative importance of each circuit. 
In the present study, we propose to test for the causal role of these two frontal-striatal circuits in reward-based 
decision-making in healthy participants that are not included on the basis of psychiatric illness. A better 
understanding of the role of these circuits in reward-based decision-making is a critical first step in developing novel 
treatment targets for intervention for psychiatric illness. In addition to building a neurobehavioral framework for 
reward-based decision-making, this study will test novel techniques for using non-invasive brain stimulation to 
increase activity within specific frontal-striatal circuits. 
   
2.2 BACKGROUND  
  
In the past few decades, non-invasive brain stimulation emerged as a promising intervention for treatment-resistant 
depression that is safe with minimal side-effect (Perera et al. 2016). The most widely available stimulation protocols 
to treat depression use transcranial magnetic stimulation (TMS) to increase neural activity in the left dlPFC (Perera 
et al. 2016) or mPFC (Downar et al. 2014; Siddiqi et al. 2020), and recent work from our lab found promising 
treatment effects using transcranial alternating current stimulation (tACS) to dlPFC (Alexander et al. 2019; Riddle et 
al. 2020a). With multiple spatial targets emerging for the treatment of depression, researchers are beginning to 

Causal role of frontostriatal circuitry in goal-directed behavior 
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understand that heterogeneity in depression symptoms alters which spatial targets are most effective at treating 
depression (Siddiqi et al. 2020). Inaccurate spatial targeting can render treatment ineffective (Fox et al. 2012). 
Therefore, improved understanding of the neural circuits that underly specific symptoms of depression is of critical 
need. One such symptom, anhedonia, is more responsive to stimulation targeting dlPFC than stimulation targeting 
mPFC (Downar et al. 2014; Drysdale et al. 2017; Duprat et al. 2018; Pettorruso et al. 2018; Siddiqi et al. 2020). 
Stimulation to left dlPFC in depressed patients with anhedonia only alleviated depression when symptoms of 
anhedonia decreased (Levkovitz et al. 2011). In contrast, stimulation to mPFC only alleviated depression in patients 
without symptoms of anhedonia (Downar et al. 2014). Despite recent evidence that dlPFC-dSTR is the optimal target 
for treating anhedonia in depression, the overall response rate is still lower than depressed patients without 
anhedonia (Krepel et al. 2020). One explanation is that stimulation efficacy is also critically dependent on the 
temporal structure of neural activity (Ali et al. 2013). Thus, investigation of the electrophysiology of dlPFC-dSTR 
during goal-directed behavior in patients with anhedonia is critical to further advance the efficacy of treatment 
interventions. 
Neural oscillations are a critical mechanism for interregional communication (Fries 2015), with low frequency 
oscillations facilitating long-distance communication and high frequency enhancing local connectivity (Buzsáki et al. 
2012). Cognitive control tasks evoke low frequency neural oscillations in prefrontal cortex that couple to high 
frequency oscillations in posterior cortex (Canolty and Knight 2010; Helfrich et al. 2017; Voytek et al. 2010; Voytek 
et al. 2015). This cross-frequency coupling is proposed to be a mechanism for prefrontal cortex to exert top-down 
control (Canolty and Knight 2010). One candidate cross-frequency coupling signal for goal-directed behavior is the 
coupling of delta oscillations (2-4Hz) in prefrontal cortex to beta oscillations (15-30Hz) in motor cortex (Riddle et al. 
2021a; Wyart et al. 2012). In the proposed experiment, we investigate the causal role of delta-beta coupling and the 
dlPFC-dSTR neural circuit in goal-directed behavior in healthy participants. We are convinced that our experiment is 
of high significance since a mechanistic understanding of the neural circuits that underlie goal-directed behavior will 
ultimately allow the rational design of novel brain stimulation techniques to more effectively treat depressed 
patients with anhedonia. 
 
2.3 RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
 
Risk of Seizure from TMS: There is a rare, but potential, risk that TMS will produce a seizure in healthy 
individuals. In order to mitigate this risk, we use multiple strategies. First, we screen participants based 
from participating in the study that present with any traits that may lower their seizure threshold or pose 
increased risk of seizure. These contraindications are well documented within the field and updated 
guidelines are released approximately every 10 years with the latest recommendation released in 2020 
(Rossi et al. 2020). Contraindications screening is conducted during phone screening and prior to each of 
the TMS sessions. Second, we calculate the motor threshold for each participant using electromyography 
or visible twitches in order to calibrate the intensity of stimulation to the endogenous electrical levels of 
the brain of the participant. This calculation is performed in the motor cortex which is one of the most 
excitable regions of the brain and then stimulation is delivered to the prefrontal cortex which is a region 
with considerably lower excitability. Third, we have chosen our stimulation parameters to be within 
recommended safety guidelines. We do not exceed the suggested pulse-per-second rate for our given 
intensity of stimulation (80% of motor threshold). Fourth, we employ a comprehensive monitoring and 
adverse event assessment in each participant. This includes consultation with our Medical Monitor, Dr. 

Causal role of frontostriatal circuitry in goal-directed behavior 
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Clio Rubinos, who is an epileptologist. Fifth, we have created an emergency response plan with our 
medical monitor in the unlikely event of a seizure. 
 
Risk of Confidentiality Breach: In the unlikely event of a breach of confidentiality, people might discover 
that an individual was involved in this research study. This is relevant to our study because some might 
not agree with the principle of participating in research for changing natural brain activity. To avoid 
breaches in confidentiality, study documents that contain personal information and including the 
informed consent document are kept in locked filing cabinets in locked rooms separate from any source 
documents containing participant dummy identifiers. The document that links study ID numbers to 
personal identifying information is encrypted and protected using a password-protected document on a 
secure server provided by UNC School of Medicine. All data is stored in locked cabinets inside locked 
offices; electronic data will be stored only on password-protected computers, and data encryption 
methods will be used during communication between investigators. Only study personnel will have access 
to the data. All study staff participate in annual human participant training that includes education about 
responsibilities to the minimize risk of confidentiality breach. 
 
Risk of Embarrassment: Self-report assessments contain questions regarding sensitive personal 
information. This risk is necessary in order to assess personality traits that might be relevant to subclinical 
expression of symptoms that were discovered to explain individual differences in this task in our previous 
data. Participants will be assured upon intake that self-identifying information will not be collected 
alongside HIPAA protected information.  
 
Risk of Injury and Discomfort: Transcranial magnetic stimulation has been cleared for use in the USA by 
the FDA. TMS (the methodology used in this experiment) has nothing to do with electroconvulsive therapy 
that applies many orders of magnitude higher stimulation current. The level of electrical stimulation 
produced by TMS is within the range of activity that is endogenous to the brain. Furthermore, the intensity 
of stimulation is calibrated to the sensitivity of the individual participant such that the level of stimulation 
is matched to that of naturally occurring activity. In order to monitor side-effects, we will be administering 
an adverse effects stimulation questionnaire after each stimulation session to determine whether these 
effects were experienced. Research personnel present during these sessions will also check with the 
participant periodically during the stimulation to see whether they are comfortable. If any side-effect 
occurs that is rated by the participant and confirmed by the researcher to be stronger than “moderate,” 
the stimulation will be immediately stopped. 
Risk of Psychological Discomfort: There is a psychological element in that some participants may become 
claustrophobic upon entering the small space of the MRI bore. To reduce psychological distress, 
participants are informed that they can withdraw consent and stop participation at any time. Participants 
are monitored throughout the MRI scans and can terminate the scan at any time by squeezing a ball held 
in the hand, and will be quickly removed from the MRI bore. There is additionally a risk of psychological 
discomfort from receiving transcranial magnetic stimulation (TMS). Due to the discomfort from receiving 
TMS and the proximity of the TMS coil to the face and head of the participant, this can result in 
psychological discomfort. Similar to MRI, participants are informed that they can withdraw consent and 
stop participation at any time. Participants are monitored throughout the TMS sessions and can stop 
receiving stimulation at any time by physically moving away from the TMS coil. The field of stimulation is 
less than a couple centimeters. Furthermore, researchers monitor the participant throughout stimulation 
and will check in with the participant approximately every 5 minutes between each task block. 

Causal role of frontostriatal circuitry in goal-directed behavior 
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Risk of Injury from MRI: MRI will be conducted within the Biomedical Research Imaging Center (BRIC) at 
UNC Chapel Hill. The BRIC has a full-time staff that is well trained in the safety involved with MRI. 
Participants complete a contraindications form for MRI upon enrollment in each study. Any questions or 
concerns from the researcher can be addressed by the staff at the BRIC. In addition, the participant 
completes an additional screening form in the presence of the staff at the BRIC to further ensure that all 
safety concerns are addressed. The specific risks that are presented to the participant are avoided by 
effective screening. These risks include physical injury from the presence of metal within the body or in 
the environment when entering the magnetic field of the MRI. The strong magnetic field will pull metal 
towards the center of the field. Thus, it is imperative that all metal is removed from the body and any 
participants with metal within the body do not enter the field. The MR technicians at the BRIC maintain 
strict boundaries and screening via metal detector before entering rooms near to the MRI, adjacent to 
the MRI room, and the MRI room. This three-staged system is standard practice for MRI. Participants are 
provided with a medical gown and private changing room within the BRIC. This ensures that there is no 
chance that participants will enter the room with metallic objects in their pockets (e.g., phones or wallet). 
In addition, technicians screen participants and walk through a check list. Another risk from the MRI is the 
chance of a skin burn from clothing that contains metallic microfibers/particles. Thus, participants wear a 
medical gown to avoid the complication from modern athletic clothing technology. These risks are well-
understood by the scientific community and extensive safety procedures are put in place by regulatory 
oversight that are maintained by the BRIC. 
 
Risk of Transient Psychological Changes from TMS: There is a rare risk that TMS will result in alterations in 
mood, trouble concentrating, or sleepiness. These side effects are not commonly reported, but given the 
diversity of cognitive functions that the prefrontal cortex supports, TMS could potentially produce a 
transient change in the above listed cognitive functions. 
 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
This study has not been designed to benefit the individual participants. However, the knowledge gained 
from this study will contribute to understanding about the psychological and biological basis of reward-
based decision-making. This knowledge is highly relevant to some psychiatric illnesses such as major 
depressive disorder that shows systematic changes in reward-based decision-making. The results from 
this study might be used to develop future interventions using non-invasive brain stimulation.  
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
The risks and benefits presented above are no more serious than for other clinical trials in healthy 
participants. These techniques are common practice within the field of cognitive neuroscience and are 
increasingly being applied to the field of psychiatry. Based on the need for complementary and 
alternative treatments for MDD, the potential risks are worth the potential future benefits as studies 
like this one are essential for the development of novel treatment targets for non-invasive brain 
stimulation. 
 
2.3.4 REFERRALS FOR MEDICAL FOLLOW-UP 

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To ensure participant comfort, a researcher will periodically check in with the participant about any side-
effects he/she may be experiencing during each stimulation session. Following the conclusion of any 
session with TMS, the participant will receive an Adverse Effects Questionnaire to report on any of the 
side-effects he/she may have experienced. This questionnaire reports side-effects on a Likert scale (0 = 
Absent, 1=Low, 2=Medium, 3=High, 4=Very high). If the participant reports side-effects of “very high” 
intensity, the researcher running that session will administer the Structured AE Interview. The majority of 
studies using TMS do not record or document Adverse Events unless a serious adverse event occurs or an 
AE of significance occurs, but that threshold is determined by the researchers of that study. For example, 
two systematic reviews of adverse events for TMS in depression in older participants (Overvliet et al., 
International Journal of Geriatric Psychiatry 2021) and TMS in Parkinson’s disease (VonLoh et al., 
Parkinsonism and Related Disorders 2013) summarized the frequency of AEs and SAEs across many studies 
(Overvliet et al. 2021; VonLoh et al. 2013). From a careful read of these studies, it is clear that the 
threshold for what constitutes an Adverse Event on the mild end of the spectrum is not agreed upon. 
Thus, by using a Likert scale (0 = absent, 1 = low, 2 = medium, 3 = high, 4 = very high) and considering all 
instances of “very high” as the threshold to be considered an Adverse Event is a conservative approach 
that will result in documentation and follow-up interviews at a level greater than 95% of studies. The 
purpose of the Adverse Events Structured Interview is to acquire more information about the experience 
of the participant with respect to the onset of symptoms, the time course of the symptoms, presence of 
symptoms at baseline, and the potential cessation of symptoms at completion of the TMS session. This 
information is written up in a comprehensive document, the Adverse Events Report Form, that is then 
communicated to the Principal Investigator, Dr. Flavio Frohlich, and the Medical Monitor, Dr. Clio Rubinos. 
The PI and Medical Monitor then determine the severity of the Adverse Event and make a plan for follow-
up with the participant if necessary. In the rare event that the researcher finds the adverse event to be 
unexpected, serious, or more than mild, then the researcher will immediately call the Medical Monitor to 
conduct an immediate assessment with the participant. 
Epileptic Activity Follow-up: There is a theoretical likelihood that stimulation of neuronal circuits can lead 
to epileptic discharge. To minimize this occurrence, we screen and exclude participants with personal and 
family history of neurological conditions from the study. We further emphasize that there has never been 
a single report of a seizure that resulted from transcranial alternating current stimulation or transcranial 
direct current stimulation. If abnormalities or a seizure is witnessed during the course of the study, a 
referral will be made to Dr. Clio Rubinos at UNC Department of Neurology for follow-up. In the exceedingly 
rare event that a seizure is witnessed, researchers will contact Dr. Clio Rubinos by her cell phone who will 
perform a check on the participant. A follow-up appointment will be scheduled in the Post-Acute 
Symptomatic Seizure Clinic where Dr. Rubinos is a specialist. Patients that developed a seizure after TMS 
are candidates for this clinic. In the theoretical event that a seizure is witnessed that involves the loss of 
consciousness, the participants will be further instructed of seizure precautions as per standard of clinical 
care. 
Neurological Abnormality Follow-up: When imaging the brain there is a chance that the MRI scan will 
reveal a neurological irregularity that might be of medical importance to the participant. These incidental 
findings are uncommon and rarely lead to early identification of neurological issues. However, as is 

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standard practice, we allow participants the option to choose to be alerted to any incidental findings. In 
the consent form, participant can opt out of being notified about incidental findings. If a researcher 
notices a neurological abnormality, then they will reach out to our collaborators in the department of 
neurology to investigate the MRI scan further. If the neurologist considers the abnormality to be of 
medical importance, then the participant will be contacted for future steps. It should be noted that the 
research MRI scans used (T1-weighted) are not diagnostic scans and are not sensitive to detecting 
common neurological problems such as brain cancer. There is no expectation that the participant 
population studied in this research program will be of greater likelihood for incidental finding. 
 
3. OBJECTIVE AND OUTCOME MEASURES  
 
 
OBJECTIVES 
OUTCOMES 
JUSTIFICATION FOR OUTCOMES 
Primary 
 
 
To investigate whether delta-
beta TMS to dlPFC-dSTR will 
produce an increase in goal-
directed behavior during 
reward-based decision-
making. 
 
Behavioral metric, percentage 
of hard trials chosen, during 
the Streamlined Expenditure 
of Effort for Reward Task (S-
EEfRT). 
Stimulation is delivered prior to the 
decision epoch and the stimulation 
parameters were determined based 
on a previous study that 
investigated a different cognitive 
construct. 
Secondary 
 
 
To investigate whether delta-
beta TMS to dlPFC-dSTR will 
result in a lasting increase in 
delta-beta coupling during 
the decision epoch. 
Neural metric, degree of 
phase-amplitude coupling 
between prefrontal delta 
oscillations and left motor 
beta oscillations, quantified 
during the decision epoch of 
the S-EEfRT. 
Our previous study found increased 
delta-beta phase-amplitude 
coupling during the decision-epoch 
in participants with high goal-
directed behavior. 
 
Exploratory 
 
 
To investigate the degree to 
which traits of motivation 
predict individual differences 
in the impact of delta-beta 
TMS on goal-directed 
behavior. 
Two-dimension factor analysis 
is run on clinical assessments 
to derive motivation and 
rumination personality 
dimensions. These scores are 
correlated with the impact of 
TMS on goal-directed 
behavior. 
Our previous study found two 
symptom dimensions within 
participants with major depressive 
disorder that captured individual 
differences in reward-based 
decision-making. Here, we utilize 
personality assessments that might 
be similar to the clinical analog. 
To investigate whether 
reward-evaluation is 
increased by theta-gamma 
TMS to medial PFC. 
Behavioral metric of reward-
evaluation is the percentage 
of hard trials chosen as a 
function of the incentive 
offered, during the S-EEfRT. 
Our previous study found reward-
evaluation was related to theta-
gamma coupling. This additional 
behavioral metric allows for the 
investigation of the circuit- and 
cognitive-specificity of TMS. 

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OBJECTIVES 
OUTCOMES 
JUSTIFICATION FOR OUTCOMES 
To investigate whether theta-
gamma coupling is increased 
by theta-gamma TMS to 
medial PFC. 
Neural metric, degree of 
phase-amplitude coupling 
between prefrontal theta 
oscillations and posterior 
parietal gamma oscillations, 
quantified during the decision 
epoch of the S-EEfRT. 
Our previous study found increased 
theta-gamma phase-amplitude 
coupling during the decision-epoch 
in participants with high reward-
evaluation behavior. 
To investigate whether 
functional connectivity 
between dorsal striatum and 
left lateral prefrontal cortex 
predicts individual 
differences in the impact of 
delta-beta TMS on goal-
directed behavior. 
Functional connectivity 
analysis of resting-state 
functional MRI is correlated 
with the impact of delta-beta 
TMS on goal-directed 
behavior. 
Previous research has suggested 
that frontal-striatal connectivity is 
related to reward-based decision-
making. Participants with reduced 
connectivity within this neural 
circuit may be predictive of the 
impact of TMS on reward-based 
decision-making.  
 
4. STUDY DESIGN  
 
4.1 OVERALL DESIGN 
This study is a pilot, four-session, crossover study with transcranial magnetic stimulation (TMS), 
electroencephalography (EEG), and magnetic resonance imaging (MRI) to understand the causal role of 
delta-beta coupling in goal-directed behavior in the dorsolateral prefrontal cortex (dlPFC) to dorsal 
striatum (dSTR) circuit. Participants that request to be in the experiment will provide verbal, documented 
consent to undergo a phone screening to assess that the participant meets initial exclusion/inclusion 
criteria. Participants complete an MRI and TMS screening form over the phone to ensure eligibility. 
The first session will be an EEG session with the reward-based decision-making task. At the start of the 
session, we will acquire written informed consent. Then, we will administer a pregnancy test if applicable. 
Participants will complete a five assessments: the Snaith Hamilton Pleasure Scale (SHAPS) (Snaith et al. 
1995), Behavioral Activation System and Behavioral Inhibition System (BIS/BAS) (Carver and White 1994), 
Temporal Experience of Pleasure Scale (TEPS) (Gard et al. 2006), the State-Trait Anxiety Inventory (STAI) 
(Spielberger 2010), and Ruminative Responses Scale (RRS) (Nolen-Hoeksema, Larson et al. 1999). Note 
that our participants are from a convenient sample and are not required to be diagnosed with major 
depressive disorder. Thus, these assessments were selected as they survey various personality traits that 
might be relevant to performance in the task. In our previous published study using this task, we 
discovered a continuum of task performance between the control participants and the participants within 
a major depressive disorder (Riddle et al. Cerebral Cortex 2022). We speculate that participants with 
personality traits related to reduced behavioral approach (quantified by the BIS/BAS) could be a precursor 
to symptoms of anhedonia (quantified by the TEPS and SHAPS). Similarly, increased personality traits of 
behavioral inhibition (quantified in the BIS/BAS) could be a precursor to symptoms of anxiety (STAI and 
RRS). Thus, we collect this data in healthy control participants as an exploratory aim of the study. 

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The scalp dimensions of each participant are calculated and a low-profile EEG net is applied. For each 
session, muscle activity from the hand and forearm are recorded. Next, the participants complete an eyes-
open and eyes-closed resting-state recording of EEG. Then, the streamlined version of the Expenditure of 
Effort for Reward Task (S-EEfRT) is completed. These data serve as baseline measurement of brain activity 
without any form of stimulation. This session takes approximately 1.5 hours to complete. After each block 
of the task, the task difficulty will increase or decrease based on performance. At the end of the session, 
if the participant chose to perform the HARD task greater than 85% of the time or less than 15% of the 
time, then the participant will not be invited to the next session of the experiment. The rationale is that 
we are studying reward-based decision-making and participants that do not dynamically change their 
response based on the incentive are not engaged with the relevant cognitive constructs under 
investigation in this study. 
Finally, in this first session we will calculate the motor threshold of the participant. In the first, third, and 
fourth session, participants will complete a TMS contraindications screening form. The same TMS 
screening form will be administered over the phone and at the start of each of the TMS session. If there 
is any ambiguity in the contraindications for the TMS form, then the medical monitor, Dr. Clio Rubinos, 
who is an epileptologist is consulted and final approval is acquired. Similar to the MRI screening form, it 
is highly unlikely that eligibility will change between sessions. Out of an excess of caution, we administer 
the TMS screening form at each TMS session to confirm that there is no contraindication, otherwise 
participation is discontinued. In the third session, the motor threshold of each participant will be 
calculated using single-pulse TMS to the hand knob of the left primary motor cortex with real-time 
monitoring of the motor-evoked potential using electrodes on the first dorsal interosseus muscle. 
Researchers may also use visible twitch to calculate the motor threshold. The motor threshold is defined 
as the percent stimulator output when a motor-evoked potential or visible twitch is observed 
approximately 50% of the time. Next, the participant will receive two abbreviated blocks of TMS similar 
to those that will be delivered during the third and fourth session. One block will deliver stimulation to 
medial PFC and the other to lateral PFC. These blocks are used as a tolerability test to ensure that the 
participant is comfortable with receiving TMS and to acclimate them to the experience. After stimulation, 
a questionnaire is provided with common side effects of TMS. Based on the results of the stimulation side 
effects questionnaire, a structured adverse events interview is conducted to acquire more information 
regarding any side effects that were selected to be “very high” by the participant. This session will take 
approximately 2 hours. 
For the second session, participants are instructed to arrive at the Biomedical Research Imaging Center 
(BRIC) in Marsico Hall on UNC-CH campus. In the 24 hours prior to this session, participants complete an 
MRI screening form. This screening form is the standard provided by the BRIC. During the phone screening, 
if there is any ambiguity in the eligibility of the participant, then we consult with the technicians at the 
BRIC for approval to conduct an MRI. Then, in the 24 hours prior to their MRI session, MR technicians at 
the center review a new screening form and confirm their eligibility to receive an MRI. Because this is the 
same form used in the screening for the experiment, the only way that a participant would fail to be 
eligible at this stage is if there was some change in their eligibility between sessions. While this is highly 

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unlikely, the participant would be discontinued from participating. Participants are instructed to arrive at 
the facility 30 minutes before the start of the scheduled MRI block to ensure that they are ready to go 
into the MRI for the 60-minute allotted timeslot. During the 60 minutes of scanning, a 5-minute structural 
MR is acquired and the remaining time is used to complete as many blocks of the EEfRT as possible. The 
minimal number of sessions required to use the data is 5 blocks, which requires approximately 25 minutes 
to collect. Note that the only other scan of significant length acquired during this time is a 5-minute 
anatomical scan and the remaining 50 minutes or more is dedicated to acquisition of the task data that is 
used for localization. Thus, we do not expect to collect less than 5 blocks of data in any given participant. 
However, if a participant was unable to complete the requisite number of sessions, then they would be 
excluded from the rest of participation. We expect that this a highly unlikely. Functional MRI data is 
analyzed before the 3rd and 4th session to localize the regions of dorsolateral PFC and medial PFC for 
stimulation. In our analysis, we will draw a region of interest mask in the head of the left caudate (dSTR) 
and in left nucleus accumbens (vSTR) and localize the region in dlPFC and mPFC with peak functional 
connectivity in task-based functional connectivity to these regions. In our pilot data, we found that the 
contrast of HARD vs EASY localized the anterior middle frontal gyrus and the contrast of HIGH vs LOW 
incentive localized the super frontal junction. Thus, we will choose regions in these anatomical areas with 
maximal connectivity to their respective nucleus in the striatum.  
The order of regions (dlPFC then mPFC, or mPFC then dlPFC) targeted by TMS in the third and fourth 
session will be randomized and counter-balanced. First, the participants will be fitted with a low-profile 
EEG net and EMG electrodes to the hand and forearm. For the third and fourth session, the same 
stimulator intensity will be used as in the first session. The structural MRI and regions of interest (dlPFC 
and mPFC) are imported into Localite neuronavigation software. The participant wears a 3D stereotaxic 
tracking headband and is registered to their structural MRI. Then, the TMS coil is targeted to either mPFC 
or dlPFC and the position of the coil relative to the head is recorded throughout the session. The 
participant performs the S-EEfRT as the patterned trains of TMS are delivered on every trial. Each block of 
the study is randomized to receive either delta-beta patterned (triplets of TMS pulses at 20 Hz every 3Hz), 
theta-gamma patterned (triplets of pulses at 50 Hz every 5 Hz), or an arrhythmic pattern (same number 
of pulses and duration with a random inter-pulse interval). After stimulation, a questionnaire is provided 
with common side effects of TMS. Based on the results of the stimulation side effects questionnaire, a 
structured adverse events interview is conducted to acquire more information regarding any side effects 
that were selected to be “very high” by the participant. This session will take approximately 2 hours. 
 
4.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
  
This study is a fully crossed target engagement study. It is not possible to include blinding in the study for 
either the participant or the experimenter. The difference between the active control pattern of TMS and 
the targeted pattern of TMS as well as the difference between dorsolateral PFC and medial PFC will not 
be meaningfully discernible to the participant as there is a difference of only a few centimeters between 
sites and only a fraction of a second for the stimulation patterns. There is no obvious association between 
the site of stimulation and the frequency of stimulation and the task itself. Therefore, not only is blinding 

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not possible, but it is not necessary for the scientific questions under investigation in this study. In a recent 
review by Duecker and Sack Frontiers in Psychology 2015, the authors survey modern approaches to 
creating a sham form of TMS. These efforts have been unsuccessful despite increasingly sophisticated 
designs. The authors found that even with moderate success in blinding in a parallel arm study where the 
participant is naïve to stimulation, when a design is crossover, the participants become aware that the 
stimulation is placebo. These observations lead to the conclusion that even when sham stimulation is 
used, the experiment should include an active control condition such as an alternate location of 
stimulation or an alternate frequency of stimulation: “TMS experiments always require an active TMS 
control condition, and sham TMS approaches can never be sufficient as they fail to demonstrate such 
specificity” (Duecker and Sack 2015). 
 
Furthermore, the experimenters cannot be blinded to the site of stimulation as this needs to be carefully 
maintained throughout the experiment using neuronavigation, nor to the frequency of stimulation as 
these are audible to the experimenter. The primary and secondary outcome of the study include a control 
condition within each session and within a participant between sessions. Thus, the scientific integrity of 
the study is provided through multiple control conditions built into the crossover experimental design: 
spatial variable (dlPFC vs mPFC), temporal variable (delta-beta vs theta-gamma vs arrhythmic), and 
cognitive variable (goal-directed behavior vs reward evaluation). Our previous study found that goal-
directed behavior was positively correlated with delta-beta coupling and reward-evaluation was positively 
correlated with theta-gamma coupling (Riddle et al. Cerebral Cortex 2022). Thus, this preliminary data 
provides a strong motivation for the type of stimulation used in this experiment. In addition, our previous 
study discovered a significant negative relationship between symptoms of anhedonia in major depressive 
disorder with goal-directed behavior and delta-beta coupling. Thus, this study will serve as a critical target 
engagement study such that future studies may use these results to develop interventions to treat 
symptoms of anhedonia in MDD. 
 
Finally, our exploratory outcomes hypothesize that theta-gamma stimulation to medial PFC will increase 
reward-evaluation during the task. Thus, all conditions of the experiment are of importance to the 
outcome of the experiment. Therefore, the experimenter will not be unconsciously biased towards one 
session or another because all of them are important to the success of the project. In addition, the type 
of stimulation for each block of the task is randomized and not known to the participant or experimenter 
until the start of the block. Thus, the experimenter will not be able to bias the experiment in any way 
because they are block to the experimental condition during the slight adjustments that occur during each 
block. Furthermore, the experimenter does not converse with the participant during the task and the task 
is computerized such that there are minimal human interactions that could bias the participant one way 
or another. In addition, the behavioral metrics of interest are patterns of decision-making within the same 
task condition. Thus, a hypothetical unconscious systematic bias would have to influence a particular 
pattern of behavior on a particular block of the task but not others within the same session. This type of 
influence is highly unlikely, if not nearly impossible, given our experimental design. 
 
4.3 JUSTIFICATION FOR DOSE 
Transcranial magnetic stimulation (TMS) is a safe, non-invasive, widely-used tool that applies focal electric fields to 
the brain using magnetic coils placed on the scalp (Rossi et al. 2009). On the first stimulation session of the study, 
participants will receive a motor thresholding procedure in which electrodes are attached to the first dorsal 
interosseous muscle of the right hand, or another muscle on the hand or arm that is accessible to be targeted by 
TMS to the motor cortex. The contralateral motor cortex will be targeted by single pulses of TMS with increased 

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stimulator output until a motor evoked potential (MEP) is 
generated: defined as a near-instantaneous increase muscle 
activity greater than 200 microvolts. Next, the intensity of single 
pulse TMS will be lowered until a MEP is generated on five out 
of ten pulses. This is defined as the motor threshold for the 
participant (Rossi et al. 2009). If the motor threshold cannot be 
determined via MEP, the experimenter will use visible twitches 
instead of MEP. Participants will receive 15 pulses of patterned 
TMS at 80% of their motor threshold during every trial. 
Patterned TMS takes three different forms (Figure 2). Delta-beta 
TMS delivers bursts of three pulses at 20 Hz (50 millisecond inter-
pulse interval) with an inter-burst interval of 3 Hz (167 
milliseconds). Theta-gamma TMS delivers bursts of three pulses 
at 50 Hz (20 millisecond inter-pulse interval) with an inter-burst 
interval of 5 Hz (200 milliseconds). As a control for the frequency-
specificity of patterned TMS, arrhythmic TMS is delivered with a 
randomized inter-pulse intervals that are generated for each 
trial. The duration of arrhythmic TMS is randomly selected from 
a uniform distribution between the duration of delta-beta and 
theta-gamma TMS. The minimum inter-pulse interval will be 20 
milliseconds. Between every train will be at least 11 seconds. An 
inter-train-interval of 11 seconds or greater allows for any 
residual effects of stimulation to return to baseline. This 
intensity, inter-pulse-interval, and inter-train-interval is well 
within the safety guidelines set forth for repetitive TMS 
(Wassermann, 1998; Rossi et al., 2009) and has been used in 
similar paradigms as the one described here. For example, 
Hermiller et al. 2020 delivered two seconds of theta-gamma 
patterned TMS (30 pulses per trial) at 80% of motor threshold 
(Hermiller et al. 2020).  In addition, many other studies have 
delivered trains of TMS at higher intensities, upwards of 120% of motor threshold, on every trial of a cognitive task 
(Thut et al. 2011; Hanslmayr et al. 2014; Albouy et al. 2017)(Riddle et al. 2019; Riddle et al. 2020c; Sauseng et al. 
2009). During a TMS session, participants will complete six blocks of 30 trials each. The participant will receive 
stimulation in either delta-beta, theta-gamma, or arrhythmic in a blocked design (the same stimulation is delivered 
for every trial in a block). The sequence of blocks will be randomized and counterbalanced such that each participant 
received each condition of TMS for 60 trials total. The third and fourth session of the experiment will be both be 
TMS sessions, where TMS is delivered to either the dorsolateral prefrontal cortex (dlPFC) or to medial prefrontal 
cortex (mPFC). The order and TMS sites will be randomized and counterbalanced across participants. Thus, at 
completion of the full experiment, participants will have received 12 blocks of 30 trials each of stimulation (180 trials 
per TMS session). In addition, two abbreviated blocks of TMS to mPFC and dlPFC will be administered at the end of 
the first session to assess for tolerability of TMS. 
The evoked electric field from stimulation will be simulated using finite-element modeling of the neuroanatomical 
MRI for each participant (Gomez, Dannhauer, Peterchev Neuroimage 2021). This method ensures that the evoked 
stimulation strength is within a safe level beyond standard stimulation methodology. The time between each 
 
Figure 2. Patterned transcranial magnetic 
stimulation (TMS) is delivered prior to each 
trial of the Streamlined Expenditure of Effort 
for Reward Task (S-EEfRT). Each train 
comprises 15 pulses. Delta-beta TMS (green) 
delivers bursts of three pulses at 20 Hz with an 
inter-burst interval of 3 Hz. Theta-gamma TMS 
(purple) delivers bursts at 50 Hz every 3 Hz. 
Arrhythmic TMS is matched for duration and 
number of pulses but with a random inter-
pulse interval. 

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patterned-train will be a minimum of 11 seconds. These stimulation parameters for individual trains and time 
between trains fall within the safety guidelines set forth by the Rossi et al., Clin Neurophysiol 2009 “The Safety of 
TMS Consensus Group: Safety, ethical considerations, and application guidelines for the use of transcranial magnetic 
stimulation in clinical practice and research”, which has guided TMS research the past decade (Rossi et al. 2009). 
Last year, these guidelines were re-affirmed with an updated safety review (Rossi et al. 2020). The longer the time 
between each train the better the safety profile from stimulation. Furthermore, patterned stimulation such as the 
theta-gamma burst pattern, used as a control frequency in this proposal, has been extensively investigated for its 
safety profile. A meta-analysis conducted by Oberman et al. J Clin Neurophysiol 2011 concluded that patterned TMS 
trains present only a minimal seizure risk with a single case of seizure out of 4,500. The participant was healthy and 
the protocol used was continuous theta-burst delivered at 100% of motor threshold to motor cortex. Thus, our use 
of 80% of motor threshold and targeting of dorsolateral and medial prefrontal cortex (less excitable regions of the 
brain) further reduces the risk. The safety of a TMS train is defined by the inter-pulse interval, with a short inter-
pulse interval presenting higher risk (Rossi et al. 2009; Rossi et al. 2020). Thus, the novel delta-beta pattern (3 Hz by 
20 Hz) proposed in this study is most likely safer than the theta-gamma pattern (5 Hz by 50 Hz). Finally, we will be 
delivering 180 trains of 5 bursts each and each train is separated by a considerable amount of time (minimum of 11 
seconds) with time for self-paced breaks between every block in the experiment. Thus, this number of pulses exceeds 
the typical number of bursts in a continuous theta-burst protocol but the overall delivery time is considerably longer. 
Of note, recent experiments using accelerated-intermittent theta-burst TMS deliver up to 10 trains of intermittent 
theta-burst per day for many consecutive days. A recent investigation of accelerated-intermittent theta-burst TMS 
that delivered iTBS 10 times per day with each iTBS train consisting of 1,800 pulses for 5 consecutive days: 18,000 
pulses per day at 90% motor threshold, 90,000 pulses in one week (Cole et al. Am J Psychiatry 2020). Our proposal 
to deliver 900 bursts (180 trains of 5 bursts) over the course of 1.5 hours with 11 seconds between train is well within 
current safety considerations. 
To further reduce risk during the stimulation session, the participant will be actively monitored by the researcher 
and any signs of duress will result in a termination of stimulation and the experimental session. There is a rare 
likelihood that the participant could undergo a seizure from stimulation. While this is unlikely, all of our researchers 
are trained in first-aid and CPR with (RedCross certificate). In addition, a collaborator of the Carolina Center for 
Neurostimulation, Dr. Clio Rubinos, is an epileptologist in the Department of Neurology that is on-call for 
emergencies and her contact information is posted in our experiment rooms. All researchers are trained in the 
Carolina Center for Neurostimulation in how to respond in the event of a seizure and are instructed in best 
monitoring practices to prevent its occurrence. This is a known, unlikely risk of TMS and our screening procedure 
was developed according to established guidelines (Rossi et al. 2009; Rossi et al. 2020) to prevent participants from 
receiving TMS that have contraindications. 
Finally, there is a theoretical risk that TMS may damage hearing over prolonged exposure given the proximity of the 
stimulator to the ears (Rossi et al. 2009; Rossi et al. 2020). Thus, we provide participants with ear plugs during motor 
threshold stimulation and with EEG-compatible ear-buds with an inflatable foam shape during task performance 
with TMS. These ear buds provide noise protection by making a tight seal and contain a small tube so that we can 
play white noise to the participant to help mask the noise of the stimulation for analysis purposes. In addition, the 
experimenter wears ear plugs during TMS to protect their hearing. 
EEG and EMG will be collected using the Geodesic 400 system (EGI INC., Eugene, OR, USA). Collecting simultaneous 
EEG and EMG with TMS does not pose any additional risk over TMS on its own. EEG and EMG do not involve brain 
stimulation and is used purely for electrophysiology (minimal risk).  

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4.4 END OF STUDY DEFINITION 
 
The end of this study is defined as when the last participant completes the study (i.e., the 24th 
participant to complete their final session). 
 
5. STUDY POPULATION 
 
5.1 INCLUSION CRITERIA 
In order to be eligible to participate in this study, a participant must meet all of the following criteria: 
• 
Between the ages of 18 and 65 
• 
Able to provide informed consent 
• 
Have normal to corrected vision 
• 
Right-handed 
• 
Willing to comply with all study procedures and be available for the duration of the study 
• 
Speak and understand English 
• 
Negative pregnancy test for female participants 
 
5.2 EXCLUSION CRITERIA 
A potential participant who meets any of the following criteria will be excluded from participation in the study: 
• 
ADHD (currently under treatment) 
• 
Neurological disorders and conditions, including, but not limited to: 
o 
History of epilepsy 
o 
Seizures (except childhood febrile seizures) 
o 
Dementia 
o 
History of stroke 
o 
Parkinson’s disease 
o 
Multiple sclerosis 
o 
Cerebral aneurysm 
o 
Brain tumors 
• 
Medical or neurological illness or treatment for a medical disorder that could interfere with study 
participation (e.g., unstable cardiac disease, HIV/AIDS, malignancy, liver or renal impairment) 
• 
Medications that interfere with the EEG signal (e.g., benzodiazepines, anticonvulsants) 
• 
Prior brain surgery 
• 
Any brain devices/implants, including cochlear implants and aneurysm clips 
• 
History of current traumatic brain injury  
• 
(For females) Pregnant or breast feeding 
• 
Anything that, in the opinion of the investigator, would place the participant at increased risk or preclude 
the participant’s full compliance with or completion of the study 

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• 
Contraindications for MRI: ferrous metal inside the body, jewelry must be removable, pacemaker or 
cochlear implant. 
 
5.3 LIFESTYLE CONSIDERATIONS 
  
None. 
 
5.4 SCREEN FAILURES 
 
In the design of this study, initial phone screening procedures will identify the participants who do not 
qualify for the study. In the phone screening, we ask question to determine eligibility according to our 
inclusion and exclusion criteria. Then, we conduct a screening for eligibility for magnetic resonance 
imaging and for transcranial magnetic stimulation. The first session will be used to titrate the difficulty of 
the task such that participants are engaged with reward-based decision-making. In our previous study 
using this task, we found that around 30% of participants did not engage with the reward-based decision-
making task (Riddle et al. 2021b). In other words, they chose the EASY task almost every time, or they 
chose the HARD task almost every time. This rate is similar to what other groups have found when using 
this task (Treadway et al. 2009). As is common practice in cognitive neuroscience studies like this one, the 
difficulty of the task needs to be titrated to the performance of the individual. While multiple efforts to 
titrate the difficulty of this task have been employed and are employed here, a high percentage (~30%) of 
participants still do not use the information about the incentive in their decision process but instead 
choose the HARD or EASY task almost exclusively. Thus, the cognitive processes under investigation in this 
study are not engaged in some participants. In addition, we are interested in the impact of stimulation on 
these performance metrics during stimulation, so a participant that is at “ceiling performance” or “floor 
performance” is unlikely to show a change in their performance. For these reasons, we expect that up to 
30% of participants will be excluded after the first session for a failure to engage the cognitive processes 
under investigation in this study. 
 
Before the MRI session, we conduct an additional MRI screening to ensure safety. Before each of the TMS 
sessions, we conduct an additional TMS screening to ensure safety. There is a small and unlikely chance 
that participants become ineligible at these later sessions as these contraindications are fairly stable over 
time. 
 
5.5 STRATEGIES FOR RECRUITMENT AND RETENTION 
This clinical trial will utilize multiple recruitment strategies to communicate this opportunity to as many 
potential participants as possible. We estimate that approximately 40 participants will be enrolled from 
the Chapel Hill/Carrboro area and 10 between Durham and Raleigh. We will advertise the study directly 
to the public on websites such as ClinicalTrials.gov, studypages.com, frohlichlab.org and 
Carolinaneurostimulation.org. We will have contact information and a summary of the clinical trial posted 
on the Frohlich Lab Facebook and Twitter pages. We may also be launching a Facebook ad to identify 
potential participants. We will also be using the UNC Mass email listserv to send out an email that has the 
studypages.com link. All participant identifiers will be stored in REDCap until recruitment is over. When 
recruitment is over, all participants who do not consent or are not eligible for the study will have their 

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responses permanently deleted in REDCap. We will also advertise the study through presentations to 
groups or classrooms. 
Retention is primarily achieved through monetary compensation. The payment is $40 for completion of 
the baseline EEG session for 2 hours. Then, the second MRI session provides $40 for 1.5 hours.  Finally, 
for the 3rd session involved TMS and EEG participants receive $40 for 2 hours, and finally $60 for the 4th 
session of 2 hours. Thus, completion of all study requirements gives $180 and take 7.5 hours. The 
escalating compensation per hour with each session incentivizes the participant to finish all sessions. The 
participant will receive payment at the end of each session on a payment card that can be loaded. The 
research staff will also give each participant a reminder call or email for upcoming sessions. Each research 
staff member will be available for the participants to contact via email or phone. 
 
6. STUDY INTERVENTION 
 
6.1 STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
We will use the MagPro X100 or R30 system (MagVenture Inc., Alpharetta, Georgia, USA) for transcranial magnetic 
stimulation. The MagPro X100 and R30 are advanced, high performance magnetic stimulators designed primarily for 
research purposes. It is a high-quality tool for researchers with a large choice of stimulating parameters and has 
stimulation rates up to 100 pulses per second at high intensities and the possibility to combine waveforms and pulse 
modes.  
The simulator has several features: 
• 
3 waveforms: Biphasic, Biphasic Burst and Monophasic. 
• 
Selectable current direction. 
• 
Stimulation rates up to 100 pulses per second. 
• 
Easily connects to external equipment via programmable input/output triggers. 
• 
System operation control via a built-in computer, eliminating the need for an external computer to set up 
and control the timing of stimulus sequences. 
• 
Controllable from an external device. 
In the USA, federal law regulates the sale of Medical Devices through the US Food and Drug Administration (FDA). 
This is done to ensure safety and effectiveness. Devices which are permitted to be marketed for their intended use 
must either have a 510(k) or PMA clearance. 
MagPro® stimulators R20, R30, R30 with MagOption, X100, and X100 with MagOption are all FDA 510(k) cleared 
(k160280, k061645, k091940 and k150641). 
k150641: The intended use is treatment of Major Depressive Disorder in adult patients who have failed to receive 
satisfactory improvement from prior antidepressant medication in the current episode. 
k160280, k061645, k091940: The intended use is for stimulation of peripheral nerves for diagnostic purposes.  

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The use of devices for other than their FDA cleared intended use is considered as investigational. Such use is only 
permitted if the Investigational Device Exemption (IDE) guidelines have been followed. For full information on this 
procedure, please consult FDA's website (www.fda.gov).  
All investigational devices must be labeled in accordance with the labeling provisions of the IDE regulation (§ 812.5) 
and must bear a label with this statement:  
CAUTION Investigational Device. Limited by Federal (or United States) law to investigational use. 
6.1.2 DOSING AND ADMINISTRATION 
 
As described in section 4.3 on justification for dose, the intensity of transcranial magnetic stimulation will 
be tailored to the sensitivity of the individual using the standardized motor thresholding procedure. This 
procedure estimates the natural level of electrical activation in the brain that leads to a muscle activation. 
In the stimulation sessions, we will then deliver trains of TMS at 80% of the motor threshold of the 
individual. Thus, the electric current generated within the brain from transcranial magnetic stimulation 
will be within the range of endogenous electrical activity. Personnel will be thoroughly trained and have 
trainings documented on the transcranial stimulation device and will be present during all stimulation 
sessions. To monitor side effects of stimulation, a stimulation effects questionnaire will be administered 
after each stimulation session. In the event that common side effects are experienced, then these will be 
documented using an adverse event structured interview. 
 
6.3 MEASURES TO MINIMIZE BIAS: CONTROL CONDITIONS, RANDOMIZATION, AND 
PREREGISTRATION 
 
Control Conditions 
As discussed in section 4.2, it is not possible for the researchers to be blinded to the form of stimulation 
that is being used. However, the outcomes of the study are a comparison between experimental 
conditions with subtle temporal and spatial differences on the order of centimeters and milliseconds 
respectively. In brief, we will compare stimulation to dorsolateral prefrontal cortex to medial prefrontal 
cortex. The proximity of these regions is only a few centimeters and the associations of these regions to 
aspects of the task is under active investigation. In addition, we are comparing delta-beta patterned 
stimulation to theta-gamma patterned stimulation to an arrhythmic stimulation condition. The difference 
between delta-beta and theta-gamma stimulation is only a small difference in frequency, on the order of 
100s of milliseconds. Similar to the stimulation site, the association of these frequencies of stimulation to 
task parameters is under active investigation and there are no online resources to draw these associations. 
Finally, we will use this task to calculate two distinct behavioral metrics: goal-directed behavior and 
reward-evaluation. These behavioral metrics are calculated from the same decision-making data and 
reflect different patterns of performance. In our previous study, we found that these two behavioral 
metrics were dissociable from each other (low correlation between these metrics across individuals). 
Thus, the paired association under investigation of delta-beta patterned TMS to goal-directed behavior 
during stimulation of dlPFC is fundamentally complex and none of these comparisons will be explained to 
the participant. Two of these three control conditions are included within each session and the site of 
stimulation is controlled between the third and fourth session. Thus, any systematic differences between 
sessions will be controlled by a within-session contrast of conditions. Finally, we prevent against 
unconscious experimenter bias in many ways that are described in section 4.2. To reiterate, conditions of 

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interest are controlled within session, upcoming blocks are not known to experimenter or participant, 
behavioral metrics are different patterns of decision-making within the same epoch of the task, all task 
sessions are meaningful to the outcomes of the study, and experimenter-participant interactions are kept 
to a minimum within the task. 
 
Randomization 
We will use computer code to randomize and counterbalance the sequence of blocks within each session. 
Each session includes six blocks of 30 trials each. Every trial within a block will be either delta-beta 
stimulation, theta-gamma stimulation, or arrhythmic patterned stimulation. The order of blocks will be 
randomized for each participant. We will enforce that the first three blocks and last three blocks include 
each stimulation condition and participants will not receive the same form of stimulation two blocks in a 
row. This randomization scheme ensures that each type of stimulation is delivered at various temporal 
phases across the overall session. Within each session, the incentive that is offered for each trial will be 
randomized and counterbalanced such that an equal number of low ($2.50, $3.00, $3.50, $4.00) and high 
($4.50, $5.00, $5.50, $6.00) value incentives are offered. Finally, the sequence of receiving stimulation to 
dlPFC and mPFC over the 3rd and 4th session will be randomized and counterbalanced across participants. 
In addition, both of the stimulation sessions include conditions of active interest to the investigators and 
so there will be no systematic bias to devalue one of the sessions. These methods for randomization and 
counterbalancing will reduce the chances that some unforeseen pattern of TMS or task parameters will 
systematically bias behavior. Thus, the experimental design has been selected to rigorously support 
scientific integrity. 
 
Preregistration 
The hypotheses of this study that are explicitly described in this protocol will be pre-registered on 
ClinicalTrials.gov. This ensures that the write-up of all manuscripts that result from this project will be 
clear to define what was a hypothesized outcome and what findings are unexpected. Furthermore, this 
process prevents any exploratory findings to be framed as hypothesized findings. By clearly defining these 
planned analyses, bias is minimized in the analysis of these data. 
 
6.4 STUDY INTERVENTION COMPLIANCE 
 
Full compliance with the intervention is defined as completing the four sessions of the experiment. The 
intervention is applied and monitored by researchers. Thus, compliance can be directly observed. 
 
6.5 CONCOMITANT THERAPY 
  
This clinical trial is conducted in a convenience sample of the population. The exclusion criteria were 
chosen to ensure the safety of participants and to reduce known sources of electrophysiological confound 
like neurological disorders or ADHD medications. We will not query, monitor, or change any concomitant 
therapy in the participants. 
 
7. STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
  
7.1 DISCONTINUATION OF STUDY INTERVENTION 

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Discontinuation of stimulation during session 3 or session 4 means that study participation is halted and 
no other sessions are completed. If a clinically significant finding is identified after enrollment, the 
investigator or qualified designee will determine if any change in participant management is needed. Any 
new clinically relevant finding will be reported as an adverse event (AE). 
 
The study intervention (i.e., patterned transcranial magnetic stimulation) will be discontinued for the 
following reasons: 
• 
Any clinical adverse event (AE), laboratory abnormality, intercurrent illness or other medical 
condition, or situation occurs such that continued participation in the study would not be in the 
best interest of the participant. 
• 
The participant meets any exclusion criteria (either newly developed or not previously 
recognized). 
 
7.2 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
• 
Any clinical adverse event (AE), laboratory abnormality, intercurrent illness or other medical 
condition, or situation occurs such that continued participation in the study would not be in the 
best interest of the participant. 
• 
The participant meets any exclusion criteria (either newly developed or not previously 
recognized). 
 
The reason for participant discontinuation or withdrawal from the study will be recorded with the 
participant files. Participants who sign the informed consent form and are not randomized will be 
replaced. Participants who sign the informed consent form, are randomized, and receive the full or part 
of the study intervention, and subsequently withdraw from the study, are withdrawn from the study, or 
discontinue the study will not be replaced. However, participants who sign the informed consent form, 
and are not randomized will be replaced. In the event that 24 participants have not completed the 
experiment but all randomization slots are taken, then we will create an additional 10 slots for 
randomization. In the unlikely event that those are also filled, then we will create an additional 10 slots.  
 
The reason for drop-out will be documented and reported in the write-up of the manuscripts that results 
from this study. This study involves stimulation during task performance and the stimulation is spread out 
over the course of an hour or more. During clinical intervention, TMS is condensed into a 2- to 10-minute 
period of time. Thus, tolerability of the manner of TMS in this study likely does not generalize into the 
clinical setting. Nonetheless, this information may be relevant to other researchers or to clinicians using 
a similar spatial targeting scheme or similar pattern of stimulation. 
 
7.3 LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for 1 scheduled visit and is 
unable to be contacted by the study site staff. All efforts will be made to ensure participants are not lost 

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to follow-up, including developing rapport and ensuring enrolled participants are reminded of their 
session dates. Research personnel will be flexible in timing, including offering this session later in the day 
as well as some weekends. 
 
Every effort will be made to contact participants who are lost to follow-up, including contacting via email 
and phone. However, if a participant is lost to follow-up, the missed session will be labeled as missing data 
and our pre-determined analysis plan takes into consideration missing data. Of note, we will continue 
data collection until the specified number of participants complete the full study. Thus, the statistical 
analysis plan will not be impacted by those participants that are lost to follow-up. 
 
8. STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 EFFICACY ASSESSMENTS  
Inclusion and exclusion criteria will be determined during the phone screening. 
 
8.1.1 ELECTROPHYSIOLOGY 
  
1. Resting-state EEG (RSEEG) recordings will be completed during the first, third, and fourth session. 
Eyes-open and eyes-closed RSEEG will be collected before any task are performed or stimulation 
is delivered. This is collected for exploratory purposes. 
2. Phase-amplitude coupling between delta-beta and theta-gamma oscillations will be acquired 
during the decision epoch of the Streamlined Expenditure of Effort for Reward Task (S-EEfRT) as 
measured in our previous study (Riddle et al. 2021a; Riddle et al. 2021b). Delta-beta coupling is 
calculated between the prefrontal cortex and motor cortex. Theta-gamma coupling is calculated 
between the prefrontal cortex and posterior parietal cortex. 
 
8.1.2 TASK PERFORMANCE 
1. Goal-directed behavior: In the Streamlined Expenditure of Effort for Reward Task (S-EEfRT), goal-
directed behavior is quantified as the percentage of trials in which the participant chose the HARD 
task instead of the EASY task. In our previous experiment, goal-directed behavior positively and 
significantly correlated with delta-beta coupling. Goal-directed behavior ranges from 0 to 100% 
and task difficulty is titrated to push goal-directed behavior down to <85%. In our previous use of 
this task, minimum goal-directed behavior was 23%. To ensure that task performance is properly 
titrated during the baseline session, we will increase the difficulty of both tasks (EASY and HARD) 
when the HARD task is chosen greater than 85% of the time, and decrease the difficulty of tasks 
when the HARD task is chosen less than 15% of the time. At the end of the baseline session, if that 
participant has selected to perform the HARD task greater than 85% of the time or less than 15% 
of the time, then this will be considered a screening failure and their participation will be 
discontinued. 
2. Reward-evaluation: In the EEfRT, reward-evaluation is quantified as the slope of the linear fit of 
percentage HARD trials for each incentive level ($2.50 to $6 in $0.50 increments), dependent 
variable, to the incentive level, independent variable. In our previous experiment, reward-
evaluation positively and significantly correlated with theta-gamma coupling. In our previous 
experiment, the average reward evaluation was 15% per $1. Participants are informed at the 

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beginning of task performance that the S-EEfRT is a game and that no additional monetary 
compensation will be provided. 
8.1.3 SELF-REPORT ASSESSMENTS 
 
1. The Behavioral Inhibition and Behavioral Activation Self Report Scales (BIS/BAS) (Carver and White 
1994) will be completed during the first session. These scales are used to monitor the perceived 
sensitivity to reward and punishment. BIS/BAS is broken into four sub-scores: BIS (7 to 28), BAS 
drive (4-16), BAS fun-seeking (4-16), and BAS reward (7-20). 
2. The State-Trait Anxiety Inventory (STAI) (Spielberger et al. 1983) for trait anxiety will be completed 
during each session. These 40 items are used to quantify frequencies of feelings of anxiety. STAI 
has two subscores, state and trait anxiety, range 20 to 80. 
3. The Snaith-Hamilton Pleasure Scale (SHAPS) (Snaith et al. 1995) will be completed online during 
the first session to stratify randomization. This scale is acquired at each session. This scale is used 
to assess anhedonia, range 14 to 56. 
4. Temporal Experience of Pleasure Scale (TEPS) is an 18-item assessment that quantifies symptoms 
of anhedonia along two sub-dimensions: consummatory (8 to 48) and anticipatory (10 to 60) 
(Gard et al. 2006). This assessment may provide additional insight into subtypes of anhedonia 
symptoms and is acquired during the first session.  
5. Ruminative Responses Scale (RRS) is a 22-item assessment that quantifies the degree to which 
participants engage in depressive rumination, range 31 to 155 (Nolen-Hoeksema et al. 1999). This 
assessment is completed at the first session. 
 
 
8.2 SAFETY AND OTHER ASSESSMENTS 
 
1. 
A stimulation side effects questionnaire will be administered at the end of each stimulation session. 
This tool will be used as a safety measure and to collect data on the experience of the participant. 
The side effects questionnaire was adapted from studies in our group that used a different form of 
stimulation (transcranial electric stimulation), and was updated to remove questions that are not 
relevant to transcranial magnetic stimulation. 
2. 
An MRI screening form will be administered over the phone during the phone screening and within 
24 hours prior to the MRI session. This screening form is the standard provided by the Brain Research 
Imaging Center (BRIC) at UNC. During the phone screening, if there is any ambiguity in the eligibility 
of the participant, then we consult with the technicians at the BRIC for approval to conduct an MRI. 
Then, in the 24 hours prior to their MRI session, MR technicians at the center review a new screening 
form and confirm their eligibility to receive an MRI. Because this is the same form used in the 
screening for the experiment, the only way that a participant would fail to be eligible at this stage is 
if there was some change in their eligibility between sessions. While this is highly unlikely, the 
participant would be discontinued from participating. 
3. 
A TMS screening form will be administered over the phone and at the start of each of the TMS 
session. If there is any ambiguity in the contraindications for the TMS form, then the medical 
monitor, Dr. Clio Rubinos, who is an epileptologist is consulted and final approval is acquired. Similar 
to the MRI screening form, it is highly unlikely that eligibility will change between sessions. Out of 
an excess of caution, we administer the TMS screening form at each TMS session to confirm that 
there is no contraindication, otherwise participation is discontinued. 

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8.3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether considered intervention-related (21 CFR 312.32 (a)).  
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of the 
investigator, it results in any of the following outcomes: death, a life-threatening adverse event, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or 
substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require hospitalization may 
be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
 All adverse events (AEs) will be assessed by the principal investigator and/or co-investigator(s) using the 
following guidelines:  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (AEs) must have their relationship to study intervention assessed by the principal 
investigator and co-investigator(s) who examines and evaluates the participant based on temporal 
relationship and their clinical judgment. The degree of certainty about causality will be graded using the 
categories below. In a clinical trial, the study product must always be suspect.  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 

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result, occurs in a plausible time relationship to study intervention administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
study intervention (dechallenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory rechallenge 
procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a 
reasonable time after administration of the study intervention, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal (dechallenge). Rechallenge information is not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study intervention administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of the 
study intervention) and in which other drugs or chemicals or underlying disease provides plausible 
explanations (e.g., the participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. 
 
 
8.3.3.3 EXPECTEDNESS  
 
The principal investigator (Dr. Frohlich), with input from the medical monitor (Dr. Clio Rubinos) when 
necessary, will determine whether an adverse event (AE) is expected or unexpected in this population.  
The principal investigator (Dr. Flavio Frohlich) is an expert in non-invasive brain stimulation and the 
medical monitor (Dr. Clio Rubinos) is an epileptologist in the department of neurology at UNC. An AE will 
be considered unexpected if the nature, severity, or frequency of the event is not consistent with the risk 
information previously described for the study intervention. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits, or the study participant may report AE or SAEs outside of a scheduled 
study visit. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of onset, 
clinician’s assessment of severity, relationship to study product (assessed only by those with the training 
and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs occurring 
while on study must be documented appropriately regardless of relationship. All AEs will be followed to 

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adequate resolution.   Any medical condition that is present at the time that the participant is screened 
will be considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE. Changes in the severity of an AE 
will be documented to allow an assessment of the duration of the event at each level of severity to be 
performed. AEs characterized as intermittent require documentation of onset and duration of each 
episode.   
 
Research personnel will record all reportable events with start dates occurring any time after informed 
consent is obtained until the last day of study participation. At each study visit, research personnel will 
inquire about the occurrence of AE/SAEs since the last visit. Events will be followed for outcome 
information until resolution or stabilization. All AEs including local and systemic reactions not meeting the 
criteria for SAEs will be captured on the appropriate case report form (CRF). Information to be collected 
includes event description, time of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis), and time of 
resolution/stabilization of the event. All AEs occurring while on study must be documented appropriately 
regardless of relationship. All AEs will be followed to adequate resolution. 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
 
8.3.5 ADVERSE EVENT REPORTING 
 
We will be adopting the following reporting procedures:  
 
What event is 
reported 
When is event 
reported 
By whom is event 
reported 
To whom is event 
reported 
Fatal or life-
threatening 
unexpected, suspected 
serious adverse 
reactions 
Within 24 hours of 
initial receipt of 
information 
Investigator 
• 
Local/internal IRB 
Non-fatal, non-life-
threatening 
unexpected, suspected 
serious adverse 
reactions 
Within 48 hours of 
initial receipt of 
information 
Research Personnel 
• 
Local/internal IRB 
Unanticipated adverse 
device effects 
Within 10 working days 
of investigator first 
learning of effect  
Investigator 
• 
Local/internal IRB 
Unanticipated Problem 
that is not an SAE 
Within 7 days of the 
investigator becoming 
aware of the problem 
Investigator 
• 
Local/internal IRB 
  
8.3.6 REPORTING OF PREGNANCY  

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There have been scientific studies using transcranial magnetic stimulation in pregnancy (see (Damar et al. 
2020; Konstantinou et al. 2020) for review). None of these studies reported side-effects specific to 
pregnancy or fetal development. Nonetheless, pregnant women will be excluded from this study because 
they are a protected group. Female participants will be asked if there is a possibility that they are pregnant 
at each session. If the participant says yes or is unsure, then we will verify pregnancy status via a urine 
pregnancy test. Only upon a verbal confirmation that pregnancy is not possible or a negative finding from 
a pregnancy test will we proceed with the experiment. 
 
8.4 UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
8.4.2 UNANTICIPATED PROBLEM REPORTING  
 
If a UE occurs, the IRB will be notified, and the study will be adjusted as needed to protect the health and 
safety of the participants. Depending on the nature of the UE, the research protocol, inclusion/exclusion 
criteria, and informed consent will be changed to reflect the possibility of this event reoccurring. During 
this time, no new participants will be recruited and the research procedures for currently enrolled 
participants will be stopped. Each UE will be recorded and reported throughout the study.   
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
Any new information gained during the study that may affect a participant’s willingness to continue in the 
study will be reported to all currently enrolled participant. 
 
9. STATISTICAL CONSIDERATIONS  
 
Statistical analyses will be performed by Dr. Justin Riddle. 
 
9.1 STATISTICAL HYPOTHESES 

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• 
Primary Outcome hypothesis: 
o Null: There is no difference in goal-directed behavior between baseline S-EEfRT and S-
EEfRT during stimulation to dlPFC as a function of stimulation type (delta-beta TMS, theta-
gamma TMS, or arrhythmic). 
o Alternate: There is a difference in goal-directed behavior between baseline S-EEfRT and 
S-EEfRT during stimulation to dlPFC as a function of stimulation type (delta-beta tACS, 
theta-gamma tACS, or active-sham). 
 
• 
Secondary Outcome hypothesis: 
o Null: There is no difference in delta-beta phase-amplitude coupling strength between 
prefrontal electrodes and left motor electrodes for the decision period of the S-EEfRT as 
a function of stimulation type to dlPFC (delta-beta TMS, theta-gamma TMS, or arrhythmic 
TMS). 
o Alternate: There is a difference in delta-beta phase-amplitude coupling strength between 
prefrontal electrodes and left motor electrodes the decision period of the S-EEfRT as a 
function of stimulation type to dlPFC (delta-beta TMS, theta-gamma TMS, or arrhythmic 
TMS). 
 
• 
Exploratory Outcome hypothesis 1: 
o Null: The impact of delta-beta TMS to dlPFC on goal-directed behavior is not correlated 
with personality traits related to motivation. 
o Alternative: The impact of delta-beta TMS to dlPFC on goal-directed behavior is correlated 
with personality traits related to motivation. 
 
• 
Exploratory Outcome hypothesis 2: 
o Null: There is no difference in reward-evaluation between baseline S-EEfRT and S-EEfRT 
during stimulation to mPFC as a function of stimulation type (delta-beta TMS, theta-
gamma TMS, or arrhythmic). 
o Alternate: There is a difference in reward-evaluation behavior between baseline S-EEfRT 
and S-EEfRT during stimulation to mPFC as a function of stimulation type (delta-beta tACS, 
theta-gamma tACS, or active-sham). 
 
• 
Exploratory Outcome hypothesis 3:  
o Null: There is no difference in theta-gamma phase-amplitude coupling strength between 
prefrontal electrodes and posterior parietal electrodes for the decision period of the S-
EEfRT as a function of stimulation type to mPFC (delta-beta TMS, theta-gamma TMS, or 
arrhythmic TMS). 
o Alternate: There is a difference in theta-gamma phase-amplitude coupling strength 
between prefrontal electrodes and posterior parietal electrodes the decision period of 
the S-EEfRT as a function of stimulation type to mPFCs (delta-beta TMS, theta-gamma 
TMS, or arrhythmic TMS). 
 
• 
Exploratory Outcome hypothesis 4: 
o Null: Functional connectivity during the S-EEfRT between dorsal striatum and lateral 
prefrontal cortex is not predictive of the impact of delta-beta TMS to dlPFC on goal-
directed behavior. 

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o Alternative: Functional connectivity during the S-EEfRT between dorsal striatum and 
lateral prefrontal cortex is predictive of the impact of delta-beta TMS to dlPFC on goal-
directed behavior. 
 
9.2 SAMPLE SIZE DETERMINATION 
 
The sample size is 24 participants in the final dataset to be used in analysis. However, to ensure that 24 
participants complete the experiment, we conservatively estimate to enroll 50 participants as a ceiling 
for the sake of IRB approval. The motivation for the sample size of 24 participants in the analysis is 
explained below. The sample size is determined based on previous experiments from our group: the 
effect size of previous findings and the reliability of our estimates. Our estimators are precise due to 
sufficient number of trials per condition with each participant and that the tasks are titrated to the 
individual. 
Primary outcome: Rhythmic TMS to lateral frontal cortex at delta-beta frequency will increase goal-
directed behavior relative to arrhythmic TMS. 
Previous Data: The planning and refinement of the proposed study was informed by our previous 
experiments that serve as preliminary data for the proposal. In our previous experiment, we delivered 
rhythmic TMS to lateral frontal cortex to increase performance in a cognitive control task (Riddle et al. 
2020b). In our previous study, there was a significant interaction between TMS site and TMS frequency in 
a two-way repeated-measures ANOVA such that the improvement in performance in the cognitive control 
task was site and frequency-specific. The effect size from the partial-eta square was 0.23, and the effect 
from a dependent t-test was 0.532, with 20 participants. The experimental design of this previous study is 
similar to the current study in that there are two sites for stimulation (lateral frontal and medial frontal) with 
two different stimulation frequencies (delta-beta and theta-gamma). Both studies used an arrhythmic 
condition to control for non-specific effects of TMS. 
Sample Size Determination and Power Calculation: Based on this previous effect size, we 
estimated that our participant count at 24 participants is powered at >95%. 
 

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Figure 3. Power calculation for the interaction effect in two-way repeated-measures ANOVA 
modeled as within factors interaction in a two-way ANOVA with partial-eta square of 0.23, and a 
correlation between variables of 0.77 based on Riddle, Scimeca et al. 2021. Power calculation run 
using the G*Power software. Proposed number of participants is 24 and is depicted in red. 
Data will be collected until we reach 24 participants. Given the similarity with our previous 
experiment (Riddle, Scimeca, et al., 2020), we are confident that our current analysis will be sufficiently 
powered. 
 
Secondary outcome: Rhythmic TMS to lateral frontal cortex at delta-beta frequency will increase 
frontal delta-beta coupling strength.  
Previous Data: The planning and refinement of the proposed study was informed by our previous 
experiments. In our previous experiment, we delivered rhythmic TMS to lateral frontal cortex and found an 
increase in oscillatory power and an increase in phase entrainment specific to the targeted frequency band 
(Riddle, McPherson, et al.). In our previous experiment that delivered theta frequency TMS (4-8Hz) to lateral 
frontal cortex, we found an increase in oscillatory power in theta frequency (effect size of 0.540) and a 
robust increase in phase alignment across trials (effect size of 1.01). We use the phase alignment metric 
(inter-trial phase coherence) to estimate the required power to find a similar impact of delta-beta stimulation 
to align the phase of delta oscillations to task-modulated beta amplitude. The analysis of our previous 
experiment used 47 participants. Based on our previous effect size for entrainment, we would need 15 
participants to reach 95% statistical power for this comparison. A more conservative estimate of a large 
effect size (0.60), we would need 24 participants to reach 80% statistical power. 
 
Figure 4. Power calculation for increased phase alignment of delta oscillations to beta power from 
delta-beta TMS. The effect size estimate is based on phase entrainment in EEG from rhythmic TMS 
(larger effect, above). A more conservative effect size estimate would be to use the impact of rhythmic 
TMS on oscillatory amplitude (large effect, below). Both effect sizes were modeled as a dependent 
t-test using the G*Power software. The proposed number of participants is 24 and is depicted in red. 

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Data will be collected until we reach 24 participants. Given the similarity in methodology between 
the current experiment and our previous experiment (Riddle, McPherson, et al.), we are confident that we 
are sufficiently powered with 24 participants. 
 
9.3 POPULATIONS FOR ANALYSES 
 
Every effort will be made to ensure all enrolled and randomized participants complete all study sessions 
as described in this protocol. For this study, enrolled eligible healthy participants will be randomized to 
receive stimulation to frontal and parietal cortex in a randomized sequence. If a participant completes 
session 4, then they will be included in all analyses moving forward. 
 
As 
previously 
stated 
in 
Section 
7 
Study Intervention 
Discontinuation 
and 
Participant 
Discontinuation/Withdrawal, enrolled participants who do not get randomized will be replaced. If 
required, then we will create additional blocks of 10 randomized sequences. Therefore, we will collect 
data until 24 participants complete the study and are eligible for analysis. 
 
9.4 STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 
All testing described below assumes a significance threshold of p = 0.05. Analyses will be deemed to be 
statistically significant if the p-value is less than this threshold. An analysis that does not exceed this 
threshold will be considered inconclusive. Continuous data will be described using means, standard 
deviations, and confidence intervals, while categorical data will be described using counts/percentages.  
 
There may be additional covariates included in the analysis. Data will be assessed for normality and, if 
deemed necessary, corrective procedures will be applied (e.g., log normalization). Based on our previous 
dataset, we expect that the variables used here will be approximately Gaussian. However, if the 
distribution of a variable displays a skewed tail and a test for normality fails, then it is justified to use a 
corrective procedure. This correction will be applied upon consideration of the variables themselves, and 
not based on the result of the intended analysis. 
 
Data will be collected until 24 participants complete the study and all data is usable. Given that 
recruitment will be feasible in a convenience sample, we expect to have complete data and all analyses 
will include the full participant pool. However, if there are technical errors that are not caught in time, 
then the affected analyses may have less participants. In this scenario, the data for a participant is then 
completely removed from the analysis. 
 
The effects of stimulation are expected to be transitory, lasting for only a second or two after stimulation. 
For this reason, stimulation is delivered “online” immediately preceding the time at which the cognitive 
processes of interest are engaged. During each session, we include a control condition (arrhythmic TMS) 
that will be subtracted from the conditions of interest (delta-beta TMS and theta-gamma TMS). Therefore, 
we control for any effects of sequence or time within each session by subtracting each metric of interest 
from the condition-matched arrhythmic TMS metric. Furthermore, any learning effects from performing 
the reward-based decision-making task should be stabilized by the 3rd session. These methods are typical 

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in cognitive neuroscience paradigms. For the reasons listed above, it is unlikely that there will be any 
effect of sequence or carryover effects between sessions. 
 
9.4.2 ANALYSIS OF THE PRIMARY OUTCOME (BEHAVIOR) 
 
Goal-directed behavior will be calculated as the average decision to perform the HARD task. The average 
of the two blocks for each stimulation conditions will be calculated (three stimulation types by two 
stimulation sites). A two-way repeated-measures analysis of variance (ANOVA) will be performed using 
within-participant factor of stimulation type (delta-beta TMS versus theta-gamma TMS; each subtracted 
by session-matched arrhythmic TMS) and within-participant factor stimulation site (dlPFC TMS versus 
mPFC TMS). We control for the effect of time with a subtraction of delta-beta TMS versus arrhythmic TMS 
and theta-gamma TMS versus arrhythmic TMS. In other words, four values are submitted to the ANOVA 
for each participant. 
 
1. 
Delta-beta TMS to dlPFC minus arrhythmic TMS to dlPFC 
2. 
Theta-gamma TMS to dlPFC minus arrhythmic TMS to dlPFC 
3. 
Delta-beta TMS to mPFC minus arrhythmic TMS to mPFC 
4. 
Theta-gamma TMS to mPFC minus arrhythmic TMS to mPFC 
 
Thus, only differences from our active control, arrhythmic TMS, are considered meaningfully worth 
interpretation. We hypothesize to find an interaction between stimulation site and stimulation type in the 
ANOVA. Post-hoc differences will be investigated using Tukey’s method to address multiple comparisons. 
We hypothesize that the predicted interaction will be driven by an increase in goal-directed behavior for 
delta-beta TMS to dlPFC. Sensitivity analyses will be conducted to evaluate the specificity of these effects: 
a similar analysis with reward-evaluation as the dependent variable and we do not expect that delta-beta 
TMS will have any effect on reward-evaluation. 
 
 
9.4.3 ANALYSIS OF THE SECONDARY OUTCOME (ELECTROPHYSIOLOGY) 
 
Delta-beta phase amplitude coupling will be calculated between the phase of delta oscillations (2-3 Hz) in 
prefrontal electrodes (FCz and surrounding electrodes) and the amplitude of beta oscillations (15- 25 Hz) 
in left motor electrodes (C3 and surrounding electrodes). The instantaneous phase and amplitude of these 
oscillations will be calculated by averaging the signal in these two regions of interest, band-filtering the 
signal to the specified range, and then performing the Hilbert transform on the signal. Phase-amplitude 
coupling (PAC) is then calculated by creating a hybrid signal using the amplitude of beta oscillations in left 
motor electrodes and the phase of delta oscillations in prefrontal electrodes:  
 
𝑃𝐴𝐶= |
∑
𝑀∗𝑒𝑖𝜃
𝑁
𝑡=1
𝑁
| , M is magnitude of beta oscillations, θ is angle of delta oscillations, N is number of time points 
The PAC value is normalized by creating a null distribution by randomly shifting the beta timeseries by at 
least 10% of the number of time points. Then, PAC is calculated between the delta-phase timeseries and 
each of these randomly shifted beta-amplitude timeseries. Finally, PACZ is calculated as the z-transformed 
true PAC value relative to the null distribution. 
 

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The average during the decision epoch of each trial of the task during stimulation will be calculated. The 
average of the two blocks for each stimulation conditions will be calculated (three stimulation types by 
two stimulation sites). A two-way repeated-measures analysis of variance (ANOVA) will be performed 
using within-participant factor of stimulation type (delta-beta TMS versus theta-gamma TMS; each 
subtracted by session-matched arrhythmic TMS) and within-participant factor stimulation site (dlPFC TMS 
versus mPFC TMS). We control for the effect of time with a subtraction of delta-beta TMS versus 
arrhythmic TMS and theta-gamma TMS versus arrhythmic TMS. In other words, four values are submitted 
to the ANOVA for each participant. 
 
1. 
Delta-beta TMS to dlPFC minus arrhythmic TMS to dlPFC 
2. 
Theta-gamma TMS to dlPFC minus arrhythmic TMS to dlPFC 
3. 
Delta-beta TMS to mPFC minus arrhythmic TMS to mPFC 
4. 
Theta-gamma TMS to mPFC minus arrhythmic TMS to mPFC 
 
Thus, only differences from our active control, arrhythmic TMS, are considered meaningfully worth 
interpretation.  We hypothesize to find an interaction between stimulation site and stimulation type in 
the ANOVA. Post-hoc differences will be investigated using Tukey’s method to address multiple 
comparisons. We hypothesize that the predicted interaction will be driven by an increase in delta-beta 
coupling for delta-beta TMS to dlPFC. Sensitivity analyses will be conducted to evaluate the specificity of 
these effects: a similar analysis with theta-gamma coupling as the dependent variable and we do not 
expect that delta-beta TMS will have any effect on theta-gamma coupling. 
 
 
9.4.4 ANALYSIS OF THE EXPLORATORY OUTCOMES 
First exploratory outcome: personality traits of motivation 
In our previous study and found that goal-directed behavior positively correlated with traits of motivation. 
Thus, we hypothesize that personality traits of motivation will positively correlate with the degree to which delta-
beta TMS will increase goal-directed behavior. The analysis will be run as a Pearson correlation between the 
impact of delta-beta TMS to dlPFC on goal-directed behavior and individual differences in traits of motivation. To 
control for the specificity of this effect, this correlation will be compared to arrhythmic TMS, personality traits of 
anxious rumination, and reward-evaluation. 
Second exploratory outcome: reward-evaluation 
 
As described in section 8.1.2, we will calculate reward-evaluation to quantify the specificity of TMS on 
specific behavioral metrics of reward-based decision-making. We will run an ANOVA as described in in the 
description of our primary outcome, but with the dependent variable as reward-evaluation instead of goal-
directed behavior. We hypothesize based on our previous study that theta-gamma TMS to mPFC will increase 
reward-evaluation. 
Third exploratory outcome: theta-gamma coupling 
 
Using the method for calculating phase-amplitude coupling in section 9.4.3, we will calculate the coupling 
between the phase of theta oscillations in prefrontal electrodes (Fz and surrounding) with the amplitude of gamma 
oscillations in posterior parietal electrodes (PO4 and surrounding). We will run an ANOVA as described in in the 
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beta coupling. We hypothesize based on our previous study that theta-gamma TMS to mPFC will increase theta-
gamma coupling. 
Fourth exploratory outcome: functional connectivity in frontal-striatal circuity 
 
Using the task-driven functional magnetic resonance imaging data, we will calculate the strength of 
functional connectivity between the dorsal striatum and the lateral prefrontal cortex. We hypothesize that that 
individual differences in this functional connectivity strength will be predictive of the change in goal-directed 
behavior with delta-beta TMS. The analysis will be run as a Pearson correlation between the impact of delta-beta 
TMS to dlPFC on goal-directed behavior and individual differences in functional connectivity between dorsal 
striatum and dlPFC. To control for the specificity of this effect, this correlation will be compared to arrhythmic 
TMS, reward-evaluation, and functional connectivity between mPFC and ventral striatum. 
 
9.4.5 SAFETY ANALYSES 
 
The stimulation questionnaire will be administered for the third and fourth session after stimulation. This 
questionnaire solicits ratings of 10 possible adverse effects associated with non-invasive brain stimulation, 
on a scale of 0 (absent), 1 (low), 2(medium), 3(high), 4 (very high). The side effects include that are 
expected to occur in some participants are headache, neck pain, scalp pain, muscle stiffness, skin tingling, 
skin itching, ringing noise, trouble concentrating, improved mood, and dizziness. Paired t-tests with 
random effect "participant" will be calculated per adverse effect to determine if there are any differences 
in adverse effect severity between sessions (delta-beta TMS, theta-gamma TMS, and arrhythmic TMS to 
dlPFC versus mPFC). Subjective severity per adverse effect will be described with mean and standard 
deviation. In addition, we will analyze the severity of each adverse event as determined by the Medical 
Monitor and PI. The process for determining the severity an adverse event is detailed in Section 2.3.4. 
 
A linear model with random effect "participant" will be calculated per adverse effect to determine if there 
are any differences in adverse effect severity between sessions (dlPFC and mPFC as categorical 
independent variables) and adverse effect severity as the continuous dependent variable. Subjective 
severity per adverse effect will be described with mean and standard deviation.  In addition, we will 
analyze the severity of each adverse event as determined by the Medical Monitor and PI. 
 
9.4.6 BASELINE DESCRIPTIVE STATISTICS 
 
All baseline descriptive statistics will be presented as a mean and standard deviation or count, e.g., age, 
sex, and personality traits. 
 
9.4.7 PLANNED INTERIM ANALYSES  
 
If there is an unexpected event that is related to TMS, then an interim descriptive analyses on the safety 
measures will be performed. Because the study is not blinded to the researchers, the analysis can be run 
by any research personnel. In addition, if the participant has a seizure, then an interim analysis will be 
performed to assess symptom severity between stimulation sites and evaluate whether stimulation side 
effects exceed those of other TMS studies. 
 

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There are no other planned interim analyses. 
 
9.4.8 SUB-GROUP ANALYSES 
 
Sub-group analyses will not be used in this study, as the sample size is too small to conduct analyses based 
on age, sex, race/ethnicity, or other demographic characteristic(s). 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study 
and continues throughout the individual’s study participation. Extensive discussion of risks and possible 
benefits of TMS will be provided to the participants and their families. Consent forms describing, in detail, 
the study intervention, device, procedures, and risks are given to the participant and written 
documentation of informed consent is required prior to the administration of any treatment. All consent 
forms will be IRB-approved and updated with any new information as modifications are made throughout 
the study. 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
During a phone call, the researcher and potential participants will review the clinical trial in its entirety. 
At several intervals during the consent review, the researcher will ask questions that will assess the 
comprehension of the information in the consent. If the participant is unsure or does not know, the 
researcher will return to that section and more carefully explain the information. Participants will not 
need a surrogate and will be able to provided consent for themselves or will not be included in the study. 
Participants will be informed that participation is voluntary and that they may withdraw from the study 
at any time, without prejudice. 
 
At the beginning of the first visit to the lab, participants will sign a physical copy of the consent document 
witnessed by research personnel. A copy of the signed informed consent document will then be given to 
the participant for their records. The rights and welfare of the participant will be protected by emphasizing 
to them that the quality of their medical care will not be adversely affected if they decline to participate 
in this study 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. If the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly 

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inform research staff, study participants, and the IRB and will provide the reason(s) for the termination or 
suspension.  Study participants will be contacted, as applicable, and be informed of changes to study visit 
schedule.   
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and 
satisfy the IRB. 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, 
and the research team. This confidentiality is extended to cover testing of biological samples and genetic 
tests in addition to the clinical information relating to participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence.   
 
All research activities will be conducted in as private a setting as possible. 
 
All data will only be referenced by dummy identifier code. Data will be stored on a password protected 
computer. A key connecting names and identifier code numbers will be kept in a locked cabinet, accessible 
only by research personnel. All data will be stored and analyzed on password protected computers, also 
only accessible by research personnel. Participants will not be identified in any report or publication about 
this study and there is no risk of deductive disclosure. At the end of the study, all records will continue to 
be kept in a secure location for as long a period as dictated by the IRB. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be entered into TraCS Clinical Research Data Management Service (REDCap). The database system 
provides secure web-based data entry with the data stored on servers that are maintained by TrACS. The 
data is encrypted during transmission. The servers are located in a secure campus area with all appropriate 
physical security measures in place. The web and database servers are monitored by the TraCS IT staff, 
patched frequently, and scanned by a third-party vendor to ensure that they are protected against known 
vulnerabilities. The scanning application is the standard service for the entire campus. Access is by 
individual user id and is restricted to the forms and/or functions that the user needs to have.   
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored within the Carolina Center for 
Neurostimulation/Frohlich Lab. After the study is completed, the data will be fully de-identified and 
archived within a locked file cabinet or an encrypted server maintained by the Carolina Center for 
Neurostimulation. 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 

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Principal Investigator 
Medical Monitor 
Study Coordinator, Statistical Analyst 
Flavio Frohlich, PhD 
Clio Rubinos, MD 
 
Justin Riddle, PhD 
The University of North 
Carolina at Chapel Hill - 
Department of Psychiatry 
 
919-966-4584 
The University of North 
Carolina at Chapel Hill - 
Department of Neurology 
 
(984) 974-1000 
The University of North Carolina at 
Chapel Hill - Department of Psychiatry 
 
984-974-6239 
Flavio_Frohlich@med.unc.edu 
CRubinos@unc.edu 
Justin_Riddle@med.unc.edu 
  
10.1.6 SAFETY OVERSIGHT 
  
Safety oversight will be under the direction of the principal investigator, medical monitor, and study 
coordinator composed of three researchers. The PI will review AEs in real time and make decisions as of 
participant’s continuation of the clinical trial. The PI will review AEs as appropriate, every three months, 
with the research team. The PI may request additional review by the medical monitor on a case-by-case 
basis.  
  
10.1.7 CLINICAL MONITORING 
 
The purpose of the monitoring plan is to present the approach of the Carolina Center for Neurostimulaton 
to monitoring clinical trials.  The plan facilitates compliance with good clinical practice. 
 
(a) The rights and well-being of human participants are protected. 
(b) The reported trial data are accurate, complete, and verifiable from source documents. 
(c) The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with 
GCP, and with applicable regulatory requirement(s). 
 
This section identifies key monitoring activities and specifies the data to be reviewed over the course of a 
clinical trial.  This is a single site, investigator initiated, clinical trial so there will be no site monitoring plan 
in place. 
 
 
10.1.7.1 THE CAROLINA CENTER FOR NEUROSTIMULATION MONITORING PLAN 
 
The latest version of the approved IRB application for this clinical trial will be followed at all times. This 
responsibility falls in the hands of the trained research personnel.  If at any time there is a deviation from 
protocol, the deviation from protocol log will be filled out.  All team members will be trained on how and 
when to use this log. Deviations will be sent to IRB every 4-6 weeks (if necessary). 
 
Data will be verified for completeness following every study session and all data will be entered into 
REDCap, a secure online database. After a participant has completed their participation (full completion 
of the study or because they withdrew prior to completion), data will be rereviewed for completeness 

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and accuracy. After all data has been collected, data will be re-reviewed by another lab member who was 
not involved with the data collection process.  
 
AE and SAE are clearly defined in the Master Protocol. Documents of AE and SAE can be found in the study 
binder on file within 77 Vilcom Center, Room 111.  It is the responsibility of trained research personnel to 
report all events to the PI. Reporting of AEs and SAEs is described within Section 8.3. 
 
The PI will have access to the REDCap database. This allows the PI to view reports that provide information 
on any missing data on an individual participant basis, but does not allow them to add, change or input 
any data. 
  
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
The Carolina Center for Neurostimulation will conduct internal quality management of study conduct, 
data and biological specimen collection, documentation and completion. Following written Standard 
Operating Procedures (SOPs), research personnel will verify that the clinical trial is conducted and data 
are generated, documented (recorded), and reported in compliance with the protocol, International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements 
(e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Trained research personnel will be responsible for the informed consent process, review for eligibility, 
questionnaire administration, data entry, device administration, EEG administration, and CRF entries. 
Research personnel will be responsible for AE/SAE documentation and reporting, while the PI will be 
responsible for the AE assessment, review of the AE documentation forms and overview of the research 
staff. 
 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) will be 
entered into a data capture system provided by TraCS Clinical Research Data Management Service 
(REDCap). The data system includes password protection and internal quality checks, such as automatic 
range checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be 
entered directly from the source documents. Trained research personnel will have complete access to the 
REDCap system. This will enable the researchers to enter the data and the PI review. The REDCap data 
management system will be programmed and overseen by Justin Riddle. 
 
As discussed in Section 10.1.3, data entered into REDCap is stored on servers that are maintained by 
TrACS. The data is encrypted during transmission. The servers are located in a secure campus area with 
all appropriate physical security measures in place. The web and database servers are monitored by the 
TraCS IT staff, patched frequently, and scanned by a third-party vendor to ensure that they are protected 
against known vulnerabilities. The scanning application is the standard service for the entire campus.  
 
10.1.9.2 STUDY RECORDS RETENTION  
  

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According to the University of North Carolina at Chapel Hill’s Archives and Record Management Services 
schedule for General Records Retention and Disposition Schedule, records will be kept for 5 years after 
the completion of the study or grant end date, whichever is later. 
 
10.1.10 PROTOCOL DEVIATIONS  
  
All deviations from the protocol will be addressed in study participant source documents. The researcher 
will complete a Protocol Deviation Log using the participant code as the identifier. This form will collect 
information such as the date the deviation occurred, details of what the deviation consisted of, any 
corrective and preventative actions that were taken as a result of the deviation, and the date that the PI 
and IRB were notified. The PI will review the information and initial once approved. A completed copy of 
the Protocol Deviation Form will be maintained in the regulatory file, as well as in the participant’s source 
document.  Protocol deviations will be sent to the IRB per their guidelines.  The site PI/study staff will be 
responsible for knowing and adhering to their IRB requirements. 
 
10.1.11 PUBLICATION AND DATA SHARING POLICY 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed 
journals. 
 
 
10.1.12 CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence is critical. Any conflict of interest 
for any persons who have a role in the design, conduct, analysis, publication, or any aspect of this trial will 
be disclosed and managed by the UNC Conflict of Interest Office. If necessary, for persons who have a 
perceived conflict of interest, management will be provided again by the UNC Conflict of Interest office. 
 
10.2 
ADDITIONAL CONSIDERATIONS 
 N/A 
 
 
 

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10.3 
ABBREVIATIONS 
 
AE 
Adverse Event/Adverse Experience 
ANOVA 
Analysis of Variance 
BIS/BAS 
Behavioral Inhibition System / Behavioral Approach System 
BRIC 
Biomedical Research Imaging Center 
CFR 
Code of Federal Regulations 
Co-I 
Co-Investigator 
CRF 
Case Report Form 
DHHS 
Department of Health and Human Services 
dlPFC 
Dorsolateral prefrontal cortex 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
dSTR 
Dorsal striatum 
EEfRT 
Expenditure of Effort for Reward Task 
EEG 
Electroencephalogram 
EMG 
Electromyography 
FDA 
Food and Drug Administration 
FDI 
First dorsal interosseous  
fMRI 
Functional magnetic resonance imaging 
GCP 
Good Clinical Practice 
HD-EEG 
High-density electroencephalography 
Hz 
Hertz 
ICF 
Informed Consent Form 
IDE 
Investigational Device Exemption 
LAR 
Legally Authorized Representative 
MEP 
Motor evoked potential 
mPFC 
Medial prefrontal cortex 
MRI 
Magnetic Resonance Imaging 
MT 
Motor threshold 
NIH 
National Institutes of Health 
NIMH 
National Institute of Mental Health 
NSR 
Non-significant risk 
OHRE 
Office of Human Research Ethics 
OHRP 
Office for Human Research Protections 
PAC 
Phase-amplitude coupling 
PACz 
Z-transformed phase amplitude coupling 
PHI 
Protected Health Information 
PI 
Principal Investigator 
RDoC 
Research domain criteria 
rTMS 
Rhythmic transcranial magnetic stimulation 
RRS 
Ruminative responses scale 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SHAPS 
Snaith-Hamilton Pleasure Scale 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedure 
STAI 
State-Trait Anxiety Inventory 
S-EEfRT 
Streamlined Expenditure of Effort for Reward Task 
TEPS 
Temporal Experience of Pleasure Scale 
TMS 
Transcranial magnetic stimulation 

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UE 
Unexpected Event 
UNC 
University of North Carolina 
UNC-CH 
University of North Carolina at Chapel Hill 
US 
United States 
vSTR 
Ventral striatum 
 
 
 

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10.4 
PROTOCOL AMENDMENT HISTORY 
  
MAINTAINED AT THE TOP OF THIS DOCUMENT 
 
 

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