Modulation of Alpha and Theta Oscillations in a Cognitive Control Retrospective Cue Task With Frequency Specific Rhythmic Transcranial Magnetic Stimulation
Phase: NA
Conditions: Executive Function
Sponsor: University of North Carolina, Chapel Hill

CONFIDENTIAL 
 
0 
MODULATION OF COGNITIVE CONTROL 
SIGNALS IN PREFRONTAL CORTEX BY 
RHYTHMIC TRANSCRANIAL MAGNETIC 
STIMULATION 
 
STUDY CODE: PATRC 
 
 
Funding Mechanism: 
N/A 
Principal Investigator: 
Flavio Frohlich, PhD 
 
Co-Investigator: 
N/A 
 
Protocol Number: 
18-1789 
 
Version Number: 
5.0 
Date: 
10 June 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Initial version: 
13 July 2018 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ....................................................................................................................................... 4 
STUDY SUMMARY ................................................................................................................................................ 5 
1 
KEY ROLES ..................................................................................................................................................... 6 
1.1 
INDIVIDUALS .................................................................................................................................................. 6 
1.2 
INSTITUTIONS ................................................................................................................................................. 6 
1.3 
OPTIONAL ..................................................................................................................................................... 6 
1.4 
FUNDING SOURCES .......................................................................................................................................... 6 
2 
INTRODUCTION ............................................................................................................................................. 6 
2.1 
BACKGROUND ................................................................................................................................................ 7 
2.2 
DOSE RATIONALE ............................................................................................................................................ 8 
2.3 
STUDY AIMS/HYPOTHESES ................................................................................................................................ 8 
2.4.1 
PRIMARY OBJECTIVE ............................................................................................................................................. 8 
2.4.1 
SECONDARY OBJECTIVE ......................................................................................................................................... 9 
3 
PARTICIPANT SELECTION AND WITHDRAWAL ................................................................................................ 8 
3.1 
INCLUSION CRITERIA ...................................................................................................................................... 10 
3.2 
EXCLUSION CRITERIA ...................................................................................................................................... 10 
3.3 
STRATEGIES FOR RECRUITMENT AND RETENTION .................................................................................................. 10 
3.3.1 
RECRUITMENT ................................................................................................................................................... 11 
3.3.2 
RETENTION ....................................................................................................................................................... 11 
4 
BASIC STUDY DESIGN ................................................................................................................................... 12 
4.1 
TREATMENT ASSIGNMENT PROCEDURES ............................................................................................................. 13 
5 
STUDY SCHEDULE ........................................................................................................................................ 14 
5.1 
SCREENING .................................................................................................................................................. 14 
5.2 
STIMULATION ............................................................................................................................................... 14 
6 
STUDY PROCEDURES/EVALUATIONS ............................................................................................................ 14 
6.1 
SELF-REPORT MEASURES ................................................................................................................................. 15 
6.2 
SPECIAL ASSAYS OR PROCEDURES .............................................................................. ERROR! BOOKMARK NOT DEFINED. 
6.3.1 
MOTOR EVOKED POTENTIAL USING EMG ...................................................................... ERROR! BOOKMARK NOT DEFINED. 
7 
STUDY INVESTIGATIONAL PRODUCT ............................................................................................................ 18 
7.1 
SAFETY FEATURES ......................................................................................................................................... 18 
7.2 
PREPARATION AND ADMINISTRATION OF STUDY INVESTIGATIONAL PRODUCT .............................................................. 18 
7.3 
ASSESSMENT OF PARTICIPANT COMPLIANCE WITH STUDY INVESTIGATIONAL PRODUCT .................................................. 18 

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POTENTIAL RISKS AND BENEFITS ................................................................................................................. 19 
8.1 
BENEFITS TO PARTICIPANTS AND SOCIETY ........................................................................................................... 19 
8.2 
POTENTIAL RISKS .......................................................................................................................................... 19 
8.2.1 
PSYCHOLOGICAL ................................................................................................................................................. 19 
8.2.1 
PHYSICAL .......................................................................................................................................................... 19 
8.3 
REFERRALS FOR MEDICAL FOLLOW-UP OR PSYCHOLOGICAL COUNSELING .................................................................... 19 
9 
DATA AND SAFETY MONITORING ................................................................................................................ 21 
9.1 
FROHLICH LAB MONITORING PLAN .................................................................................................................... 21 
9.2 
SAFETY OVERSIGHT BY THE DSMB ............................................................................ ERROR! BOOKMARK NOT DEFINED. 
9.3 
EARLY WITHDRAWAL OF PARTICIPANTS .............................................................................................................. 21 
9.3.1 
REASONS FOR WITHDRAWAL ................................................................................................................................ 21 
9.3.2 
DATA COLLECTION FOR WITHDRAWN PARTICIPANTS ................................................................................................. 21 
9.4 
TERMINATION OF STUDY ................................................................................................................................. 22 
10 
SAFETY & REPORTING ................................................................................................................................ 23 
10.1 
SAFETY PARAMETERS ................................................................................................................................... 23 
10.2 
METHODS AND TIMING FOR ASSESSING, RECORDING, AND ANALYZING SAFETY PARAMETERS ....................................... 23 
10.2.1 
ADVERSE EVENTS ............................................................................................................................................. 23 
10.2.1 
SERIOUS ADVERSE EVENTS ................................................................................................................................. 23 
10.2.2 
UNANTICIPATED PROBLEMS ............................................................................................................................... 24 
10.3 
REPORTING PROCEDURES .............................................................................................................................. 24 
10.4 
TYPES AND DURATION OF FOLLOW-UP OF PARTICIPANTS AFTER ADVERSE EVENTS ...................................................... 25 
11 
STATISTICAL PLAN ..................................................................................................................................... 26 
11.1 
STATISTICAL ANALYSIS STRATEGIES .................................................................................................................. 26 
11.2 
SAMPLE SIZE DETERMINATION ........................................................................................................................ 27 
11.3 
DATA MANAGEMENT ................................................................................................................................... 27 
12 
DATA HANDLING AND RECORD KEEPING ................................................................................................... 29 
12.1 
PHI AND HIPAA ........................................................................................................................................ 29 
12.2 
CONFIDENTIALITY ........................................................................................................................................ 29 
12.2.1 
ACCESS TO SOURCE DOCUMENTS ........................................................................................................................ 29 
12.2.3 
OTHER ........................................................................................................................................................... 29 
12.3 
SOURCE DOCUMENTS .................................................................................................................................. 29 
12.4 
DATA MANAGEMENT RESPONSIBILITIES ............................................................................................................ 30 
12.5 
DATA CAPTURE METHODS (REDCAP) ............................................................................................................. 30 
12.6 
PROTOCOL DEVIATIONS ................................................................................................................................ 30 
12.7 
RECORD RETENTION .................................................................................................................................... 30 
13 
ETHICAL CONSIDERATIONS ........................................................................................................................ 31 
13.1 
ETHICAL STANDARD ..................................................................................................................................... 31 
13.2 
INSTITUTIONAL REVIEW BOARD (IRB) .............................................................................................................. 31 
13.3 
INFORMED CONSENT PROCESS ....................................................................................................................... 31 

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13.4 
EXCLUSION OF WOMEN, MINORITIES, AND CHILDREN (SPECIAL POPULATIONS) ......................................................... 32 
13.5 
PARTICIPANT CONFIDENTIALITY ...................................................................................................................... 32 
13.6 
STUDY DISCONTINUATION ............................................................................................................................. 32 
14 
PUBLICATION POLICY ................................................................................................................................. 32 
15 
LITERATURE REFERENCES .......................................................................................................................... 33 
APPENDIX A: SCHEDULE OF EVENTS ................................................................................................................... 35 
APPENDIX B: AE REPORT FORM .......................................................................................................................... 35 
APPENDIX C: IRB AMENDMENT TRACKING LOG .................................................................................................. 37 
APPENDIX D: AE REPORT FORM ......................................................................................................................... 38 
APPENDIX E: INFORMED CONSENT QUIZ ............................................................................................................ 39 
APPENDIX F: NOTE TO FILE ................................................................................................................................. 40 
APPENDIX G: TELEPHONE SCRIPT ....................................................................................................................... 41 
 
 
 
 
 

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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
ANOVA 
aMFG 
Analysis of Variance 
Anterior Middle Frontal Gyrus 
BIS/BAS 
Behavioral Inhibition System / Behavioral Approach System 
CFR 
Code of Federal Regulations 
Co-I 
Co-Investigator 
CRF 
Case Report Form 
DC 
Direct current 
DHHS 
Department of Health and Human Services 
DMV 
Department of Motor Vehicles 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders (Version 5) 
DSMB 
dPM 
Data and Safety Monitoring Board 
Dorsal Premotor cortex 
eCRF 
Electronic Case Report Form 
EEG 
Electroencephalogram 
EMG 
Electromyography 
EOG 
Electrooculography 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
Hz 
Hertz 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IDE 
IFJ 
Investigational Device Exemption 
Inferior Frontal Junction 
IRI 
Interpersonal Reactivity Index 
LAR 
Legally Authorized Representative 
M1 
Primary motor cortex 
NAMI 
National Alliance on Mental Illness 
NIH 
National Institutes of Health 
NIMH 
National Institute of Mental Health 
NRB 
Neurosciences Research Building 
OHRE 
Office of Human Research Ethics 
OHRP 
Office for Human Research Protections 
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SMC 
Safety Monitoring Committee 
SPI 
Serial Peripheral Interface 
SOP 
Standard Operating Procedure 
TMS 
Transcranial Magnetic Stimulation 
UE 
Unexpected Event 
UNC 
University of North Carolina 
UNC-CH 
University of North Carolina at Chapel Hill 
US 
United States 

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STUDY SUMMARY 
Title 
Modulation of cognitive control signals in prefrontal cortex by rhythmic transcranial 
magnetic stimulation 
Short Title 
PATRC 
Protocol Number 
18-1789  
Phase 
Pilot 
Methodology 
Four-session, crossover design, active sham controlled 
Study Duration 
This study is expected to last eighteen months. 
Study Center(s) 
This is a four-session and single-site study performed at The University of North 
Carolina at Chapel Hill. 
Objectives (Purpose) 
The purpose of this pilot study is to modulate oscillatory activity in the prefrontal 
cortex using rhythmic transcranial magnetic stimulation during performance of a 
cognitive control task. 
Number of Participants 
100 (until 48 are completed) 
Diagnosis and Main 
Inclusion Criteria 
Eligible participants will be healthy adults between the ages of 18-35 with no history 
of mental or psychiatric disorder. 
Description of 
Intervention 
(Procedures/methods) 
The participants will perform a cognitive control task. During the task, rhythmic 
trains of transcranial magnetic stimulation will be delivered. 
Electroencephalography will be collected throughout every session. 
Related IRB Applications 
17-0149 
 
 
 

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1 
KEY ROLES 
1.1 
INDIVIDUALS 
Principal Investigator 
Flavio Frohlich, PhD 
Medical Monitor 
N/A 
Flavio Frohlich, PhD – Principal Investigator 
UNC – Chapel Hill Department of Psychiatry 
Email: flavio_frohlich@med.unc.edu 
Office: 4109F Neuroscience Research Building 
Phone: (919) 966-4584 
 
Justin Riddle, PhD – Study Coordinator 
UNC – Chapel Hill Department of Psychiatry  
Email:  justin_riddle@med.unc.edu 
Office: Medical School Wing C 245A 
Phone: (919) 523-3127 
 
Trevor McPherson, BS – Research Assistant 
UNC – Chapel Hill 
Email: trevor_mcpherson@med.unc.edu   
Office: Medical School Wing C – Room 245A 
Phone: (919) 445-0227 
 
1.2 
INSTITUTIONS 
The University of North Carolina at Chapel Hill 
1.3 
OPTIONAL 
IRB 
The University of North Carolina – Chapel Hill 
Medical School Building 52 
Mason Farm Road 
CB #7097 
Chapel Hill, NC 27599-7097 
(919) 966-3113 
1.4 
FUNDING SOURCES 
Please list below the funding sources for this project:  
Sponsor Name 
UNC Ramses 
Number 
Sponsor Type 
Prime Sponsor 
Name 
Prime Sponsor 
Type 
Sponsor/Grant 
Number 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
External Funding: This project is not externally funded. 
UNC-CH Funding: This project is not funded through UNC-CH. 
Classified: This project is not classified. 
 
2 
INTRODUCTION 

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This document is a protocol for a human research study. This study is to be conducted according to U.S. and 
international standards of Good Clinical Practice (FDA Title 21 Part 312 and International Conference on 
Harmonization guidelines), applicable government regulations and Institutional research policies and procedures. 
2.1 
BACKGROUND 
Neural oscillations are proposed to be a mechanism of coordinating information processing across distributed 
regions of cortex (Fries 2015). Different neural oscillations may correspond to different underlying neural 
computations (Wang 2010). Noninvasive brain stimulation allows experimenters to modulate specific neural 
oscillations by targeting particular frequency bands (Romei et al. 2016). By collecting simultaneous 
electroencephalography (EEG), rhythmic transcranial magnetic stimulation (TMS) has been previously 
demonstrated to entrain neural oscillations at the frequency of stimulation (Thut et al. 2011; Hanslmayr et al. 
2014; Albouy et al. 2017). Furthermore, when the frequency of entrained neural oscillations is matched to the 
frequency of endogenous activity in a cognitive task, the brain stimulation improves behavioral performance 
(Albouy et al. 2017). Therefore, noninvasive brain stimulation is a promising tool for improving cognition by 
inducing optimal neural activity via externally applied electromagnetic fields; e.g. cognitive control improvements 
(Alekseichuk et al. 2016; Albouy et al. 2017; Reinhart 2017; Wolinski et al. 2018).  
Previous evidence has implicated neural activity in the alpha band (8-12 Hz) in information suppression and activity 
in the theta band (4-7 Hz) in information processing (Klimesch et al. 2007; Dé et al., 2014). Cognitive control task 
paradigms have been shown to elicit distinct activity in both of these bands (Popov er al., 2018). In this task, the 
presented stimuli can be lateralized to the right and left visual field during encoding, while a cue informs 
participants which stimuli (right or left) are relevant to be remembered for testing later. In this paradigm, alpha 
activity in parietal cortex is found contralateral to irrelevant stimuli—supporting the role of alpha in information 
suppression—while theta activity in frontal cortex increases with the number of stimuli to be remembered—
supporting the role of theta in active information processing (Wallis et al., 2015).  
For the current study, we propose to deliver rhythmic trains of TMS in either alpha frequency, theta frequency, or 
an arrhythmic control to modulate neural processing during a cognitive control task. By collecting simultaneous 
EEG with TMS, we will be able to measure the entrained oscillations from rhythmic TMS. The goal of this 
experiment is to boost the observed theta and alpha activity that is seen with the successful prioritization and 
suppression of information during the task.  
To provide causal evidence that parietal cortex generates alpha activity and frontal cortex generates theta activity, 
we will apply rhythmic TMS stimulation to two scalp location, the anterior middle frontal gyrus and inferior 
intraparietal sulcus. By applying alpha frequency, theta frequency, and arrhythmic TMS at each location, we will be 
able to examine the causal relationship of frontal theta oscillations to information prioritization and parietal alpha 
oscillations to information suppression.  
 

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2.2 
DOSE RATIONALE 
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 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. 
The contralateral motor cortex will be targeted by single pulses of TMS 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 an MEP is generated on five out of ten pulses. This is defined as 
the participant’s motor threshold (Rossi et al. 2009). For the subsequent stimulation days, participants will receive 
TMS at 120% of their motor threshold. Participants will receive trains of 5 pulses at 5 hertz, 10 hertz, or arrhythmic 
randomized pulse intervals not to exceed an inter-pulse-interval of 20 milliseconds. Between every train will be at 
least 5 seconds. An inter-train-interval of 5 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 (Thut et al. 2011; Hanslmayr et al. 2014; Albouy et al. 2017). EEG will be collected using the 
Geodesic 400 system (EGI INC., Eugene, OR, USA). Collecting simultaneous EEG and TMS does not pose any 
additional risk over TMS on its own. EEG does not involve brain stimulation and is used purely for neuroimaging 
(minimal risk). 
2.3 
STUDY AIMS/HYPOTHESES 
2.3.1 
PRIMARY OUTCOME – WORKING MEMORY CAPACITY 
RATIONALE. Participants make a button press on a keyboard to indicate if the probed items are matched or 
non-matched to the items held in memory. The investigators will calculate the accuracy for these 
responses and convert this to Pashler's working memory capacity metric for each condition. Theta 
oscillations are known to be generated in frontal cortex when cued to the contralateral visual field. Alpha 
oscillations are known to be generated in parietal cortex when cued to the ipsilateral visual field. 
ALTERNATIVE HYPOTHESIS. When the frequency of TMS to either frontal or parietal cortex is compatible with 
the endogenous activity, working memory capacity should increase relative to TMS that is incompatible. 
Therefore, we will report the TMS compatibility effect as the average of “theta minus alpha TMS to frontal 
cortex for retro-cue right” and “alpha minus theta TMS to parietal cortex for retro-cue left”. We will 
report the mean and standard deviation of the TMS compatibility effect across participants. This effect 
will be investigated using repeated-measures two-way ANOVA, and an interaction between TMS site and 
TMS frequency is hypothesized. 
NULL HYPOTHESIS. There is no systematic effect of frequency specific TMS on working memory capacity. 
2.3.2 
PRIMARY OUTCOME – SPECTRAL POWER 
RATIONALE. The electrical activity of the brain is recorded during performance of the task and during brain 
stimulation. The investigators will perform Morelet wavelet convolution on the recorded electrical signal 
to calculate the spectral power of theta (5-8 hertz) and alpha (8-12 hertz). Theta oscillations are known to 
be generated in frontal cortex when cued to the contralateral visual field. Alpha oscillations are known to 
be generated in parietal cortex when cued to the ipsilateral visual field. 
ALTERNATIVE HYPOTHESIS. When the frequency of TMS to either frontal or parietal cortex is compatible with 
the endogenous activity, spectral power in the stimulated frequency band should increase relative to TMS 
that is incompatible. Therefore, we will report the TMS compatibility effect as the average of “theta 
power for theta minus alpha TMS to frontal cortex for retro-cue right” and “alpha power for alpha minus 

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theta TMS to parietal cortex for retro-cue left”. We will report the mean and standard deviation of the 
TMS compatibility effect across participants. This effect will be investigated using repeated-measures two-
way ANOVA, and an interaction between TMS site and TMS frequency is hypothesized. 
NULL HYPOTHESIS. There is no systematic effect of frequency specific TMS on spectral power. 
 
2.3.3 
SECONDARY OUTCOME – RESPONSE TIME 
RATIONALE. Participants make a button press on a keyboard to indicate if the probed items are matched or 
non-matched to the items held in memory. The investigators will calculate the response time for each 
condition. Theta oscillations are known to be generated in frontal cortex when cued to the contralateral 
visual field. Alpha oscillations are known to be generated in parietal cortex when cued to the ipsilateral 
visual field. 
ALTERNATIVE HYPOTHESIS. When the frequency of TMS to either frontal or parietal cortex is compatible with 
the endogenous activity, response time should decrease relative to TMS that is incompatible. Therefore, 
we will report the TMS compatibility effect as the average of “theta minus alpha TMS to frontal cortex for 
retro-cue right” and “alpha minus theta TMS to parietal cortex for retro-cue left”. We will report the 
mean and standard deviation of the TMS compatibility effect across participants. This effect will be 
investigated using repeated-measures two-way ANOVA, and an interaction between TMS site and TMS 
frequency is hypothesized. 
NULL HYPOTHESIS. There is no systematic effect of frequency specific TMS on response time. 
 
 

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3 
PARTICIPANT SELECTION AND WITHDRAWAL 
A total of 48 participants will complete this study and all data will be collected at UNC-CH. No specific plans have 
been made to enroll participants from vulnerable populations.  
3.1 
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 35 
• 
Right handed 
• 
Able to provide informed consent 
• 
Have normal to corrected vision 
• 
Willing to comply with all study procedures and be available for the duration of the study 
• 
Speak and understand English 
3.2 
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) 
• 
Prior brain surgery 
• 
Any brain devices/implants, including cochlear implants and aneurysm clips 
• 
History of current traumatic brain injury  
• 
(For females) Pregnancy 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 
Justifications for any exclusions based on race, gender, or ethnicity: There are no exclusion criteria based on race, 
gender, or ethnicity. However, non-English speaking individuals are excluded because the ability to accurately and 
completely communicate study information, answer questions about the study, and obtain consent are necessary. 
Justification for excluding women or women who become pregnant: Pregnant participants will be excluded 
despite the fact that theoretical risk to mother or fetus is exceedingly small, since no safety data for pregnancy is 
known to exist for TMS studies. Female participants will be asked if there is a possibility that they are pregnant at 
every stimulation 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 will we 
proceed with the experiment. 
 
 
 
3.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 

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3.3.1 
RECRUITMENT 
The target population of this study includes healthy individuals between the ages of 18 to 35 recruited 
from UNC Chapel Hill and the surrounding area, including approximately 30,000 candidates for 
participation. Recruitment will occur via two methods: flyers to be distributed at major locations on the 
campus (libraries, gyms, classroom buildings, etc.) and a mass email to all individuals with a UNC-affiliated 
email address.  
3.3.2 
RETENTION 
Our retention strategy includes a payment schedule of one time per session per participant. The payment 
amount increases with each session to encourage study completion. The participant will receive payment 
at the end of each session. 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. 
 

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4 
BASIC STUDY DESIGN 
This study is a pilot, four-session study with TMS and EEG to understand the neural oscillatory basis of cognitive 
control. Participants will perform a cognitive control task in which a retro-cue is used to distinguish between 
relevant and irrelevant lateralized stimuli that need to be accurately recalled for testing in each trial. The rhythmic 
TMS manipulation targets the previously localized EEG frequencies and previously localized regions of the brain 
from MEG (Wallis et al., 2015). The frequencies of stimulation will be theta (5 hertz), alpha (10 hertz), and 
arrhythmic. The regions of stimulation will be anterior-MFG, inferior-IPS. The study consists of an initial screening 
session, a baseline session, and two counterbalanced stimulation sessions with TMS delivered during task 
performance. During the initial screening session, participants will earn and perform the cognitive control task at 
varying levels of difficulty in order to titrate their performance accuracy. During the baseline session, participants 
will perform the titrated cognitive control task while EEG is recorded. The motor threshold (MT) for each 
participant will also be calculated either on this day or during the Stimulation 1 session. MT is calculated by placing 
the TMS coil at a 45-degree angle from the midline along the central sulcus (just above the ears). An electrode is 
attached to the contralateral first dorsal interosseous muscle. Then the primary motor cortex is stimulated with 
single pulse TMS until a motor evoked potential (MEP) is generated in the contralateral hand muscle, defined as a 
near-instantaneous increase in electrical activity above 200 microvolts. Then the intensity of TMS is lowered until 
an MEP is evoked on five out of ten pulses. Additionally, visible hand twitches may be used as instead of visual 
twitches to determine MT. The MT allows for TMS to be calibrated to the particular sensitivity level of the 
individual participant’s brain. On the subsequent TMS session we will stimulate at 110% of MT. We ensure that 
TMS is driving neural activity but that this activity is within the range of endogenous activity and hence is at an 
appropriately safety level according to guidelines established for TMS (Rossi et al. 2009). On the third and fourth 
session (Stimulation 1 and Stimulation 2) the anterior-MFG and inferior-IPS is targeted by rhythmic TMS during 
performance of the cognitive control task. The sequence of TMS targets will be randomized and counterbalanced 
across participants. However, it is not possible to double-blind the study because the location of the TMS coil 
needs to be aligned to the targeted brain region with neuro-navigation software (Localite, Sankt Augustin, 
Germany). In other words, the region targeted by TMS is necessarily visible to the experimenter for accurate 
targeting. The study will be single blinded as the participant will not know the anatomical differences between the 
targeted regions and the position on the scalp differs by only a few centimeters between each site. Critically, the 
manipulation of interest is the frequency of stimulation. On each trial, the frequency will be randomly selected, 
counter-balanced, and inter-mixed. The effects of rhythmic TMS do not last for more than a few cycles beyond 
stimulation itself (Thut et al. 2011; Hanslmayr et al. 2014; Albouy et al. 2017). Therefore, the experimental design 
randomly intermixes the frequency of stimulation within every task block. The critical analysis is the within 
participant comparison of frequency specific TMS effects for a single site. The sequence order of target sites will 
have no impact because all analyses will be run as a difference from our active control (arrhythmic TMS) from 
within the same session. In addition, a brief resting-state EEG recording will be collected at the beginning of the 

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baseline and stimulation sessions.  
 
 
4.1 
TREATMENT ASSIGNMENT PROCEDURES 
The three frequencies of interest (theta, alpha, and arrhythmic) are randomly intermixed within every task block. 
The randomization is uniquely generated for each participant and session. The order of regions targeted (a-MFG 
and i-IPS) will be randomized and counterbalanced across participants. The primary analysis of the experiment is to 
analyze the frequency specific effect of rhythmic TMS versus arrhythmic TMS within the same session. Therefore, 
the experiment is designed such that sequence order is irrelevant as every analysis is performed as a within session 
difference. Using neuro-navigation software, precludes a double-blinding as the experimenter must be aware of 
the targeted region. The participant will not be keen to the anatomical differences between these regions that are 
separated by only a few centimeters. 
 
 

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5 
STUDY SCHEDULE 
In order to increase data quality, the assessments for an individual participant will be administered by the same 
researcher. It is important to note that consent, scales, and experiments will all take place in a private room. Any 
phone calls will take place in a private lab environment as well.  
5.1 
SCREENING 
The phone screening allows researchers to screen out participants based on self-report responses and for potential 
participants to become familiar with the study schedule, including procedures. During the telephone screening, 
researchers will provide a brief background about TMS. The timeline of visits will be explained, including the 
number of visits and the time commitment required. The participant will be informed of compensation, both 
amount and payment schedule. The participant will be asked if they have any questions. Once all questions have 
been answered, the participant will be asked if he/she is still interested in participating in the study. If yes, the 
researcher will ask if the participant will provide verbal consent to begin the initial phone screening which will 
determine eligibility for the stimulation session. A telephone script, which includes the screening questions, is 
provided in Appendix G. If the participant meets initial criteria with these two assessments, the stimulation session 
will be scheduled and a reminder call or email will be given at least 24 hours before the stimulation session. 
 
5.2 STIMULATION SESSIONS 
Participants will undergo four sessions: one screening, one baseline, and two active sessions. During all four 
sessions, participants will be guided through the consent form. To ensure that all aspects of the research are 
understood, participants may be asked a series of questions about the research they are about to take part in 
(Appendix E). Once it is clear that the participant understands the consent form they may sign the form.  
Session 1: Screening  
• 
In this initial session, participants will be explained the procedure and reminded of their expectations and 
rights (informed consent).After obtaining consent, a pregnancy screening will be 
administered.Following this the participant will practice and perform cognitive control task. Participants 
have a self-paced break between blocks of the task.  
• 
Participant will receive $20 in compensation  
Session 2: Baseline  
• 
The following questionnaires will be administered during the session or will becompleted remotely by 
the participant through an online survey weblink before the session - These measures are listed below 
under “self-report measures” 
• 
Preparation - The EEG net will be applied.Resting state EEG – Participant will be asked to relax with eyes 
open and eyes-closed while EEG is collected simultaneously.Following this the participant will practice 
and perform cognitive control task.Motor thresholding using single pule TMS for use in future sessions 
(performed once for each participant, either on Baseline or Stimulation 1 day).Electrodes and net will be 
removed and participant can wash their hair and faceParticipant will receive $30 in compensation  

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Session 3 and 4: Stimulation 1 and 2  
• 
The procedure for these sessions will follow the same timeline as the second, with the exclusion of 
informed consent, questionnairesMotor threshold may be performed on Stimulation 1 day if it was not 
done during the Baseline session.  
• 
Before practice and performance of the cognitive control task, the TMS coil will be position over the 
targeted region. During performance of the task, stimulation will be delivered on every trial.At the end 
of the session, participants will receive $40, and $60 in compensation for sessions 3, and 4, respectively.  
 
6 
STUDY PROCEDURES/EVALUATIONS 
6.1 
SELF-REPORT MEASURES 
Study coordinator will use a standard questionnaire to screen TMS candidates. The following questions include the 
standard contraindications for TMS research. 
 
1. Do you have epilepsy or have you ever had a convulsion or a seizure? 
2. Have you ever had a fainting spell or syncope? If yes, please describe in which occasion(s) 
3. Have you ever had severe (i.e., followed by loss of consciousness) head trauma? 
4. Do you have any hearing problems or ringing in your ears? 
5. Are you pregnant or is there any chance that you might be? 
6. Do you have metal in the brain/skull (except titanium)? (e.g. splint, fragments, clips, etc.) 
7. Do you have cochlear implants? 
8. Do you have an implanted neurostimulator? (e.g., DBS, epidural/subdural, VNS) 
9. Do you have a cardiac pacemaker or intracardiac lines or metal in your body? 
10. Do you have a medication infusion device? 
11. Are you taking any medications? (Please list) 
12. Did you ever have a surgical procedure to your spinal cord? 
13. Do you have spinal or ventricular derivations? 
14. Did you ever undergo TMS in the past? 
Affirmative answers to one or more of questions 1–13 do not represent absolute contraindications to 
TMS, but the risk/benefit ratio should be carefully balanced by study coordinator. 
 
In addition, several self-report measures will be collected throughout this study. These measures are listed below 
and can be found in the attached documents. 
 
A. THE STATE-TRAIT ANXIETY INVENTORY (STAI) is a 20-item self-report assessment that assesses either temporary 
or chronic anxiety. For the purposes of this study, the state version will be used to measure anxiety as a 
result of the stress condition. The STAI is commonly used to assess both types of anxiety, and has 
applications in both clinical and research settings (Spielberger et al. 1983). 
B. THE BEHAVIORAL INHIBITION AND BEHAVIORAL APPROACH SYSTEM SCALES (BIS/BAS) are a set of 24 questions used to 
assess an individual’s sensitivity to approach vs. inhibition in motivating behavior. This scale is commonly 
used to measure behavior and has been demonstrated to be reliable (Carver and White 1994). 

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C. THE POSITIVE AND NEGATIVE AFFECT SCHEDULE (PANAS) is a 20-item self-report assessment using a 5-level Likert 
scale to assess the positive and negative affect of an individual over the past week. This scale has been 
shown to be a reliable measure of both positive and negative affect with little participantivity to 
demographic variables (Watson et al. 1988). 
D. THE EDINBURGH HANDEDNESS INVENTORY is a 20-item scale to assess the hand dominance of a person in 
everyday activities (Oldfield 1971). 
E. THE BIG FIVE PERSONALITY QUESTIONNAIRE is a 50-item self-report assessment using a 5-level Likert scale to 
assess five dimensions of personality (John and Srivastava 1999). 
F. 
REPETITIVE THINKING QUESTIONNAIRE is a 31-item self-report assessment using a 5-level Likert scale to assess 
levels of rumination (McEvoy et al. 2010). 
G. MONTGOMERY-ASBERG DEPRESSION RATING SCALE SELF-REPORT is a 9-item self-report assessment using a 7-level 
Likert scale to assess level of depression (Montgomery and Asberg 1979) 
H. MAGICAL IDEATION SCALE is a 30-item self-report assessment using a 5-level Likert scale to assess traits of 
schizotypy (Eckblad and Chapman 1983). 
 
6.2 
SPECIAL ASSAYS OR PROCEDURES 
Each participant will receive stimulation on all four sessions, separated by a week. The baseline session will involve 
single pulse TMS for calculating the motor threshold. The other three sessions will involve train of rhythmic TMS 
during performance of a cognitive control task. For stimulation day, the rhythmic TMS trains are delivered on every 
trial of the task (there are 600 trials per session). Each train of TMS consists of 5 pulses. There will be a total of 
2400 pulses delivered per session. Each TMS train will be separated by a minimum of 5 seconds. There are three 
possible trains: alpha frequency with a 100 milliseconds inter-pulse interval, theta frequency with a 200 
milliseconds inter-pulse interval, and arrhythmic with a variable inter-pulse interval (not to exceed a minimum of 
20 milliseconds inter-pulse interval). The inter-pulse interval, inter-train interval, number of trains, and TMS 
intensity are all under the safety guidelines set forth by Rossi et al. 2009 and is typical for experiments that deliver 
online TMS (Hanslmayr et al. 2014; Albouy et al. 2017). 
 
6.3 
SAFETY MEASURES 
We will be monitoring the safety of our participants throughout the study with the following measures. These 
measures are listed below and can be found in the attached documents. 
A. A stimulation adverse effects questionnaire used in previous studies (IRB #14-1622, #14-3285, and #14-
0600) will be administered at the end of each stimulation session. This questionnaire will be used as a 
safety measure and to collect data on participant experience. Please see 9.1 Safety Parameters for more 
information.  
6.4 
LABORATORY EVALUATIONS 
6.4.1 
SCREENING LABORATORY EVALUATIONS 
A urine pregnancy test will be performed for all female participants. 
INSTRUCTIONS FOR SPECIMEN PREPARATION, HANDLING, AND STORAGE. For this evaluation, an FDA approved 
commercial home-based kit will be used (HCG Urine Pregnancy Test Strip). Results are available after only 
a few minutes. Once the results are clear, the researcher will make a note and the sample will be 
disposed. All samples will be handled using single-use disposable medical gloves. 
 

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6.5  
COGNITIVE TASKS 
6.5.1 COGNITIVE CONTROL TASK 
The cognitive control task used in this paradigm consists of the presentation of colored squares on the left 
and right side of a computer screen. Stimuli are presented briefly, followed by a brief delay.  After this, an 
arrow pointing to the left, right, or both left and right will briefly appear on the screen.  This informs the 
participants which set of squares (left or right) they must remember and will be tested on. The cue is 
followed by another delay, and finally a new set of squares is presented.  Participants press a button to 
indicate whether the squares are the same or different from the ones they originally saw. Between 
presentation of stimuli there is a small centrally presented fixation cross upon which participant maintain 
their gaze. Participants will complete 10 blocks of the task, each composed of 20-30 trials each. 
Participants will have a self-paced break between each of the blocks.  
 
 
 
 
 
 
 

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7 
STUDY INVESTIGATIONAL PRODUCT 
 
We will use the MagPro X100 system (MagVenture Inc., Alpharetta, Georgia, USA) for transcranial magnetic 
stimulation. The MagPro X100 is 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.  
 
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. 
 
7.1 
SAFETY FEATURES 
 
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.  
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." 
 
7.2 
PREPARATION AND ADMINISTRATION OF STUDY INVESTIGATIONAL PRODUCT 
After participants have completed the questionnaire, they will be comfortably seated. The study coordinator 
and/or the research assistant will be thoroughly trained and have trainings documented on the transcranial 
magnetic stimulation device and will be present during all stimulation sessions. To monitor side effects of 
stimulation, a questionnaire will be administered after each stimulation.  
7.3 
ASSESSMENT OF PARTICIPANT COMPLIANCE WITH STUDY INVESTIGATIONAL PRODUCT 
Compliance for this study is determined as completion of all four sessions. 

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8 
POTENTIAL RISKS AND BENEFITS 
8.1 
BENEFITS TO PARTICIPANTS AND SOCIETY 
This research has the potential to provide critical data for understanding the neural basis of cognitive control. The 
current study has no immediate benefit to the healthy participants that participate. However, the results of this 
study may be used to develop novel tools for the treatment of psychiatric mood-disorders that involve a detriment 
in cognitive control. Furthermore, simultaneous neuro-imaging with brain stimulation will provide increased 
understanding of the neural mechanisms that underlie the efficacy of brain stimulation. 
8.2 
POTENTIAL RISKS 
8.2.1 
PSYCHOLOGICAL 
Risk of Embarrassment: Self-report questionnaire contains questions regarding personal information. This 
risk is necessary in order to assess symptomology and associated psychopathology. Participants will be 
assured upon intake that only study personnel will see any answers. 
Risk of Confidentiality Breach. To avoid breaches in confidentiality, study documents that contain 
personal information, including the informed consent, and the document that links study ID numbers to 
personal identifying information are kept in locked filing cabinets in locked rooms, separate from any 
source documents containing participating dummy identifiers. 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 these data. All study staff participate in annual human participating training that includes education 
about responsibilities to minimize the 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 and some 
people might not agree with the principle of participating in research or of changing natural brain activity.  
8.2.1 
PHYSICAL 
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 (rated by the participant as stronger than “moderate”) or the participant is experiencing 
severe discomfort, the stimulation will be immediately stopped. 
 
8.3 
REFERRALS FOR MEDICAL FOLLOW-UP OR PSYCHOLOGICAL COUNSELING 
There is a purely 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. If abnormalities or a seizure is witnessed during the course of the study, a referral will 
be made to the UNC Department of Neurology for follow-up. In the theoretical event that a seizure is witnessed 
that involves the loss of consciousness, the participants will be told not to operate a motor vehicle until cleared by 
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To ensure participant comfort, a study coordinator or research assistant will periodically check in with the 
participant about any side-effects he/she may be experiencing during each stimulation session. Following the 
conclusion of the stimulation session, 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 
(1=Absent, 2=Mild, 3=Moderate, 4=Severe). If the participant reports side-effects of Moderate to Severe intensity, 
a study coordinator or research assistant will discuss the side-effects experienced and note this response. The 
medical monitor will be contacted based on the reported intensity on the Adverse Events Questionnaire and the 
participant’s verbal confirmation of intensity.  
9.3.1 
PREGNANCY FOLLOW-UP 
Pregnancy tests will be administered on the first session of the experiment to all female participants. 
After testing negative, the experiment can continue. On subsequent sessions, female participants will be 
asked if it is possible that they may have become pregnant since the previous session. If the participant 
responds yes, or is unsure, then a pregnancy test will be administered. After testing negative at a given 
session (meeting inclusion criteria), if a participant reports becoming pregnant during the course of the 
study, she will be withdrawn from further participation. There are no plans to follow participants who 
become pregnant while enrolled in the study. 
 
 

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9 
DATA AND SAFETY MONITORING 
9.1 
FROHLICH LAB MONITORING PLAN 
The purpose of this monitoring plan is to present the Frohlich Lab’s approach to monitoring clinical trials. The plan 
facilitates compliance with good clinical practice (GCP): 
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. 
The latest version of the approved IRB application for this clinical trial will be followed at all times. This 
responsibility falls into the hands of the study coordinator and research assistants. 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. The most up-to-date IRB application will be on file in the Clinical Trials office in 
Room 233 of the Medical School Wing C. Deviations will be sent to the IRB every 4-6 weeks (if necessary). 
Periodically, study staff should review 3 randomly selected informed consent forms to ensure that (1) these forms 
have been filled out appropriately, and (2) the consent form process was followed and properly documented. 
Should any consent form be in violation, the research team will perform and document a complete review of all 
consent forms.  
AE and SAE are clearly defined in this document. Documents of AE and SAE can be found in the study binder on file 
in the Clinical Trials office in Room 233 of the Medical School Wing C. It is the responsibility of the study 
coordinator to report all events to the PI in a timely manner. All AEs and SAEs will be discussed with the PI. For our 
practices, we have adapted the decision tree provided by the UNC-CH IRB to assist with reporting of such events. 
 
9.2 
SAFETY OVERSIGHT  
Safety oversight will be under the direction of the PI, who will review AEs in real time and make decisions 
regarding a participant’s continuation of the clinical trial.  
 
9.3 
EARLY WITHDRAWAL OF PARTICIPANTS 
9.3.1 
REASONS FOR WITHDRAWAL 
A study participant will be discontinued from further participation if: 
• 
The participant meets any exclusion criteria (either newly developed or not previously 
recognized). 
• 
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. 
Participants are free to withdraw from participation in the study at any time upon request. 
9.3.2 
DATA COLLECTION FOR WITHDRAWN PARTICIPANTS 
We will collect safety data on any participant discontinued because of an AE or SAE. In any case, every 
effort will be made to undertake protocol-specific follow-up procedures. If voluntary withdrawal occurs, 
the participant will be asked to continue scheduled evaluations and complete an end-of-study evaluation. 

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If an AE has been reported, researchers will help the participant seek the medical care they need and a 
follow-up will be performed by the PI In the case of an early withdrawal, the researcher will make a note 
to file indicating this. 
9.4 
TERMINATION OF STUDY 
If a seizure occurs at the time of a study visit, a temporary hold will be placed over the study and further 
investigation will ensue. This could lead to stopping the study prematurely or continuing on with further safety 
measures in place. If two seizures are witnessed during the study visits, the entire study will be stopped 
prematurely. These individuals would be referred for further medical attention. It is very unlikely that a seizure will 
occur. 
The study will also be stopped (at least temporarily) if studies provide evidence that transcranial current/magnetic 
stimulation caused brain damage or other harmful effects on participants, either short-term or long-term. 
Examples of findings that might trigger a safety review are the number of SAEs overall, the number of occurrences 
of a particular type of SAE, severe AEs/reactions, or increased frequency of events. 
The IRB will also be informed promptly and provided the reason(s) for the termination of suspension of by the 
investigator, as specified by the applicable regulatory requirement(s). 
 
 

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10 
SAFETY & REPORTING 
It is important to assess safety over the course of this study. This section describes in detail how safety is assessed, 
reporting of Adverse Events, Serious Adverse Events, and Unanticipated Problems. This section is a reference for 
internal use. 
10.1 
SAFETY PARAMETERS 
STIMULATION SIDE EFFECTS. A stimulation adverse effects questionnaire used in previous studies will be administered 
at the end of each stimulation. This questionnaire will be used as a safety measure and to collect data on 
participant experience. The adverse effects questionnaire asks participants to respond on a 4 point Likert scale on 
the severity of symptoms experienced during the stimulation session (1 = absent, 2 = mild, 3 = moderate, 4 = 
severe). The side effects listed are headache, neck pain, scalp pain, tingling, itching, ringing/buzzing noise, burning 
sensation, local redness, sleepiness, trouble concentrating, improved mood, worsening of mood, dizziness, 
flickering lights, and other (specify). Participants are also asked to rate on a 5 point Likert scale how related they 
believe the side effects to be to stimulation (1 = no relation, 2 = remote, 3 = possible, 4 = probable, 5 = definite). 
10.2 
METHODS AND TIMING FOR ASSESSING, RECORDING, AND ANALYZING SAFETY 
PARAMETERS 
10.2.1 ADVERSE EVENTS 
All AEs, including local and systemic reactions not meeting the criteria for “serious adverse events”, will 
be captured on the appropriate CRF. In addition, the AE Report Form will be completed by the study 
coordinator (Appendix B). The AE Report Form includes the following: 
• 
What is known about the therapy 
• 
What is known about previous reported side effects 
• 
If the AE occurred in temporal relation to the therapy 
• 
Whether or not the AE improves or disappears when treatment is stopped 
• 
Whether the AE is worsening of baseline symptoms 
• 
Whether the AE is related to concurrent medical condition or medication use 
Once complete, this form will be given to the PI, who will review, comment, and sign this form. 
Completed forms will be placed in the participant’s folder. 
In addition, the study coordinator will document any AE occurrence on the AE log (Appendix D), which 
includes information such as the date of the AE, severity, relationship to the treatment (assessed by the 
PI*), actions taken, and outcome(s). The log will be reviewed and initialed by the PI 72 hours after being 
completed. All AEs will be followed to adequate resolution and will be graded for severity and relationship 
to study. Any medical condition noted at the stimulation session will be considered at baseline and not 
reported as an AE. 
*Relationship to Study Products: The PI will determine whether an AE is associated with the study 
treatment. The event will be labeled associated if the event is temporally related to the administration of 
a therapy and no other factors can explain the event. The event will be labeled as not associated if the 
event is temporally independent of the study treatment and can be explained by external factors, such as 
major life events. 
10.2.1 SERIOUS ADVERSE EVENTS 
Serious Adverse Event (SAE): An SAE, as defined by the NIH, consists of adverse events that result in 
death, require either inpatient hospitalization or the prolongation of hospitalization, are life-threatening, 
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important medical events, based upon appropriate medical judgment, may also be considered Serious 
Adverse Events if a trial participant’s health is at risk and intervention is required to prevent an outcome 
mentioned. 
All SAEs will be recorded on the Serious Adverse Events Form (Appendix B), documented in the UE/SAE 
log and reported to the IRB.  The SAE Form will be completed by the study coordinator, and includes 
information relating to the onset and nature of the SAE, relationship to the study treatment, seriousness 
of the SAE, treatment required as a response to the SAE, and outcome.  This form will be filed in the 
participant’s folder at the resolution of the event.  The study coordinator will complete the UE/SAE log 
(Appendix D) which includes information such as the date of the event, time at which the study team was 
informed of the event, details, when the IRB was notified, and the date that the SAE form was completed. 
10.2.2 UNANTICIPATED PROBLEMS 
Unexpected Events (UE) will be recorded on the UE/SAE log (Appendix D) and will include information 
such as the date of the event, when the study team was informed of this event, details of the event, when 
the IRB was notified, and whether the SAE form was completed.  The IRB will be notified of each UE that 
may occur during the study. 
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 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 (in the guidance document, 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. 
If an 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.      
 
 
 
10.3 
REPORTING PROCEDURES 
We will be adopting the following table for reporting procedures: 
What Event is Reported 
When is Event Reported 
By Whom the Event is 
Reported 
To Whom the Event is 
Reported 
Fatal or life-threatening 
unexpected, suspected 
serious adverse reactions 
Within 24 hours of initial 
receipt of information 
Investigator 
Local/internal IRBs 

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Non-fatal, non-life 
threatening unexpected, 
suspected serious 
adverse reactions 
Within 48 hours of initial 
receipt of information 
Study Coordinator 
Local/internal 
IRBs/Institutional 
Officials, DSMB 
Unanticipated adverse 
device effects 
Within 10 working days 
of investigator first 
learning of effect 
Investigator 
Local/internal IRBs 
Unanticipated problem 
that is not an SAE 
Within 7 days of the 
investigator becoming 
aware of the problem 
Investigator 
Local/internal 
IRBs/Institutional officials 
All Unanticipated 
Problems 
Within 30 days of the 
IRB’s receipt of the report 
of the UP from the 
investigator 
IRB 
OHRP 
Investigator 
External IRBs 
11.3.1 REPORTING OF PREGNANCY 
Pregnancy tests will be administered on the first session of the experiment to all women of child-bearing 
potential (CBP). After testing negative, the experiment can continue. On subsequent sessions, female 
participants will be asked if it is possible that they may have become pregnant since the previous session. 
If the participant responds yes, or is unsure, then a pregnancy test will be administered. Within the study 
target population (ages 18-35), menstruating females, regardless of age are considered “CBP”. Women 
who have had a hysterectomy or a bilateral oophorectomy are not considered of “CBP”. There are no 
studies that suggest TMS would interfere with pregnancy. However, should a participant become 
pregnant during the study, her participation will be immediately terminated. 
 
10.4 
TYPES AND DURATION OF FOLLOW-UP OF PARTICIPANTS AFTER ADVERSE EVENTS 
Medical monitors and PI will follow up with participants within one week of an AE. 
 
 
 
 

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11 
STATISTICAL PLAN 
The statistician for this study is Dr. Justin Riddle.  
11.1 
STATISTICAL ANALYSIS STRATEGIES 
To control for non-specific effects of rhythmic TMS, we will use an active control: arrhythmic TMS (randomized 
inter-pulse-interval) that is matched to the target stimulation in number of pulses and temporal duration. All 
analyses will be run on the difference from condition-matched arrhythmic TMS. The key analysis is a two-way 
repeated-measures ANOVA with factors TMS frequency (theta vs alpha) and location (inferior-IPS vs anterior-
MFG). Post-hoc t-tests will be run on a significant main effect of TMS frequency, TMS site, or interaction. We will 
use Tukey’s adjusted significance for post-hoc testing to correct for multiple comparisons.  
Primary outcome: working memory capacity. Two-way repeated-measures ANOVA run on the difference from 
arrhythmic TMS with factors (TMS site and TMS frequency). The direction of the retro-cue is held consistent for 
each site: for TMS to frontal cortex (anterior-MFG) the retro-cue to the right is used, and for TMS to parietal cortex 
(inferior-IPS) the retro-cue to the left is used. We hypothesize that theta frequency rhythmic TMS will improve 
behavioral performance when applied to anterior-MFG; i.e. a main effect of TMS frequency and/or an interaction 
between TMS frequency and cue. We hypothesize that alpha frequency rhythmic TMS will improve behavioral 
performance for retro-cue trials when applied to inferior-IPS; i.e. an interaction between TMS frequency and cue.  
Primary outcome: Spectral power. We collected EEG recording during the delivery of rhythmic TMS. We 
hypothesize, based on previous studies with identical rhythmic TMS trains, that rhythmic TMS will entrain neural 
oscillations in the targeted frequency. We will quantify entrainment from rhythmic TMS by analyzing the spectral 
decomposition of the EEG signal during TMS and immediately after TMS. We will run a six-cycle Morlet wavelet 
convolution with the EEG signal to estimate spectral density (microvolts per hertz). We hypothesize that the 
amplitude of theta activity will be increased following theta rhythmic TMS relative to theta activity following 
arrhythmic TMS. Similarly, alpha amplitude will be increased following alpha rhythmic TMS relative to alpha 
amplitude following arrhythmic TMS. The direction of the retro-cue is held consistent for each site: for TMS to 
frontal cortex (anterior-MFG) the retro-cue to the right is used, and for TMS to parietal cortex (inferior-IPS) the 
retro-cue to the left is used. We hypothesize an interaction between TMS frequency and cue. 
Primary outcome: response time. Two-way repeated-measures ANOVA run on the difference from arrhythmic TMS 
with factors (TMS site and TMS frequency). The direction of the retro-cue is held consistent for each site: for TMS 
to frontal cortex (anterior-MFG) the retro-cue to the right is used, and for TMS to parietal cortex (inferior-IPS) the 
retro-cue to the left is used. We hypothesize that theta frequency rhythmic TMS will improve behavioral 
performance (decreased response time) when applied to anterior-MFG; i.e. a main effect of TMS frequency and/or 
an interaction between TMS frequency and cue. We hypothesize that alpha frequency rhythmic TMS will improve 
behavioral performance (decreased response time) for retro-cue trials when applied to inferior-IPS; i.e. an 

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interaction between TMS frequency and cue.  
11.2 
SAMPLE SIZE DETERMINATION 
Based on a previous study with the current behavioral paradigm and similar TMS manipulation, the effect size of 
the interaction between TMS site and TMS frequency on WM capacity was 0.532 and used 21 participants. A 
power analysis of this effect suggests that to reach 95% statistical power we would need to recruit 48 participants. 
Therefore, we will run our final analysis on 48 participants. Previous studies using a similar methodology of 
concurrent rhythmic TMS and EEG to look for changes in oscillatory power of the frequency of rhythmic TMS have 
used 10 participants for alpha frequency TMS (Thut et al., 2011) and 17 participants for theta rhythmic TMS 
(Albouy et al. 2017). Here, we propose to collect 48 participants. Therefore, our statistical power exceeds that of 
previous studies published in high-impact journals using a nearly identical methodology. Furthermore, we utilize a 
repeated-measures inter-mixed design in order to maximize our ability to control for confounding variables and 
increase statistical power. Based on a previous study by Thut et al., 2011 that found an increase in alpha oscillatory 
power from alpha rhythmic TMS relative to arrhythmic TMS with an effect size of 0.83 and 10 participants, we 
would need 21 participants to reach 95% statistical power for this comparison. Based on a previous study by 
Albouy et al., 2017 that found an increase in theta oscillatory power from theta rhythmic TMS relative to 
arrhythmic TMS with an effect size of 0.56 and 17 participants, we would need 44 participants to reach 95% 
statistical power for this comparison. Therefore, we estimate that based on these previously reported effect sizes 
for the impact of rhythmic TMS on behavior and oscillatory power measured by EEG in similar studies and our 
proposed sample size of 48 participants, we conclude that the proposed study has sufficient statistical power to 
answer the posed hypotheses.  
 
11.3 
DATA MANAGEMENT 
Data will be stored in a password-protected cloud-based data system that does not contain any participant 
information. Individual records are referred to by dummy identifiers that cannot be traced back to the study 
participants except with the master code list that is stored separately in a secured location. 
 
Information about study participants will be kept confidential and managed according to the requirements of the 
Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those regulations require a signed participant 
authorization informing the participant of the following:  
 
-What protected health information (PHI) will be collected from the participants in this study  
 
-Who will have access to that information and why  
 
-Who will use or disclose that information  
-The rights of a research participant to revoke their authorization for use of their PHI. 
In the event that a participant revokes authorization to collect or use PHI, the investigator, by regulation, retains 
the ability to use all information collected prior to the revocation of participant authorization. For participants that 

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have revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect at least 
vital status (i.e., that the participant is alive) at the end of their scheduled study period.  
The responsibilities designated to each member of the research team are documented on the Delegation of 
Authority Form. The study coordinator and research assistants will be responsible for the informed consent 
process, review for eligibility, questionnaire administration, data entry, device administration, EEG administration, 
and CRF entries. The study coordinator 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.  
All data (including AEs, concomitant medications, and expected adverse reactions data) will be entered into a data 
capture system provided by 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.  
All assessments completed by the participant at home will be completed via REDCap as well, ensuring participant 
security and confidentiality.  
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.  
According to the University of North Carolina at Chapel Hill’s Archives and Record Management Services schedule 
for General Records Retention and Disposition Schedule 6.10, records will be kept for 5 years after the completion 
of the study or grant end date, whichever is later.  
  
 
 
 

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12 
DATA HANDLING AND RECORD KEEPING 
The study coordinator and research assistants are responsible for the accuracy, completeness, legibility, and 
timeliness of the data reported. 
12.1 
PHI AND HIPAA 
Information about study participants will be kept confidential and managed according to the requirements of the 
Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those regulations require a signed participant 
authorization informing the participant of the following: 
• 
What protected health information (PHI) will be collected from the participants in this study 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 
• 
The rights of a research participant to revoke their authorization for use of their PHI. 
In the event that a participant revokes authorization to collect or use PHI, the investigator, by regulation, retains 
the ability to use all information collected prior to the revocation of participant authorization. For participants that 
have revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect at least 
vital status (i.e., that the participant is alive) at the end of their scheduled study period. 
12.2 
CONFIDENTIALITY 
12.2.1 ACCESS TO SOURCE DOCUMENTS 
The research coordinator, research assistants, and PI will have access to all of the source documents 
collected over the course of the study. The medical monitor will have access to files upon request, as they 
will need access to the locked filing cabinets and rooms in which these documents are located.  
Data will stay on a password-protected computer. Subsequently, a copy will be processed on a separate, 
password-protected desktop computer in the Frohlich Lab (Neuroscience Research Building 4129). 
12.2.3 OTHER 
Please note that there is no significant risk of deductive disclosure in this study. In addition, none of the 
groupings or subgroupings used in analysis will be small enough to allow individuals to be identified. 
 
12.3 
SOURCE DOCUMENTS 
Source data is all information, original records of clinical findings, observations, or other activities in a study 
necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents. 
Source data include: 
PARTNERS HUMAN RESEARCH COMMITTEE (IRB). 
• 
All IRB correspondences are documented 
• 
The study staff is IRB approved prior to performing any study procedures 
• 
Adverse events and deviations are reported to the IRB per current guidelines and stored appropriately 
• 
All versions of the IRB protocols and informed consent forms are on file 
INFORMED CONSENT. 
• 
Ensure that participant identification is not recorded on the ICF (i.e., no participant ID) 
• 
There is documentation that the participant is given a copy of the consent form 
• 
The participant and study representative signed and dated the consent form for him/herself 
• 
The participant initialed and dated all appropriate pages on the informed consent form 

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• 
Note to file (Appendix F) made for any informed consent deviations 
• 
Ensure a valid (current version date) copy of the consent form was used 
PROTOCOL DEVIATIONS. 
• 
Any and all protocol deviations (exceptions and violations) are documented in the participant folder and 
reported to the IRB as required 
OTHER SOURCE DOCUMENTS. 
• 
Each participant folder will contain a checklist to ensure that all source documents are administered and 
collected properly. The checklist will be dated by the researcher for each time an assessment is 
administered 
• 
Review participant folders to ensure the accuracy, completeness, and legibility of the data. 
• 
Any correction made to the source documents is dated, initialed, and explained. The original entry should 
not be obscured. 
• 
The protocol-specific source documents are on file. 
• 
Source documents are completed in ink. 
• 
Note to files (Appendix F) are made for missing or incomplete data and to explain any discrepancies or 
additional comments. 
12.4 
DATA MANAGEMENT RESPONSIBILITIES 
The responsibilities designated to each member of the research team are documented on the Delegation of 
Authority Form. The study coordinator and research assistants will be responsible for the informed consent 
process, review for eligibility, questionnaire administration, data entry, device administration, EEG administration, 
and CRF entries. The study coordinator 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.  
12.5 
DATA CAPTURE METHODS (REDCAP) 
All data (including AEs, concomitant medications, and expected adverse reactions data) will be entered into a data 
capture system provided by 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. 
All assessments completed by the participant at home will be completed via REDCap as well, ensuring participant 
security and confidentiality.  
12.6 
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. 
12.7 
RECORD RETENTION 
According to the University of North Carolina at Chapel Hill’s Archives and Record Management Services schedule 
for General Records Retention and Disposition Schedule 6.10, records will be kept for 5 years after the completion 
of the study or grant end date, whichever is later. 
 
 

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13 
ETHICAL CONSIDERATIONS 
13.1 
ETHICAL STANDARD 
The investigator will ensure that this study is conducted in full conformity with the principles set forth in the 
Belmont Report: Ethical Principles and Guidelines for the Protection of Human Participants of Research, as drafted 
by the US National Commission for the Protection of Human Participants of Biomedical and Behavioral Research 
(April 18, 1979) and codified in 45 CFR Part 46 and/or the ICH E6; 62 Federal Regulations 25691 (1997). 
13.2 
INSTITUTIONAL REVIEW BOARD (IRB) 
The Office of Human Research Ethics is responsible for ethical and regulatory oversight of research at UNC-Chapel 
Hill that involves human participants. The OHRE administers, supports, and guides the work of the Institutional 
Review Boards and all related activities. Any research involving human participants proposed by faculty, staff, or 
students must be reviewed and approved by an IRB before research may begin, and before related grants may be 
funded. OHRE and the IRBs are critical components of the coordinated Human Research Protection Program, which 
serves to protect the rights and welfare of human participants. All components of this program must work 
together to ensure institutional compliance with ethical principles and regulatory requirements. The following is a 
mission statement for the coordinated Human Research Protection Program: 
The University of North Carolina at Chapel Hill is committed to expanding and disseminating knowledge for the 
benefit of the people of North Carolina and the world. An important part of that commitment to knowledge is 
research of the highest quality on all aspects of the health and behavior of people, and such research is only 
possible through the participation of humans as research participants. Human participants are partners in research 
and a precious resource to the university. At UNC-Chapel Hill, human participant research is a privilege, but not a 
right. Consistent with that philosophy, it is the mission of the UNC-Chapel Hill Human Research Protection Program 
to ensure that: 
a. The rights and welfare of human participants are paramount in the research process; 
b. The highest standards of ethical conduct are employed in all research involving human participants; 
c. 
Research investigators are properly trained in the ethical and regulatory aspects of research with human 
participants; 
d. Research investigators deal honestly and fairly with human participants, informing them fully of 
procedures to be followed, and the risks and benefits of participating in research; and 
e. Research using human participants at UNC-CH conforms to applicable local, state, and federal laws and 
regulations and the policies of the university. 
13.3 
INFORMED CONSENT PROCESS 
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 or assessments used in this study. All consent 
forms will be IRB-approved and updated with any new information as modifications are made throughout the 
study. 
Together, the researcher and potential participants will review the study in its entirety by reviewing the consent 
form together in a private location. At several intervals during the consent review, the researcher will ask the 
participant 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 must sign the informed consent document prior to any procedures taking place.  If needed, the 
participants will have the opportunity to discuss the study with their surrogates or think about it prior to agreeing 

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to participate.  Participants may withdraw consent at any time throughout the course of the trial.  A copy of the 
informed consent document will be given to the participants for their records.  The rights and welfare of the 
participants 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. 
13.4 
EXCLUSION OF WOMEN, MINORITIES, AND CHILDREN (SPECIAL POPULATIONS) 
Individuals that do not speak English are excluded because the ability to accurately and complete communicate 
study information, answer questions about the study, and obtain consent is necessary. Pregnant participants will 
be excluded despite the fact that theoretical risk to mother or fetus is exceedingly small, since no safety data for 
pregnancy is known to exist for transcranial magnetic/electrical stimulation studies.  
13.5 
PARTICIPANT CONFIDENTIALITY 
Participant confidentiality 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. 
All data will only be referenced by dummy identifier code. Data will be stored on a password protected computer. 
A key connecting names and 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. See 10 Data Handling and Record 
Keeping for more information on source documentation storage and security. 
13.6 
STUDY DISCONTINUATION 
In the event that the study is discontinued, participants who have completed or who are still enrolled in the study 
will be notified.  Any new information gained during the course of the study that might affect participant’s 
willingness to continue will be communicated within 2 days of the PI learning this information. 
 
14 
PUBLICATION POLICY 
There are no restrictions on publications since this is an investigator-initiated study funded by a grant agency that 
has no influence on the publications resulting from this study.  
 
 

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15 
LITERATURE REFERENCES 
 
Albouy P, Weiss A, Baillet S, Zatorre RJ. Selective Entrainment of Theta Oscillations in the Dorsal Stream Causally 
Enhances Auditory Working Memory Performance. Neuron. Elsevier Inc; 2017 Mar 21;94(1):1–14.  
Alekseichuk I, Turi Z, de Lara GA, Antal A, Paulus W. Spatial Working Memory in Humans Depends on Theta and 
High Gamma Synchronization in the Prefrontal Cortex. Current Biology. Elsevier Ltd; 2016 May 23;26(12):1–
10.  
Antzoulatos EG, Miller EK. Increases in Functional Connectivity between Prefrontal Cortex and Striatum during 
Category Learning. Neuron. Elsevier Inc; 2014 Jul 2;83(1):216–25.  
Badre D. Cognitive control, hierarchy, and the rostro–caudal organization of the frontal lobes. Trends in Cognitive 
Sciences. 2008 May;12(5):193–200.  
Badre D, D'Esposito M. Functional Magnetic Resonance Imaging Evidence for a Hierarchical Organization of the 
Prefrontal Cortex. Journal of Cognitive Neuroscience. 2007 Nov 12;:1–27.  
Badre D, Hoffman J, Cooney JW, D'Esposito M. Hierarchical cognitive control deficits following damage to the 
human frontal lobe. Nat Neurosci. 2009 Mar 1;12(4):515–22.  
Badre D, Nee DE. Frontal Cortex and the Hierarchical Control of Behavior. Trends in Cognitive Sciences. Elsevier 
Ltd; 2017 Dec 8;22(2):1–19.  
Carver C, White T. Behavioral inhibition, behavioral activation, and affective responses to impending reward and 
punishment: the BIS/BAS Scales. Journal of Personality and Social Psychology. 1994;67:319–33.  
Eckblad M, Chapman L. Magical Ideation as an Indicator of Schizotypy. Journal of Consulting and Clinicial 
Psychology. 1983;51(2):215–25.  
Fries P. Rhythms for Cognition: Communication through Coherence. Neuron. Elsevier Inc; 2015 Oct 7;88(1):220–35.  
Hanslmayr S, Matuschek J, Fellner M-C. Entrainment of Prefrontal Beta Oscillations Induces an Endogenous Echo 
and Impairs Memory Formation. Current Biology. Elsevier Ltd; 2014 Apr 14;24(8):904–9.  
John O, Srivastava S. The big five trait taxonomy: history, measurement, and theoretical perspectives. Handbook of 
personality Theory and research. 1999. pp. 102–38.  
McEvoy PM, Mahoney AEJ, Moulds ML. Are worry, rumination, and post-event processing one and the same?: 
Development of the repetitive thinking questionnaire. Journal of Anxiety Disorders. Elsevier Ltd; 2010 Jun 
1;24(5):509–19.  
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. The British Journal of 
Psychiatry. 1979 Apr 1;134(4):382–9.  
Oldfield R. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia. 1971;9:97–
113.  
Reinhart R. Disruption and rescue of interareal theta phase coupling and adaptive behavior. Proceedings of the 
National Academy of Sciences. 2017 Oct 24;114(43):11542–7.  

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Romei V, Thut G, Silvanto J. Information-Based Approaches of Noninvasive Transcranial Brain Stimulation. Trends 
in Neurosciences. Elsevier Ltd; 2016 Nov 1;39(11):782–95.  
Rossi S, Hallett M, Rossini PM, Pascual-Leone A, Group TSOTC. Safety, ethical considerations, and application 
guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clinical 
Neurophysiology. International Federation of Clinical Neurophysiology; 2009 Dec 1;120(12):2008–39.  
Spielberger C, Gorsuch R, Lushene R, Vagg P, Jacobs G. Manual for the State-Trait Anxiety Inventory. Palo Alto, CA: 
Consulting Psychologists Press; 1983.  
Thut G, Veniero D, Romei V, Miniussi C, Schyns P, Gross J. Rhythmic TMS Causes Local Entrainment of Natural 
Oscillatory Signatures. Current Biology. Elsevier Ltd; 2011 Jul 26;21(14):1176–85.  
Voytek B, Kayser AS, Badre D, Fegen D, Chang EF, Crone NE, et al. Oscillatory dynamics coordinating human frontal 
networks in support of goal maintenance. Nat Neurosci. 2015 Jul 27;18(9):1318–24.  
Wang X-J. Neurophysiological and Computational Principles of Cortical Rhythms in Cognition. Physiological 
Reviews. 4 ed. 2010 Jul;90(3):1195–268.  
Watson D, Clark L, Tellegen A. Development and validation of brief measures of positive and negative affect: the 
PANAS scales. Journal of Personality and Social Psychology. 1988;54(6):1063–70.  
Wolinski N, Cooper NR, Sauseng P, Romei V. The speed of parietal theta frequency drives visuospatial working 
memory capacity. Jensen O, editor. PLoS Biol. 2018 Mar 14;16(3):e2005348–17.  
Wutz A, Loonis R, Roy JE, Donoghue JA, Miller EK. Different Levels of Category Abstraction by Different Dynamics in 
Different Prefrontal Areas. Neuron. Elsevier Inc; 2018 Jan 23;97(3):1–27.  
 
 
 

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APPENDIX A: SCHEDULE OF EVENTS 
 
Procedures 
Telephone 
Screening 
Interview 
Session 1: 
Screening 
Session 2: 
Baseline 
Sessions 3 & 4: 
Stimulation 
Provide Verbal Consent 
x 
 
 
 
Signed Consent Form 
 
x 
 
 
Assessment of Eligibility 
Criteria 
x 
x 
 
 
Urine Pregnancy Test 
 
x 
 
 
Baseline Self-Report 
Assessments  
 
 
x 
 
Baseline EEG (Resting 
state) 
 
 
x 
x 
Cognitive control task 
 
x 
x 
x 
Task EEG (during 
cognitive control task) 
 
 
x 
x 
Stimulation during task 
 
 
 
x 
Stimulation Questionnaire 
 
 
 
x 
 
APPENDIX B: AE REPORT FORM 
 
Adverse Effects Report:  
Reasons for Report (adverse event, time, date and place of occurrence if available):  
1. What do we already know about the stimulation? 
a.  
2. What is the temporal relationship of the AE to the stimulation? 
a.  
3. Does the AE improve or disappear when the stimulation is stopped? 
a.  
4. Is the AE a worsening of baseline symptom(s)? 
a.  
5. Is the AE a result of an underlying concurrent medical condition(s) or concurrent medication(s)? 
a.   
6. Additional Information provided by research team  
a.  
Research team member signature ______________________________________ Date____________ 
Co-Investigator:  

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_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
________________________________________________ 
 
Steps to be taken (if applicable) 
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_______________________________________________________________________ 
Co-I signature _______________________________________________________Date___________ 
 
PI Comments:  
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
________________________________________________ 
 
Steps to be taken (if applicable) 
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_______________________________________________________________________ 
 
PI signature _______________________________________________________Date___________ 

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APPENDIX C: IRB AMENDMENT TRACKING LOG 
 
Change Initiated By: 
Description of IRB: Type and Brief Summary 
Date 
Submitted 
to IRB 
Date of 
IRB 
Response 
Requires 
Stipulations? 
(Y/N) 
Requires 
Updated 
Consent 
Form? 
(Y/N) 
Stipulation 
Submission 
Date 
IRB 
Approval 
Date 
Initials 
Reference 
ID 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX D: AE REPORT FORM 
 
Participant 
ID 
Ö if AE 
meets 
definition 
of serious* 
Grade/Intensity 
1. Asymptomatic 
2. Mild 
3. Moderate 
4. Severe 
 
Date of 
Incident 
Relationship to 
study device 
1. Related 
2. Possibly 
3. Not Likely 
4. Not Related 
Was 
Action 
Taken? 
 
 
 
 
Action(s) Taken: 
Outcome: 
1. Recovered 
2. Not Recovered 
3. Recovered 
w/Sequel 
4. Fatal 
5. Unknown 
PI Initials / Date 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 

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39 
APPENDIX E: INFORMED CONSENT QUIZ 
Name of Research Study:  
You have been asked to be in a research study. This sheet will help you think of questions to ask but you may have 
other questions.  This is not a test.  We want to be sure you understand what it means to be in this research study.  
You should understand the research before you decide whether or not to participate. 
1. What is the purpose of the research? 
2. What are the possible benefits of the research? 
3. What are the possible risks of the research? 
4. Will everyone receive the same treatment? 
5. How is this research different than the care or treatment I would get if I wasn’t in the research study?  
6. Does in the research cost me anything extra? 
7. Can you stop being in the research once you’ve started? 
8. Who will view your medical records? 
9. Who do you call if I have questions about being a research participant? 
10. Any questions?   
 
 

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APPENDIX F: NOTE TO FILE 
 
IRB#: 
18-1789  
 
 
 
 
 
 
      
         PI: Flavio Frohlich 
Study Title: [Insert Short Name] 
Researcher: ________________ 
 
 
 
 
       Date of Occurrence: ____________ 
Participant ID: _________________ 
 
Reason for Note: 
_____________________________________________________________________________________________
_____________________________________________________________________________ 
 
Note: 
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____ 
 
Corrective action (if applicable): 
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________ 
 
 
Signature: ______________________________  
     Date: _______________ 
 
 
 
 

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APPENDIX G: TELEPHONE SCRIPT 
Telephone Consent and Screening (TMSEEG) 
Date: ________________ 
ParticipantID: _________ 
Criteria fulfilled: r Yes r No 
 
Hello, my name is _________. I’m calling in regards to your interest in our study on the effects 
of brain stimulation on brain activity. Do you have about 10 minutes now to hear about the 
study, answer a few screening questions, and possibly schedule your visit?  
 
(If ‘No’, ask for a good time to call back) 
(If ‘Yes’, proceed) 
 
First, I need to ask for your verbal consent to conduct the screening interview. I will ask 
questions about your age, medication and drug use, and family and personal health history. You 
may decline to answer any questions, but please keep in mind that this may affect our ability to 
determine if you qualify for the study. Of course, the information you provide is strictly 
confidential, and will not be used for any purpose other than eligibility. Do you consent to 
participate in the screening interview? 
 
(If ‘No’, thank them for their time and hang up.) 
(If ‘Yes’, proceed) 
 
Great! This study is looking at how brain activity responds to magnetic stimulation. In this study, 
a magnetic field will be applied to your scalp. Some participants have reported mild muscle 
twitching and headache, but no other side effects have been found. It is not a shock and should 
not cause pain. 
 
This study will include four sessions scheduled at your convenience, each lasting approximately 
1-3 hours. You will be compensated for your time after each session, with total compensation 
amounting to $150. We will ask that you maintain a regular sleep schedule during the study, and 
adhere to restrictions on alcohol consumption the day prior to each session. Are you still 
interested in participating? 
 
(If ‘No’, thank them for their time) 
(If ‘Yes’, proceed) 
 
 
 
 
Great! In order to make sure you’re eligible for the study, I need to ask you a few questions. 
Please answer yes, no, I do not know, or I prefer not to answer. If you are not sure what the 
question is asking please ask for clarification. You do not need to provide any details in your 
answer.  
 
 
         Age:_________   Sex:_________  
 

PATRC 
 
Version 5 
IRB: 18-1789 
 
10 June 2019 
CONFIDENTIAL 
 
42 
 
1. Have you ever had a serious illness/accident that required 
hospitalization? Are you currently receiving any medical treatment? 
............................................................................................................... 
................................................................................................................ 
............................................................................................................... 
r 
No 
r 
Yes 
2. Have you ever had suffered from a brain disease (e.g. epilepsy) or 
concussion? 
      ............................................................................................................ 
r 
No 
r 
Yes 
3. Have you ever been diagnosed with a learning disability or 
ADD/ADHD? 
     ............................................................................................................. 
r 
No 
r 
Yes 
4. Do you suffer from a mental/psychiatric disease, such as depression 
or schizophrenia? 
............................................................................................................. 
r 
No 
r 
Yes 
5. Is there any family history of mental/psychiatric diseases? 
       ............................................................................................................ 
r 
No 
r 
Yes 
6. Do you consume any elicit drugs, such as cannabis? 
............................................................................................................. 
r 
No 
r 
Yes 
7. Is there any chance that you are pregnant or could become pregnant 
during the course of the study? (If female) Please note that we will 
also administer a pregnancy test at the start of every stimulation 
session if you answer yes or are unsure. 
............................................................................................................. 
r 
No 
r 
Yes 
8. Do you have any implanted electronic devices? 
............................................................................................................. 
r 
No 
r 
Yes 
Study obligations 
 
 
1. Do you think you can comply with all the study duties, which include 
maintaining a regular sleep schedule, and no caffeine, alcohol, or 
excessive exercise the day before or of a session? 
 
r 
No 
r 
Yes 
 
Keeping in mind sessions last about 3 hours, what days and times work best for you?