Rational Optimization of tACS for Targeting Thalamo-Cortical Oscillations (Experiment 3)
Phase: NA
Conditions: Depression, Major Depressive Disorder, Premenstrual Dysphoric Disorder, Depressive Episode
Sponsor: University of North Carolina, Chapel Hill

 
 
CONFIDENTIAL 
 
0 
RATIONAL OPTIMIZATION OF TACS FOR 
TARGETING THALAMO-CORTICAL 
OSCILLATIONS: SINGLE SESSION IN A 
DEPRESSIVE EPISODE, EXPERIMENT III 
 
Funding Mechanism: 
NIMH R01 
Principal Investigator: 
Flavio Frohlich, PhD 
Co-Investigator: 
Crystal Schiller, PhD; David Rubinow, MD 
Protocol Number: 
N/A 
Version Number: 
1.0 
Date: 
NCT Number: 
4/29/19  
NCT03449979 
 
 
 
 
 
 
 
 
 
 
Initial version: 
4/29/19 

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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 ......................................................................................................................... 7 
2 
INTRODUCTION ............................................................................................................................. 8 
2.1 
BACKGROUND ................................................................................................................................ 8 
2.2 
INVESTIGATIONAL AGENT ................................................................................................................. 9 
2.3 
DOSE RATIONALE ............................................................................................................................ 9 
2.4 
STUDY AIMS/HYPOTHESES ............................................................................................................... 9 
3 
SUBJECT SELECTION AND WITHDRAWAL ...................................................................................... 10 
3.1 
INCLUSION CRITERIA ...................................................................................................................... 10 
3.2 
EXCLUSION CRITERIA ..................................................................................................................... 10 
3.3 
STRATEGIES FOR RECRUITMENT AND RETENTION ................................................................................. 11 
3.3.1 
RECRUITMENT ................................................................................................................................... 11 
3.3.2 
RETENTION ....................................................................................................................................... 11 
4 
BASIC STUDY DESIGN ................................................................................................................... 12 
4.1 
TREATMENT ASSIGNMENT PROCEDURES ............................................................................................ 12 
4.1.1 
RANDOMIZATION PROCEDURES ............................................................................................................ 12 
5 
STUDY SCHEDULE ........................................................................................................................ 14 
5.1 
SCREENING .................................................................................................................................. 14 
5.2 
STUDY VISITS ............................................................................................................................... 14 
5.4.1 
STUDY VISIT ...................................................................................................................................... 14 
5.4.3 
UNBLINDING PROCEDURES .................................................................................................................. 15 
6 
STUDY PROCEDURES/EVALUATIONS ............................................................................................ 16 
6.1 
SELF-REPORT MEASURES ................................................................................................................. 16 
6.2 
SPECIAL ASSAYS OR PROCEDURES ...................................................................................................... 16 
6.3 
SAFETY MEASURES ........................................................................................................................ 16 
6.4 
LABORATORY EVALUATIONS ............................................................................................................ 16 
6.4.1 
SCREENING LABORATORY EVALUATIONS ................................................................................................. 17 

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6.4.3 
SALIVA SAMPLES ................................................................................................................................ 17 
7 
STUDY INVESTIGATIONAL PRODUCT ............................................................................................ 18 
7.1 
DEVICE DESCRIPTION ...................................................................................................................... 18 
7.2 
SAFETY FEATURES ......................................................................................................................... 18 
7.3 
PREPARATION AND ADMINISTRATION OF STUDY INVESTIGATIONAL PRODUCT ............................................ 19 
7.4 
ASSESSMENT OF PARTICIPANT COMPLIANCE WITH STUDY INVESTIGATIONAL PRODUCT ................................ 20 
8 
POTENTIAL RISKS AND BENEFITS .................................................................................................. 21 
8.1 
BENEFITS TO SUBJECTS AND SOCIETY ................................................................................................. 21 
8.2 
POTENTIAL RISKS .......................................................................................................................... 21 
8.2.1 
PSYCHOLOGICAL ................................................................................................................................ 21 
8.2.2 
PHYSICAL .......................................................................................................................................... 21 
8.3 
REFERRALS FOR MEDICAL FOLLOW-UP OR PSYCHOLOGICAL COUNSELING .................................................. 22 
8.3.1 
PREGNANCY FOLLOW-UP .................................................................................................................... 22 
9 
DATA AND SAFETY MONITORING ................................................................................................ 23 
9.1 
FROHLICH LAB MONITORING PLAN ................................................................................................... 23 
9.2 
SAFETY OVERSIGHT ....................................................................................................................... 23 
9.3 
EARLY WITHDRAWAL OF PARTICIPANTS ............................................................................................. 23 
9.3.1 
REASONS FOR WITHDRAWAL ............................................................................................................... 23 
9.3.2 
DATA COLLECTION AND FOLLOW-UP FOR WITHDRAWN PARTICIPANTS ....................................................... 24 
9.4 
TERMINATION OF STUDY ................................................................................................................ 24 
10 
SAFETY & REPORTING ................................................................................................................ 25 
10.1 
SAFETY PARAMETERS .................................................................................................................. 25 
10.2 
METHODS AND TIMING FOR ASSESSING, RECORDING, AND ANALYZING SAFETY PARAMETERS ..................... 25 
10.2.1 
ADVERSE EVENTS ............................................................................................................................. 25 
10.2.1 
SERIOUS ADVERSE EVENTS ................................................................................................................ 26 
10.2.2 
UNANTICIPATED PROBLEMS .............................................................................................................. 26 
10.3 
REPORTING PROCEDURES ............................................................................................................. 27 
10.3.1 
REPORTING OF PREGNANCY ............................................................................................................... 27 
10.4 
TYPES AND DURATION OF FOLLOW-UP OF PARTICIPANTS AFTER ADVERSE EVENTS .................................... 27 
11 
STATISTICAL PLAN ..................................................................................................................... 28 
11.1 
STATISTICAL ANALYSIS STRATEGIES ................................................................................................. 28 
11.2 
SAMPLE SIZE DETERMINATION ....................................................................................................... 28 
11.3 
DATA MANAGEMENT .................................................................................................................. 28 
12 
DATA HANDLING AND RECORD KEEPING ................................................................................... 29 
12.1 
PHI AND HIPAA ........................................................................................................................ 29 

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12.2 
CONFIDENTIALITY ....................................................................................................................... 29 
12.2.1 
ACCESS TO SOURCE DOCUMENTS ....................................................................................................... 29 
12.2.2 
SENSITIVE INFORMATION .................................................................................................................. 29 
12.2.3 
OTHER ........................................................................................................................................... 29 
12.3 
SOURCE DOCUMENTS .................................................................................................................. 30 
12.4 
DATA MANAGEMENT RESPONSIBILITIES ........................................................................................... 30 
12.5 
DATA CAPTURE METHODS ............................................................................................................ 31 
12.6 
PROTOCOL DEVIATIONS ............................................................................................................... 31 
12.7 
RECORD RETENTION .................................................................................................................... 31 
13 
ETHICAL CONSIDERATIONS ........................................................................................................ 32 
13.1 
ETHICAL STANDARD .................................................................................................................... 32 
13.2 
INSTITUTIONAL REVIEW BOARD (IRB) ............................................................................................. 32 
13.3 
INFORMED CONSENT PROCESS ...................................................................................................... 32 
13.4 
EXCLUSION OF WOMEN, MINORITIES, AND CHILDREN (SPECIAL POPULATIONS) ....................................... 33 
13.5 
PARTICIPANT CONFIDENTIALITY ..................................................................................................... 33 
13.6 
STUDY DISCONTINUATION ............................................................................................................ 33 
14 
PUBLICATION POLICY ................................................................................................................ 34 
15 
LITERATURE REFERENCES .......................................................................................................... 35 
APPENDIX A: SCHEDULE OF EVENTS ................................................................................................... 38 
APPENDIX B: AE REPORT FORM ......................................................................................................... 39 
APPENDIX C: IRB AMENDMENT TRACKING LOG ................................................................................. 41 
APPENDIX D: AE REPORT FORM ......................................................................................................... 41 
APPENDIX F: NOTE TO FILE ................................................................................................................. 44 
APPENDIX G: TELEPHONE SCRIPT ....................................................................................................... 45 
APPENDIX H: TRAINING LOG .............................................................................................................. 45 
 
 
 

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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
ANOVA 
Analysis of Variance 
CFR 
Code of Federal Regulations 
CNS 
Central Nervous System 
Co-I 
Co-Investigator 
CRF 
CTRC 
Case Report Form 
Clinical Trials Research Center  
DMV 
Department of Motor Vehicles 
eCRF 
Electronic Case Report Form 
EEG 
Electroencephalogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
Hz 
IAF 
Hertz 
Individualized Alpha Frequency 
ICF 
Informed Consent Form 
LAR 
Legally Authorized Representative 
NIH 
National Institutes of 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 
tACS 
Transcranial Alternating Current Stimulation 
tDCS 
Transcranial Direct Current Stimulation 
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 
Rational optimization of tACS for targeting thalamo-cortical oscillations: Single 
session in a depressive episode, Experiment III 
Short Title 
SSDE 
Protocol Number 
Version 1.0   
Phase 
Pilot 
Methodology 
Double-blind, randomized, active sham controlled 
Study Duration 
This study will take 18 months to complete. 
Study Center(s) 
This is a single-site study performed at the University of North Carolina at Chapel 
Hill.  
Objectives (Purpose) 
The primary objective of this study is to investigate the effects of non-invasive 
transcranial alternating current stimulation (tACS) on healthy participants and 
participants with mood disorders.  
Number of Subjects 
80 
Diagnosis and Main 
Inclusion Criteria 
Eligible participants will be adults between the ages of 18-65 in a current depressive 
episode OR age and sex-matched health adults with no history of mental or 
psychiatric illness.   
Description of 
Intervention 
(Procedures/methods) 
The participants will be randomized into one of two arms: either 40 minutes of sham 
tACS or 40 minutes of IAF tACS while in a relaxed, yet experimentally controlled 
state, by watching a nature movie such as “Reefscape” during stimulation. 
Related IRB Applications 
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1 
KEY ROLES 
1.1 
INDIVIDUALS 
Principal Investigator 
Flavio Frohlich, PhD 
Co-Investigator 
Crystal Schiller, PhD 
David Rubinow, MD 
Medical Monitor 
Crystal Schiller, PhD 
 
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 
 
Crystal Schiller, PhD – Co-Investigator, Medical Monitor 
UNC – Chapel Hill Department of Psychiatry 
 
David Rubinow, MD – Co-Investigator 
UNC – Chapel Hill Department of Psychiatry 
 
Morgan Alexander – Project Manager/Study Coordinator 
UNC – Chapel Hill  
Email:  morgan_alexander@med.unc.edu 
Office: Medical School Wing C – Room 233 
Phone:  (919) 966-4755 
 
Justin Riddle – Research Assistant 
UNC – Chapel Hill  
Email:  justin_riddle@med.unc.edu 
Office: Mary Ellen Jones Building  
 
Charles Zhou, BS – Research Assistant 
Neuroscience Center 
Email: zhouz@email.unc.edu 
Office: Neuroscience Research Building 
Phone: (919) 260-0796 
 
 
1.2 
INSTITUTIONS 
The University of North Carolina at Chapel Hill 
1.3 
OPTIONAL 
IRB 

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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 
NIH National 
Institute of 
Mental Health 
(NIMH) 
N/A 
Federal 
N/A 
N/A 
R01MH101547 
External Funding: This project is externally funded but UNC-CH is not the direct recipient of federal funds. 
UNC-CH Funding: This project is not funded through UNC-CH. 
Classified: This project is not classified. 
 
 

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2 
INTRODUCTION 
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 
The objective is to use non-invasive electrophysiology to demonstrate that transcranial alternating current 
stimulation (tACS) indeed modulates human thalamo-cortical alpha oscillations. To achieve translational relevance, 
we will evaluate the stimulation patterns not only in occipito-parietal cortex, where alpha oscillations are maximal, 
but also in frontal areas, where altered alpha oscillations correlate with impaired approach motivation. The 
rationale for this aim is that validation in humans of tACS based on the mechanistic insights on modulation of 
thalamo-cortical network dynamics will enable and accelerate the further study of optimized tACS in healthy and 
patient populations. 
The study of alpha oscillations (~10 Hz) as a brain stimulation target is significant due to its central role in 
mediating long-range functional connectivity (von Stein & Sarnthein, 2000), attentional modulation of cortical 
information processing (Saalmann, Pinsk, Wang, Li, & Kastner, 2012), and disease states such as depression 
(Leuchter, Hunter, Krantz, & Cook, 2015) and autism (Murias, Webb, Greenson, & Dawson, 2007). Pursuing alpha 
oscillations is further motivated (1) by other emerging low-intensity stimulation modalities for mood disorders that 
target alpha oscillations, such as synchronizing transcranial magnetic stimulation (sTMS; Frohlich, 2015; Leuchter, 
Cook, et al., 2015; Leuchter, Cook, Jin, & Phillips, 2013) and (2) by the observation that the clinically used 10Hz 
repetitive TMS entrains alpha oscillations (Thut et al., 2011). 
Previous tACS studies from other groups have shown that 10Hz tACS is capable to increase alpha oscillations during 
tACS application and in the post stimulation interval compared to a non-stimulation baseline (Helfrich et al., 2014; 
Neuling, Rach, & Herrmann, 2013; Vossen, Gross, & Thut, 2015; Zaehle, Rach, & Herrmann, 2010). However, 
questions of significant importance have remained unanswered. It is unclear to what extent the findings were 
contaminated by changes in overall state (e.g. drowsy vs. alert) independent of stimulation.We will answer this 
question by monitoring state by pupillometry. Measurements of pupil diameter in humans index arousal levels 
that correlate with the activation of the noradrenergic system (Koss, 1986; Murphy, Robertson, Balsters, & 
O'Connell R, 2011) and power of the alpha oscillation (Hong, Walz, & Sajda, 2014). In addition, alpha tACS studies 
measuring EEG had rather small sample sizes (12-30 participants). Experiment 1 aims at validating the effect of 
alpha tACS and its state dependence in a bigger dataset of healthy participants using comparable electrode 
locations (over occipital regions). Furthermore, we use for the first time a high density EEG (128 electrodes) that 
will allow to explore the spatial distribution of the effect of alpha tACS. 
Experiment 1 serves us to understand how the state might affect the interaction between tACS and alpha 
oscillations by targeting the alpha oscillation that is correlated with state (arousal/drowsiness). However, several 
studies have shown that frontal alpha oscillation properties (strength, distribution etc) reflect cognitive processing 
and impairments in frontal alpha are implicated in psychiatric disorders (Klimesch 2012, Allen and Reznik 2015). 
Hence, we target the frontal alpha oscillations in Experiments 2 and 3.  
Despite behavioral effects of frontal alpha-tACS, it is unclear if target engagement for frontal alpha oscillations 
follows the same principles. In addition, it remains untested if tACS also engages pathologically altered alpha 
oscillations. Considering that patients with reduced approach motivation, such as depression, show altered frontal 
alpha power topographies (e.g. asymmetry) answering these questions is of fundamental importance (Debener et 
al., 2000). Our second experiment using stimulation electrodes over the frontal cortex in patients with decrease in 
approach motivation will directly address these questions. 

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On purpose, we refrain from using the clinical diagnosis of major depressive disorder but rather (following the 
RDoC principles; Craske 2012) cast a wider net to capture a more complete set of patients that are likely to have 
altered alpha oscillations. Changes in the symmetry between alpha power in the left and the right hemisphere 
have been reported to be correlated with a decrease in approach motivation as measured by the BAS scale (de 
Pascalis et al. 2013), which corresponds to a construct in the RDoC domain of positive valence. In addition, patients 
with depresssion (MDD and Bipolar depression) often rate higher in the BIS scale compared to healthy individuals 
(Kasch et al. 2002, Johnson et al. 2003). In this study, we aim to study the effect of transcranial alternating current 
stimulation on the alpha oscillation in healthy individuals as well as patients who show altered alpha dynamics.  
 
2.2 
INVESTIGATIONAL AGENT 
Transcranial Alternating Current Stimulation (tACS) is one method that has been demonstrated to enhance alpha 
oscillations in healthy participants by applying weak electrical currents to the scalp to modulate rhythmic brain 
activity patterns (Lustenberger et al, 2015).  
2.3 
DOSE RATIONALE 
Stimulation intensity and duration is based on the completed first experiment under this protocol. 
2.4 
STUDY AIMS/HYPOTHESES 
Central Hypothesis: Non-invasive brain stimulation that enhances alpha oscillation increases endogenous alpha 
power and reduces frontal alpha asymmetry when present. 
Aim 1: Our first objective is to study the effect of tACS in healthy humans on neurophysiology measured using 
hdEEG  
Aim 2: Our third objective is to study the effect of tACS on neurophysiology in patients with mood disorders and 
impaired alpha oscillations and compare it to the effect in healthy humans 
 
 

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3 
SUBJECT SELECTION AND WITHDRAWAL 
A total of 80 participants will be recruited for 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 one of the following sets of criteria: 
Inclusion Criteria for individuals with depressed mood 
• 
Ages 18-65 years 
• 
Hamilton Depression Rating Scale score >8 
• 
Capacity to understand all relevant risks and potential benefits of the study (informed consent) 
• 
Low suicide risk which will be determined through the use of both the Structured Clinical Interview for the 
DSM-5 and by scoring less than 3 (0,1, or 2) in the Hamilton rating depression scale. 
• 
Negative pregnancy test for female participants 
Inclusion Criteria for healthy controls 
• 
Ages 18-65 years 
• 
Hamilton Depression Rating Scale score <8 
• 
Capacity to understand all relevant risks and potential benefits of the study (informed consent) 
• 
Negative pregnancy test for female participants 
3.2 
EXCLUSION CRITERIA 
A potential participant who meets any of the following criteria will be excluded from participation in the study: 
Exclusion Criteria for individuals with depressed mood 
• 
DSM-5 diagnosis of alcohol use disorder within the last 12 months 
• 
DSM-5 diagnosis of substance dependence (other than nicotine) within the last 12 months 
• 
DSM-5 diagnosis of substance abuse (other than nicotine or marijuana) within the last 12 months 
• 
Eating disorder (current or within the past 3 months) 
• 
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 
• 
Neurological disorders, including but not limited to history of seizures (except childhood febrile seizures 
and ECT induced seizures), dementia, history of stroke, Parkinson's disease, multiple sclerosis, cerebral 
aneurism. 
• 
Medical or neurological illness (unstable cardiac disease, AIDS, malignancy, liver or renal impairment) or 
treatment for a medical disorder that could interfere with study participation 
• 
History of traumatic brain injury, reoccurring seizures or later cognitive rehabilitation or causing cognitive 
sequellae 
• 
Prior brain surgery 
• 
Any brain devices/implants, including cochlear implants and aneurysm clips 
• 
Co-morbid neurological condition (i.e. seizure disorder, brain tumor) 
• 
Use of illicit drugs, confirmed by a drug test 
• 
Non-English speakers 
• 
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• 
Current use of benzodiazepines or anti-epileptic drugs 
Exclusion Criteria for healthy controls 
• 
History of major neurological or psychiatric illness, including epilepsy 
• 
Medication use associated with neurological or psychiatric illnesses 
• 
Currently undergoing counseling or psychotherapy treatment for depression, anxiety, eating disorders, 
PTSD or other behavioral conditions 
• 
First degree relative (parent, sibling, child) with major neurological or psychiatric illness 
• 
Prior brain surgery 
• 
Major head injury 
• 
Any brain devices/implants (including cochlear implants and aneurysm clips) 
• 
Use of illicit drugs, confirmed by a drug test 
• 
Braids or other hair styling that prevents direct access to the scalp (if removal not possible) 
• 
Skin allergies or very sensitive skin 
• 
Non English speakers 
• 
Pregnant or nursing females 
Justifications for any exclusions based on race, gender, or ethnicity: 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 tDCS/tACS studies. We will verify pregnancy status via a urine pregnancy test for all female 
participants prior to receiving treatment on Day 1 of Stimulation. 
3.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 
3.3.1 
RECRUITMENT 
Subjects at this time will be recruited by Jointheconquest.com, a mass email distributed through the UNC 
service, an email sent to previously interested participants in Dr. Schiller's lab, and flyers posted at 
locations on campus. We have also created a social media advertisement for Facebook. We believe this 
multimodal approach will allow us to reach the projected number of participants. 
3.3.2 
RETENTION 
Subjects only complete a single session of the experiment. Therefore, retention is of minimal risk. When 
collecting data, we are mindful of the time commitment for the participant and ensure that all data is 
collected and procedures are carried out in a time efficient manner. 
 

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4 
BASIC STUDY DESIGN 
The design for this study is a pilot, randomized, double-blind, sham-controlled, clinical trial which will be used to 
demonstrate feasibility and collect effectiveness data for further refinement of a tACS approach and for the 
subsequent design of a follow-up, multi-site, large scale study. We are seeking 80 healthy participants, both male 
and female, between the ages of 18-65 who belong to one of two cohorts: those experiencing a depressive 
episode or age and sex-matched health controls. All women of child-bearing potential will be asked to take a 
pregnancy test during the initial session in order to determine eligibility for the study. 
This is a double-blind, randomized crossover study. We estimate 18 months to complete study enrollment. 
Participants will be randomly assigned to one of 2 arms. 
 
Figure 1. 
 
 
Active sham treatment will include 10 seconds of ramp-in to 1 minute of 10 Hz tACS and a ramp-out of 10 seconds, 
for a total of 80 seconds of stimulation. The choice of an active sham is motivated to enhance success of patient 
blinding by mimicking skin sensations associated with tACS. The verum condition will have a 10 second ramp-in 
and ramp-out with 40 minutes of stimulation for a total of 2420 seconds of stimulation. Stimulation waveform is a 
sine-wave with 2mA amplitude. In both arms, participants will stay in a relaxed yet controlled state by watching a 
nature movie (“Reefscape”) during stimulation. 
Eligible participants will have a single visit approximately 4 hours. All time estimates take into consideration breaks 
and time variance in administration. 
4.1 
TREATMENT ASSIGNMENT PROCEDURES 
Participants will be randomized into one of 2 arms (see Figure 1 above). This is a double-blind study, so neither the 
participant nor the researcher will know which treatment the participant is receiving, if any. 
4.1.1 
RANDOMIZATION PROCEDURES 
Charles Zhou will randomize a series of 6-digit stimulation codes which will be used by the study 
coordinator and research assistants and will be linked to the participant numbers of enrolled participants. 
These stimulation codes are directly linked to which treatment participants receive (sham or tACS at IAF) 
at each session, and will be used with the XSCITE 100 stimulator. An unblinded code sheet that matches 
these stimulation codes to treatment arm will be kept by Charles Zhou and will not be available to the 
study coordinator or research assistants.  
The unblinded code sheet will have the following information: 
1. The initial identifier codes for all potential participants 
2. Stimulation code: 6-digit numerical code for the stimulation session 
3. Condition number: Numerical code for the condition 
4. Condition name: Name of the condition 
Phone Screening
Randomization
Sham tACS
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A copy of this code sheet with condition number and condition name REMOVED is provided to the study 
coordinator and research assistants. This blinded code sheet will be used to ensure the correct 
stimulation code is provided for each session. 
These linked codes ensure that the study coordinator and research assistants are kept blinded to which 
treatment each participant receives. Please see Data and Safety Monitoring for more information on 
unblinding this information. 
 
 

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5 
STUDY SCHEDULE 
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 screening process will involve a telephone call with the potential participant to inform of expectations and 
determine eligibility. A researcher will conduct a screening with each participant prior to scheduling the first 
session. If a participant is determined to be ineligible, data from the screening will be retained.  
Prior to attending the session, each participant will complete a screening questionnaire (online or phone) to 
determine preliminary eligibility. This will also include some online assessments (Structured Clinical Interview for 
the DSM-5 Personality Disorders Screening, as well as the Childhood Trauma Questionnaire, State-Trait Anxiety 
Inventory (STAI) – Trait, Rumination Scale, BIS/BAS, and Demographics). Participants are not required to fill in 
these prior to the initial session, but completing these assessments may reduce the duration of their session. 
Participants will provide verbal consent through the phone screening prior to completing these assessments. 
5.2 
STUDY VISITS 
All participants will undergo a single study visit with the same procedure; the only change will be the stimulation 
condition. 
5.4.1 
STUDY VISIT  
At the beginning of the session, the participants will be guided through the informed consent and asked 
to sign the form. Once the consent has been signed, all female participants will be asked to take a Urine 
Pregnancy Test in order to determine eligibility. All participants will also take a urine drug test to 
determine eligibility as well. 
The session will begin with the Mini International Neuropsychiatric Interview (MINI) and the Hamilton 
Depression Rating Scale (HDRS). Both of these assessments will determine suicide risk - if the 
participant's responses indicate a high risk of suicide (e.g., current plans, 3 or 4 on the suicide item on 
the HDRS), Dr. Crystal Schiller will be contacted for a brief assessment and to determine the next 
actions to be taken (if necessary). Following these assessments, the participant will complete the 
Temporal Experience of Pleasure Scale (TEPS), the Snaith-Hamilton Pleasure Scale - Clinician Administered 
(SHAPS-C) and and the Beck Depression Inventory (BDI) prior to the stimulation. Treatment resistance will 
be assessed using the Maudsley Staging Method by the study coordinator. Breaks will be provided when 
needed. The participant will also provide a saliva sample that will be used to genotype a single 
polymorphism called brain derived neurotropic factor (BDNF). These assessments will be administered 
prior to stimulation in order to determine participant eligibility, with the MINI being used as a diagnostic 
tool. In total, the assessments should take approximately 1 hour to complete. If the participant is not 
deemed eligible, they will be compensated for their time and the visit will end. If the participant is 
deemed eligible, the study visit will proceed as follows. 
A study coordinator will apply the stimulation and EEG electrodes to the participant’s scalp. Participants 
will complete a 2-minute eyes closed resting state EEG recording. Participants will complete an EEG 
reward-processing task. Participants will be told that the better they are at this task, the more money 
they will earn as a "bonus". This task is visual, with participants responding to stimuli with button clicks 
and is expected to last about 25 minutes. Participants will then complete an emotional response EEG task, 

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which includes pictures. We anticipate this to last approximately 6 minutes. Pre-stimulation resting state 
EEG will be collected for 5 minutes with eyes open. Participants will respond to the STAI-State, the state 
complacency scale, and the positive and negative affect schedule (PANAS) following this. Stimulation 
(tACS or sham tACS) will then be applied for 40 minutes. Post-stimulation resting state EEG with eyes 
open will be collected for 5 minutes Participants will then respond to the STAI-State, State complacency 
scale, the PANAS, and the Stimulation Side Effects Questionnaire. To assess any possible change in the 
emotional response EEG task, it will be repeated. Finally, all equipment will be removed and participants 
will be compensated. 
5.4.3 
UNBLINDING PROCEDURES 
There are no current plans to systematically unblind participants to the treatment they may or may not 
have received during the clinical trial. However, following the completion of data collection, participants 
may contact the Frohlich Lab for unblinding information.  
 
 

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6 
STUDY PROCEDURES/EVALUATIONS 
6.1 
SELF-REPORT MEASURES 
During the telephone screening, researchers will collect demographics, which include medical history and 
medication history. In addition, several other self-report measures will be used 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 & White, 1994).  
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 subjectivity to demographic 
variables (Watson et al, 1988).  
D. REPETITIVE THINKING QUESTIONNAIRE (RTQ) is a 22-item self-report assessment using a 4-level Likert scale to 
assess the frequency of repetitive negative thinking and rumination. This questionnaire has been used to 
assess traits of worrying about past events with transdiagnostic relevance.  
E. CHILDHOOD TRAUMA QUESTIONNAIRE (CTQ) is a 28-item self-report assessment using a 5-level Likert scale to 
assess a history of childhood sexual, emotional, and physical abuse or neglect.  
F. 
STATE COMPLACENCY SCALE (SCS) is a 19-item self-report assessment using a continuous analog scale to assess 
satisfaction with the current mood and difficulty changing mood. 
6.2 
SPECIAL ASSAYS OR PROCEDURES 
Each participant will receive one session of stimulation, either with an active sham condition or tACS at IAF. For 
more information on the stimulation procedures, see section 7.2 Preparation and Administration of Study 
Investigational Product.  
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 10.1 Safety Parameters for more 
information.  
B. A study coordinator will be present at all times to ensure safety. 
 
 
6.4 
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6.4.1 
SCREENING LABORATORY EVALUATIONS 
A urine pregnancy test will be performed for any female participant who is of child-bearing potential. All 
participants will also undergo a urine drug test. 
INSTRUCTIONS FOR SPECIMEN PREPARATION, HANDLING, AND STORAGE. For this laboratory evaluation, 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. 
6.4.3 
SALIVA SAMPLES 
We will be collecting a saliva sample to test for a single nucleotide polymorphism in the BDNF gene whose 
presence may have an influence on effectiveness of brain stimulation. Within the central nervous system, 
BDNF regulates survival, proliferation, and synaptic growth as well as directly influences synaptic plasticity 
in the adult human brain (Antal et al., 2010). Egan et al. (2003) demonstrated that Val66Met, a single 
nucleotide in the BDNF gene, has function consequences in healthy humans, including decreased episodic 
memory and hippocampal inducing a reduction in recall capacity. This polymorphism is common in over 
one third of the Caucasian population (65% Val66Val to 35% Val66MET) (Pezawas et al, 2004; Hariri and 
Weinberger, 2003). Kleim et al. (2006) found that individuals with the Val/Val polymorphism respond to 
tDCS and transcranial magnetic stimulation (TMS) treatments with expected change, whereas, individuals 
expressing Val/MET allele do not. These authors indicate the difference to be caused by the impairment in 
synaptic plasticity caused by the Val/MET allele. These findings suggest that individual efficacy of 
treatments using brain stimulation may be partially genetically predetermined and should be taken into 
account when preforming such procedures. Accordingly, we will conduct genotyping of all participants in 
this study in order to assess BDNF status.  We will perform exploratory analyses in which we group 
participants by BDNF status. 
INSTRUCTIONS FOR SPECIMEN PREPARATION, HANDLING, AND STORAGE. The saliva sample will be collected using 2mL 
DNA collection kit from DNA Genotek. Before sample collection, it is imperative that the participant does 
not eat, drink, smoke or chew gum for at least 30 minutes before providing a sample.  Once the 
participant provides the 2mL sample, the collection tube is closed and a liquid from the lid will be released 
into the tube. The original lid will be removed and replaced with a small cap and the tube will be agitated 
for 5 seconds.  The sample is then returned to the plastic packaging and labeled with the date of 
collection, the study name, and the participant ID.  These samples are kept in a secure location until the 
completion of data collection. 
 
 

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7 
STUDY INVESTIGATIONAL PRODUCT 
7.1 
DEVICE DESCRIPTION 
We will be using the XCSITE100 stimulator designed in the Frohlich Lab for investigational purposes. The device is 
not implanted and has not been designed for or being used to support or sustain human life. This device does not 
have a potential for serious risk to the health, safety, or welfare of the participant. There has never been an 
instance of serious side-effect reported due to the use of transcranial brain stimulation. Previous studies in the 
Frohlich lab that used comparable devices (i.e., the commercial, CE-certified Neuroconn Plus stimulator) have 
always been classified as “non-significant risk” by the full UNC IRB. The Neuroconn Plus stimulator and the 
XCSITE100 stimulator are electrically equivalent and provide the same stimulation.  
The XSCITE100 is the first non-invasive brain stimulator designed for research purposes to provide an active sham 
for tACS and record the stimulation output for later validation. This stimulator may apply either tDCS or tACS for 
up to 40 minutes (2400 seconds) with appropriate current ramp-up at the beginning of stimulation and ramp-down 
at the end of stimulation. Both tDCS and tACS may be applied for currents between 100 μA and 2 mA (peak-to-
peak for tACS). 
The stimulator has two main components: 
1. Android tablet with user interface application (i.e., App) 
2. Stimulator with: 
a. Microprocessor 
b. Function generator chip 
c. 
Voltage controlled current source 
d. Safety circuitry 
To ensure appropriate blinding for each stimulation session, there are designated unblinded individuals to ensure 
the appropriate stimulation parameters are applied to each participant. These individuals will not interact with 
participants and will only be involved with the creation of a study file and validation of stimulation waveform. 
7.2 
SAFETY FEATURES 
Current Sensor Circuit. A 33.2 Ω sense resistor is placed in series with the stimulation electrodes on the high side. 
Since high-side current sensing is used, any short circuit of the electrode terminals to ground will be detected. The 
stimulation current flows through this resistor and creates a voltage. The voltage across this resistor is sensed and 
amplified by the AD628 difference amplifier. The gain of the difference amplifier is set to 9.9039. The current 
sensor voltage is then shifted before it is read by the microprocessor and the hardware current safety feature. 
Voltage Sensor Circuit. The differential voltage across the electrodes is measured so that the impedance can be 
calculated. The voltage is measured by buffering the positive electrode and negative electrode each with a unity 
gain op-amp circuit. The voltage output is then shifted before it is read by the microprocessor using the same level 
shifting circuit described in the current sensor section. 
The device is equipped with 4 different stages of safety precautions, all of which protect the participant from high 
currents. The stages are as follows: 
1. AUTOMATIC SOFTWARE CURRENT CUTOFF. The output of the current sensor described above is read by a 
microprocessor, which compares the reading to a value of ±3 mA peak. If the current exceeds these limits, 

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stimulation is stopped, a relay in series with the electrode is opened, and the power supply used for 
stimulation is turned off. The user is then given the option to investigate the issue , and cancel or resume 
the test. Since high-side current sensing is used (described above), any short circuit of the electrode 
terminals to ground will be detected. 
2. AUTOMATIC HARDWARE CURRENT CUTOFF. The output of the current sensor is fed into a pair of comparators 
which detect if the current exceeds ±4.5 mA. If so, the fault is latched such that the relay in series with the 
electrodes is opened. Additionally, the microprocessor is notified of this instance through an interrupt. 
Upon this interrupt, the microprocessor immediately stops stimulation and the power supply used for 
stimulation is turned off. 
Figure 1. Example of a successful hardware cutoff function 
 
3. PERMANENT HARDWARE CURRENT CUTOFF. A 5 mA fast-acting fuse is in series with the electrode connector. If 
the above two over-current detection methods fail, the fuse will below, and the stimulator will no longer 
be electronically connected to the device. 
4. POWER SUPPLY FUSE. Finally, if for no other reason the entire device draws too much current, the main 
power supply fuse is blown. This fuse is sized with a cutoff of 200% of steady-state operating current.  
7.3 
PREPARATION AND ADMINISTRATION OF STUDY INVESTIGATIONAL PRODUCT 
After participants have completed the questionnaires, they will be comfortably seated.  The research team will first 
measure their heads electrode placement using the 10-20 system. Participants will then be fitted with the 3 
electrodes for stimulation. The participant will be in the relaxed yet, experimentally controlled state by watching a 
nature movie. One session of stimulation will be performed per visit for 40 minutes. During the 10 Hz tACS 
Yellow: Relay control line 
Green: Current through 
electrode (goes from 
negative current to zero) 
Blue: Current sensor output 
(has lowpass filter)

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condition, participants will have a 10 second ramp in and ramp out with 40 minutes of stimulation for a total of 
2420 seconds. Stimulation waveforms are sine-waves with a peak-to-peak amplitude of 2 mA.  The sham 
stimulation will include 10 seconds of ramp in to 1 minute of 10 Hz tACS with a ramp out of 10 seconds for a total 
of 100 seconds of stimulation. Electrodes will be saline soaked, 5x5cm and placed over F3 and F4 with a 5x7cm 
placed over CZ as a return electrode.  
Stimulation devices will be preprogrammed and codes will be randomized to one of the two experimental arms. 
Researchers will enter the participant-specific code into the App that controls the stimulation and monitor 
participants during the 40 minutes of the stimulation. 
The study coordinator and/or the research assistant will be thoroughly trained and have trainings documented on 
the transcranial stimulation device and will be present during all stimulation sessions. Please see Appendix F for an 
example of the training documentation log. To monitor side effects of stimulation a questionnaire will be 
administered after each stimulation session.  Please see Attachment 1 for an example of the daily stimulation 
questionnaire, and Attachment 2 for an example of the endpoint stimulation questionnaire.  
7.4 
ASSESSMENT OF PARTICIPANT COMPLIANCE WITH STUDY INVESTIGATIONAL PRODUCT 
Compliance for this study includes attendance of the study visit. Individuals who miss the session and are unable to 
reschedule will be dropped from the study.  
 
 

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8 
POTENTIAL RISKS AND BENEFITS 
8.1 
BENEFITS TO SUBJECTS AND SOCIETY 
Our novel approach introduces non-invasive brain stimulation for mental illnesses and has the potential to treat 
symptoms in mood disorders. Furthermore, we will enhance the understanding of cortical network dynamics 
through addressing the role of modulating alpha oscillations with brain stimulation to improve symptoms in 
patients with mood disorders. 
 
This study is not designed to benefit the individual participants. However, participants in this study may experience 
some degree of relief from mood symptoms as a result of tACS treatment. 
 
8.2 
POTENTIAL RISKS 
8.2.1 
PSYCHOLOGICAL 
Emotional Distress: We will show some images in the emotional memory task that participants might find 
objectionable, including sexually explicit and violent images that may be difficult to look at. Importantly, 
these images have been extensively used in several thousand participants in other studies and have been 
rated (e.g., Affective Picture System Scale (Lang et al., 1999), Nencki Affective Picture Scale (Wierba et al., 
2015; Riegel et al., 2015; Marchewka et al., 2015). We will do the following points to minimize the risk: 
(1) Each image is only shown for a very short time period (1 second). 
(2) We will provide the following information in the consent form, stressing that the participant may 
withdraw at any time for any reason: 
  
If you decide to take part in this study, you will be asked to view a variety of pictures that have been 
categorized to be pleasant, neutral, or unpleasant. If any of the media presented should make you feel 
too uncomfortable to continue with the study, you are free to immediately withdraw your participation 
and leave without giving up payment. The content of the pictures may include images considered 
objectionable, such as sexually explicit and violent images that may be difficult to view, which could cause 
emotional distress. Importantly, these images have been used extensively in several thousand participants 
in other studies and have been standardized by other study groups and belong to a validated picture 
system (exemplary standardized systems used are: Affective Picture System Scale or Nencki Affective 
Picture Scale). We will do the following to minimize risk: 
(1) The images are only shown for 1 second 
(2) The task can be aborted early if you feel too uncomfortable during it 
(3) If you experience any discomfort or concerns after viewing the images, please inform the study 
coordinator, who can contact the clinician associated with this trial if necessary. 
  
All personnel associated with this study and who might be exposed to the images along with some 
example pictures. If any personnel feels too uncomfortable, they will not assist during the task and/or 
administer the task. 
 
Embarrassment: Self-report assessments contain questions regarding sensitive personal information. This 
risk is necessary in order to assess mood symptoms and associated psychopathology. Subjects will be 
assured upon intake that only study personnel will see any rating form responses. 
 
8.2.2 
PHYSICAL 

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Risk of Injury and Discomfort: Transcranial current stimulation has been used without any reports of 
serious side-effects. Therefore, transcranial current stimulation represent an extremely safe and non-
invasive therapeutic approach. Passing weak electric current through the scalp is also routinely done for 
measuring electrode resistance in all EEG recordings. Importantly, this stimulation mode has NOTHING 
to do with electroconvulsive therapy that applies many orders of magnitude higher stimulation current. 
Rather, transcranial current stimulation is so weak that it does not produce super-threshold activation 
of neurons (Frohlich and McCormick, 2010). 
Some subjects report a transient mild tingling, burning, or itching underneath the electrodes and 
headache, but no other side effects have been noted. There is also a rare/theoretical likelihood that 
stimulation of neuronal circuits can lead to epileptic discharges. To minimize this occurrence, we screen 
and exclude patients with personal and family history of neurological conditions from the study. During 
stimulation, the research assistant will ask the subject about his/her comfort level. If the subject reports 
any pain, stimulation will immediately be stopped.  
 
8.3 
REFERRALS FOR MEDICAL FOLLOW-UP OR PSYCHOLOGICAL COUNSELING 
We have no indication that our treatment paradigms will in any way increase suicide risk. Patients with high 
suicide risk will not be included in this study. If an enrolled patient shows signs of suicide risks that were not 
apparent during enrollment, a referral to a UNC Psychiatry clinician will be required. 
  
After obtaining participant informed consent, the Hamilton Depression Rating Scale (HDRS) will be administered, 
which contains a question related to suicidal thoughts/actions. If someone answers greater than 2 (i.e., either 
"suicidal ideas or gesture" or "attempts at suicide"), their participation in the study will be immediately stopped 
and Dr. Fryml will be contacted for acute assessment. In the case that they do not see anyone for their depression, 
Dr. Fryml will assist the participant in seeking medical care.  
  
This may include facilitating contact with the subject’s psychiatrist/primary care physician in order to establish a 
plan for safety, continued care, and follow-up. If the patient does not have an established provider, Dr. Fryml will 
assist the patient in establishing care. If at any point in the assessment, the patient is deemed to be an imminent 
risk of harm to self or others, study personnel will enlist the aid of campus security to ensure that the patient is 
safely escorted to the Emergency Department for further care.  
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. 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. 
8.3.1 
PREGNANCY FOLLOW-UP 
Every female participant will take a pregnancy test on Day 1 of Stimulation. If, after testing negative at 
Day 1 of Stimulation (meeting inclusion criteria), 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 subjects 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 inform 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 (see 9.3 Reporting Procedures). 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 medical monitor, who will review AEs in real time and make 
decisions regarding a participant’s continuation of the clinical trial. The PI will review AEs weekly with research 
team and may request additional review on a case-by-case basis. The medical monitor will also be present in order 
to discuss/explain any event(s) that may occur. 
9.3 
EARLY WITHDRAWAL OF PARTICIPANTS 
9.3.1 
REASONS FOR WITHDRAWAL 
A study participant will be discontinued from further participation if: 
• 
The participant fails to adhere to rules, including stress, exercise, and sleep restrictions 
• 
The participant meets any exclusion criteria (either newly developed or not previously 
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• 
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 AND FOLLOW-UP 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 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, given that previous studies using tDCS in patients with depression and schizophrenia have had no seizures 
occur (Berlim et al., 2013, Brunelin et al., 2012). 
The study will also be stopped (at least temporarily) if studies provide evidence that transcranial current 
stimulation caused brain damage or other harmful effects on subjects, 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 reasons for stopping the study and asking for further investigation include: 
• 
If a seizure occurs during a study visit, a temporary hold will be placed on the clinical trial 
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 session. 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). 
In addition to this survey, the study coordinator or research assistant will periodically check in with the participant 
during the stimulation session to assess side effects.  
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 and Co-Is, 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 
and Co-Is), actions taken, and outcome(s). The log will be reviewed and initialed by the PI 72 hours after 
being completed. All AEs occurring during the clinical trial will be documented appropriately regardless of 
relationship to tACS. All AEs will be followed to adequate resolution and will be graded for severity and 
relationship to study treatment. Any medical condition noted at the initial session will be considered at 
baseline and not reported as an AE. 
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• 
ASYMPTOMATIC. The participant is exhibiting no symptoms due to this event; no treatment 
needed. 
• 
MILD. Event results in mild or transient discomfort, not requiring intervention or treatment; does 
not limit or interfere with daily activities (e.g., insomnia, mild headache) 
• 
MODERATE. Event is sufficiently discomforting so as to limit or interfere with daily activities; may 
require interventional treatment (e.g., fever requiring antipyretic medication). In the case of a 
moderate AE, the medical advisor may recommend an over the counter medication. 
• 
SEVERE AND UNDESIRABLE. Event results in significant symptoms that prevent normal daily activities; 
may require hospitalization or invasive intervention (e.g., anemia resulting in blood transfusion). 
Changes in the severity of an AE will be documented with the Note to File document (Appendix E) and will 
be filed in the participant’s folder. 
*Relationship to Study Products: The PI and Co-Is will together 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, 
result in a persistent or significant disability/incapacity or result in congenital anomaly/birth defect.  Other 
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 
subjects or others to include, in general, any incident, experience, or outcome that meets all of the 
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• 
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 subject 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 subjects 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 
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 
10.3.1 REPORTING OF PREGNANCY 
Pregnancy tests will be administered on Day 1 of Stimulation to all women of child-bearing potential. 
There are no studies that suggest tACS would interfere with pregnancy. However, should a participant 
become pregnant during the study, their participation will be immediately terminated and will be sent to 
consult with the Co-I and medical monitor. 
10.4 
TYPES AND DURATION OF FOLLOW-UP OF PARTICIPANTS AFTER ADVERSE EVENTS 
Medical monitors and Co-Is 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. Flavio Frohlich.   
11.1 
STATISTICAL ANALYSIS STRATEGIES 
The analysis will rely on a repeated-measures ANOVA model for the paired response [Safter, Sbefore] conditional on 
cohort (mood disorder vs healthy).  We will test the null hypothesis that "The mean difference (Sdiff = Safter-Sbefore) in 
both subpopulations is exactly zero."  The expected result is that the estimated mean difference will be large in 
both cohorts.  We will also test the null hypothesis that "mean Sdiff[mood disorder] is exactly equal to mean 
Sdiff[healthy]."  We anticipate that this test is highly likely to be inconclusive because we believe that (mean Sdiff[mood 
disorder] - mean Sdiff[healthy] ) is near zero or small for the target subpopulations from which we are sampling.  We will 
address the questions "How large is the effect of stimulation in each of the two target subpopulations?"  and "How 
large is the between-subpopulation difference?" Based on studies that we have described above (Neuling et al. 
2013), we expect to see large effect sizes for the main effect and small effect sizes for the interaction. 
 
Primary outcomes: 
• 
Interaction in the effect of tACS on left frontal alpha oscillation in the depressed group. Two-way 
interaction of within-participant factor of before/after tACS and between-participant factor of 
alpha-tACS/placebo. 
• 
Interaction in the effect of tACS on left frontal alpha oscillation in the healthy group. Two-way 
interaction of within-participant factor of before/after tACS and between-participant factor of 
alpha-tACS/placebo. 
• 
Three-way interaction in the effect of tACS on left frontal alpha oscillations between both groups 
(healthy and patient), session (before and after), and stimulation (alpha-tACS and placebo). 
 
11.2 
SAMPLE SIZE DETERMINATION 
Number of included participants in this experiment allows us to obtain significance (significance level 0.05) on a 
mixed measure ANOVA with a power of 80% for effects with a large effect size (f>=0.4). Two ANOVAs will be run, 
one for each group (healthy and patient):  two-way with between-participant factor stimulation (verum and sham) 
and within-participant factor session (before and after). We expect to see a large effect sizes when assessing the 
main effect session on alpha power (primary outcome). Alpha power for the 2 sessions will be highly correlated 
based on previous studies (r-value ~ 0.9)(Mathewson et al., 2015). Thus, we have planned to have at least 40 
participants in each ANOVA (40 per group healthy and patient).  
 
11.3 
DATA MANAGEMENT 
Data will be stored in a password-protected cloud-based data system that does not contain any patient 
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. 
 
 

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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 subject 
authorization informing the subject 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 subject 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 subject is alive) at the end of their scheduled study period. 
12.2 
CONFIDENTIALITY 
To ensure confidentiality, all data will only be referenced by a dummy identifier. Source documents (i.e. paper 
forms) will be kept in a locked file cabinet in a locked office. In addition, all data will be de-identified and stored on 
a password-protected computer. The key linking dummy identifiers with participant information will be securely 
located separate from all other data collected, and will never appear in an electronic format.  
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 Co-Is and medical monitor will have access to files upon 
request, as they will need access to the locked rooms and filing cabinets 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 4109). 
12.2.2 SENSITIVE INFORMATION 
Sensitive information may be collected during the screening process in order to determine eligibility 
(medical history, recreational drug use, etc.). Such information will be de-identified and stored in a secure, 
locked file cabinet, and will not be used in any further proceedings in the study. 
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. 

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12.3 
SOURCE DOCUMENTS 
Source data is all information, original records of clinical findings, observations, or other activities in a clinical trial 
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 
• 
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. 
DNA. 
• 
Participant names will not be on any of the samples collected. DNA is sequenced to check for one 
nucleotide. When testing is performed, only de-identified information is shared with an outside party. 
This information will not be shared with anyone outside of the study personnel, including the participant.  
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 

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process, review for eligibility, questionnaire administration, data entry, device 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. The CTRC nurse will 
serve as the medical monitor for the study. 
12.5 
DATA CAPTURE METHODS  
Data will be entered directly from the source documents and stored on a password-protected computer in the 
Frohlich Lab by a researcher. All stored data will be de-identified and will not contain any reference to participant 
name or other personal information, such as email or phone number.   
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 Subjects of Research, as drafted by 
the US National Commission for the Protection of Human Subjects 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 
tACS will be provided to the participants. 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. 
The researcher and potential participants will review the clinical trial in its entirety by reviewing the consent form 
together in a private location. If the participant is unclear on any part of the consent form, the research will return 

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to the section and explain further. Participants must sign the informed consent document prior to any procedures 
taking place. 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.  
13.4 
EXCLUSION OF WOMEN, MINORITIES, AND CHILDREN (SPECIAL POPULATIONS) 
Non-English speaking individuals are excluded because the ability to accurately and complete communicate study 
information, answer questions about the study, and obtain consent is necessary. Female participants will be asked 
if there is any reason to believe they might be 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 
transcranial current stimulation studies. All women of child-bearing potential will be asked to take a pregnancy test 
during the initial session in order to determine eligibility for the study. 
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. 
 
 

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14 
PUBLICATION POLICY 
This study will be registered on clinicaltrials.gov once IRB approved. There are no restrictions on publications since 
this is an investigator-initiated study funded by a grant agency (NARSAD) that has no influence on the publications 
resulting from this study. The aim is to publish the results of this study in a peer-reviewed, highly-ranked psychiatry 
journal. 
 
 

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15 
LITERATURE REFERENCES 
Allen, J. J. B. and S. J. Reznik (2015). "Frontal EEG asymmetry as a promising marker of depression vulnerability: 
summary and methodological considerations." Current Opinion in Psychology 4: 93-97. 
Antal, A., Chaieb, L., Moliadze, V., Monte-Silva, K., Poreisz, C., Thirugnanasambandam, N., & ... Paulus, W. (2010). 
Brain-derived neurotrophic factor (BDNF) gene polymorphisms shape cortical plasticity in humans. Brain 
Stimulation, 3(4), 230-237. doi:10.1016/j.brs.2009.12.003 
Carver, C. S., & White, T. L. (1994). Behavioral inhibition, behavioral activation, and affective responses to 
impending reward and punishment: The BIS/BAS scales. Journal of Personality and Social Psychology, 67, 319-333. 
Craske, M. G. (2012). "The R-DoC initiative: science and practice." Depress Anxiety 29(4): 253-256. 
Debener, S., Beauducel, A., eacute, Nessler, D., Brocke, B., Heilemann, H., . . . rgen, u. (2000). Is resting anterior 
EEG alpha asymmetry a trait marker for depression? Neuropsychobiology, 41(1), 31-37. 
Egan M.F., Kojima M., Callicott J.H., Goldberg T.E., Kolachana B.S., Bertolino A., et al. (2003). The BDNF val66met 
polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell, 
112(2), pp. 257–269.  doi:10.1016/S0092-8674(03)00035-7 
Frohlich, F. (2015). Tuning out the Blues - Thalamo-Cortical Rhythms as a Successful Target for Treating Depression. 
Brain Stimul. doi: 10.1016/j.brs.2015.07.040 
Hariri, A. R., Goldberg, T. E., Mattay, V. S., Kolachana, B. S., Callicott, J. H., Egan, M. F., & Weinberger, D. R. (2003). 
Brain-Derived Neurotrophic Factor val⁶⁶ met Polymorphism Affects Human Memory-Related Hippocampal Activity 
and Predicts Memory Performance. The Journal Of Neuroscience, 23(17), 6690-6694. 
Helfrich, R. F., Schneider, T. R., Rach, S., Trautmann-Lengsfeld, S. A., Engel, A. K., & Herrmann, C. S. (2014). 
Entrainment of brain oscillations by transcranial alternating current stimulation. Current Biology, 24(3), 333-339. 
Hong, L., Walz, J. M., & Sajda, P. (2014). Your eyes give you away: prestimulus changes in pupil diameter correlate 
with poststimulus task-related EEG dynamics. PLoS One, 9(3), e91321. doi: 10.1371/journal.pone.0091321 
Johnson, S. L., et al. (2003). "BIS/BAS levels and psychiatric disorder: An epidemiological study." Journal of 
Psychopathology and Behavioral Assessment 25(1): 25-36. 
Kasch, K. L., et al. (2002). "Behavioral activation and inhibition systems and the severity and course of depression." 
J Abnorm Psychol 111(4): 589-597. 
Kleim, J. A., Chan, S., Pringle, E., Schallert, K., Procaccio, V., Jimenez, R., & Cramer, S. C. (2006). BDNF val66met 
polymorphism is associated with modified experience-dependent plasticity in human motor cortex. Nature 
Neuroscience, 9(6), 735-737. doi:10.1038/nn1699 
Klimesch, W. (2012). "alpha-band oscillations, attention, and controlled access to stored information." Trends Cogn 
Sci 16(12): 606-617. 
Koss, M. C. (1986). Pupillary dilation as an index of central nervous system alpha 2-adrenoceptor activation. J 
Pharmacol Methods, 15(1), 1-19. 

SSDE 
 
Version 1.0 
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36 
Leuchter, A. F., Cook, I. A., Feifel, D., Goethe, J. W., Husain, M., Carpenter, L. L., . . . George, M. S. (2015). Efficacy 
and Safety of Low-field Synchronized Transcranial Magnetic Stimulation (sTMS) for Treatment of Major 
Depression. Brain Stimul, 8(4), 787-794. doi: 10.1016/j.brs.2015.05.005 
Leuchter, A. F., Cook, I. A., Jin, Y., & Phillips, B. (2013). The relationship between brain oscillatory activity and 
therapeutic effectiveness of transcranial magnetic stimulation in the treatment of major depressive disorder. Front 
Hum Neurosci, 7, 37. doi: 10.3389/fnhum.2013.00037 
Leuchter, A. F., Hunter, A. M., Krantz, D. E., & Cook, I. A. (2015). Rhythms and blues: modulation of oscillatory 
synchrony and the mechanism of action of antidepressant treatments. Ann N Y Acad Sci, 1344, 78-91. doi: 
10.1111/nyas.12742 
Mathewson, K. J., Hashemi, A., Sheng, B., Sekuler, A. B., Bennett, P. J., & Schmidt, L. A. (2015). Regional 
electroencephalogram (EEG) alpha power and asymmetry in older adults: a study of short-term test–retest 
reliability. Frontiers in aging neuroscience, 7. 
Murias, M., Webb, S. J., Greenson, J., & Dawson, G. (2007). Resting state cortical connectivity reflected in EEG 
coherence in individuals with autism. Biological psychiatry, 62(3), 270-273. 
Murphy, P. R., Robertson, I. H., Balsters, J. H., & O'Connell R, G. (2011). Pupillometry and P3 index the locus 
coeruleus-noradrenergic arousal function in humans. Psychophysiology, 48(11), 1532-1543. doi: 10.1111/j.1469-
8986.2011.01226. 
Neuling, T., Rach, S., & Herrmann, C. S. (2013). Orchestrating neuronal networks: sustained after-effects of 
transcranial alternating current stimulation depend upon brain states. Front Hum Neurosci, 7, 161. doi: 
10.3389/fnhum.2013.0016. 
de Pascalis, V., et al. (2013). "Relations among EEG-alpha asymmetry, BIS/BAS, and dispositional optimism." Biol 
Psychol 94(1): 198-209. 
Pezawas L.,Verchinski B.A., Mattay V.S., Callicott J.H., Kolachana B.S., Straub R.E., Egan M.F., Meyer-Lindenberg A, 
Weinberger D.R. (2004). “The Brain-Derived Neurotrophic Factor val66met Polymorphism and Variation in Human 
Cortical Morphology.” The Journal of Neuroscience 24 (45): 10099–102. doi:10.1523/JNEUROSCI.2680-04.2004. 
Saalmann, Y. B., Pinsk, M. A., Wang, L., Li, X., & Kastner, S. (2012). The pulvinar regulates information transmission 
between cortical areas based on attention demands. Science, 337(6095), 753-756. doi: 10.1126/science.1223082 
Spielberger, C. D., Gorsuch, R. L., Lushene, R., Vagg, P. R., & Jacobs, G. A. (1983). Manual for the State-Trait Anxiety 
Inventory. Palo Alto, CA: Consulting Psychologists Press. 
Thut, G., Veniero, D., Romei, V., Miniussi, C., Schyns, P., & Gross, J. (2011). Rhythmic TMS causes local entrainment 
of natural oscillatory signatures. Current biology : CB, 21(14), 1176-1185. doi: 10.1016/j.cub.2011.05.049 
von Stein, A., & Sarnthein, J. (2000). Different frequencies for different scales of cortical integration: from local 
gamma to long range alpha/theta synchronization. Int J Psychophysiol, 38(3), 301-313. 
Vossen, A., Gross, J., & Thut, G. (2015). Alpha power increase after transcranial alternating current stimulation at 
alpha frequency (?-tACS) reflects plastic changes rather than entrainment. Brain stimulation, 8(3), 499-508. 

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Watson, D., Clark, L. A., & Tellegan, A. (1988). Development and validation of brief measures of positive and 
negative affect: The PANAS scales. Journal of Personality and Social Psychology, 54(6), 1063–1070. 
  
 

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APPENDIX A: SCHEDULE OF EVENTS 
 
 
 
Procedures 
Phone 
Screening 
Stimulation Day 
Provide Verbal Consent 
x 
 
Signed Consent Form 
 
x 
Assessment of Eligibility Criteria 
x 
x 
Urine Pregnancy Test 
 
x 
Urine Drug Test 
 
x 
Baseline Assessments 
 
x 
Saliva Sample 
 
x 
EEG during task 
 
x 
EEG during rest 
 
x 
Stimulation 
 
x 
EEG during rest 
 
x 
EEG during task 
 
x 
Stimulation Questionnaire 
 
x 
 
 
 

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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 therapy? 
a.  
2. What is the temporal relationship of the AE to the study therapy? 
a.  
3. Does the AE improve or disappear when the therapy 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:  
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________ 
 
Steps to be taken (if applicable) 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________ 
Co-I signature 
_______________________________________________________Date___________ 
 
PI Comments:  
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________

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______________________________________________________________________________
______________________________________________________________________________
______________________________ 
 
Steps to be taken (if applicable) 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________ 
 
PI signature 
_______________________________________________________Date___________ 
 

 
 
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41 
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) 
Initials 
Reference 
ID 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. Recover
2. Not Recov
3. Recover
w/Seque
4. Fatal
5. Unknow
 
 
 
 
 
Yes  /  No 
 
 

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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. Recover
2. Not Recov
3. Recover
w/Seque
4. Fatal
5. Unknow
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 

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Appendix E: Informed Consent Quiz 
 
Abbreviated Study Title:  
 
 
Participant Name:  
               Date of Birth:  
 
 
Please INITIAL next to “Yes” or “No” by each line as appropriate (if “No,” an explanation MUST be provided in the 
notes section below). 
 
Yes 
 
No 
Participant and/or the participant’s legally authorized representative (LAR) was given 
a copy of the consent document to read. 
 
Yes 
 
No 
Ample time was provided for reading the consent document, and the participant (or 
participant’s LAR) was encouraged to ask questions. 
 
Yes 
 
No 
All questions and concerns were addressed to the satisfaction of the participant (or 
participant’s LAR) prior to signing the consent document. 
 
Yes 
 
No 
The PI or Sub-I was available for questions prior to the subject signing the consent.  
 
Yes 
 
No 
The subject (or subject’s LAR) agreed to participate in the study and signed/dated the 
consent document. 
 
Yes 
 
No 
A copy of the signed consent document was provided to the participant (or 
participant’s LAR). 
 
 
 
 
q Verbal consent was obtained (per IRB approved consent process).  Documentation 
of the process and the individual(s) witnessing the process is described below. 
 
Yes 
 
No 
No procedures specifically related to the study were performed prior to the 
participant signing the consent document. 
 
The details of this research study were discussed with the participant (or participant’s LAR), including an 
explanation of all of the elements of the consent document.  The IRB-approved consent document was signed and 
dated by the participant (or participant’s LAR) and a copy of the signed consent document was placed in the 
participant’s medical record (unless otherwise noted).  No activities specifically related to the research were 
initiated until after the execution of the consent document.  The principal investigator was notified of the 
participant’s consent to be enrolled in the study and agrees with enrollment of subject. 
The participant (or participant’s LAR) signed consent document version  
 
 
 
 on 
  
 
 
(date) at  
 
(time). 
Notes:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Person Obtaining Consent 
 
 
Date 
 
 
 
Time 

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APPENDIX F: NOTE TO FILE 
 
IRB#:   
 
 
 
 
 
 
 
      
         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 (16-1911 Experiment 3) 
Date: ________________ Screening ID: _________ Criteria fulfilled: r Yes r No 
 
Hello, my name is _________. I’m calling in regards to your interest in our study on tACS stimulation. 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 a single session of transcranial alternating current stimulation, or tACS, 
influences brain activity in patients with depressed mood and in non-patient controls. In this study, a weak 
electrical current will be applied to your scalp. Some participants have reported a mild tingling feeling while being 
stimulated, but no other side effects have been found. It is not a shock and should cause no pain.  
 
This study will include a single 4 hour session. You will be compensated for your time, regardless if you qualify, 
with a total possible compensation of $90. We will ask that you maintain a regular sleep schedule during the study, 
and adhere to restrictions on exercise, caffeine, and alcohol in the day prior to the session. We will also administer 
a urine drug test, and female participants will be required to take a urine pregnancy test. We also administer 
electroencephalogram or EEG during this visit. Have you heard of EEG before? (Explain EEG if necessary, clarify, 
ensure participant understands). Are you still interested in participating?   
 
(If ‘Yes’, thank them for their time) 
(If ‘No’, proceed) 
 
Great! In order to make sure you are 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.  
 
 
 
 
 
 

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         Age:_________   Sex:_________  
1. Have you ever, or are you currently being treated for a neurological condition (i.e., epilepsy, 
migraines)? 
r No 
r Yes 
2. Are you currently taking medication for the treatment of depression or any other psychiatric 
illness? What medications are you taking? 
r No 
r Yes 
3. Are you currently taking any medication for ADD or ADHD? 
r No 
r Yes 
4. Are you currently diagnosed with a psychiatric illness? (Depression?) 
r No 
r Yes 
5. Are you currently undergoing counseling or psychotherapy treatment for depression, anxiety, 
eating disorders, PTSD, or other behavioral conditions? 
r No 
r Yes 
CONTROL GROUP 
 
 
a. Do you have a first degree relative (parent, sibling, or child) with a history of 
neurological or psychiatric illness? 
r No 
r Yes 
DEPRESSED GROUP 
 
 
a. Have you been diagnosed with a depressive condition by a professional (i.e., a 
psychiatrist or licensed clinician)? 
r No 
r Yes 
b. Have you ever been hospitalized? 
• 
If yes, was it related to depression or psychiatric illness? 
• 
If yes, when did this occur? _______________________ 
r No 
r No 
r Yes 
r Yes 
c. 
How long have you been depressed? ___________________ 
 
 
6. Have you ever had a traumatic brain injury or serious concussion? 
r No 
r Yes 
7. Have you ever had brain surgery? 
r No 
r Yes 
8. Do you have any brain devices or implants, including a cochlear implant or aneurysm clip? 
r No 
r Yes 
9. Do you use any drugs, including cannabis? Please note that we will administer a urine drug test 
at the first session. 
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 
2. We will also ask you to fill out a series of questionnaires electronically before your first session. 
These questionnaires will ask for information about your sleep habits, personality traits, etc. All 
responses will be deidentified and stored securely in the UNC REDCap system. Would you be 
comfortable with filling out these questionnaires? 
r No 
r Yes 
 
 

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APPENDIX H: TRAINING LOG 
Title of Training:______________________________ 
DATE:__________________________ 
By signing below, each staff member verifies they have been trained on the information and understand the 
obligations/responsibilities associated with this training. 
Trainer Name (if relevant):_____________________________ 
Trainer Signature (if relevant):_________________________  
Training Date 
(if different than above) 
Trainee Name 
(please print) 
Trainee Signature 
T
(ie Pre