Rational Optimization of tACS for Targeting Thalamo-Cortical Oscillations (Experiment 2)
Phase: NA
Conditions: Healthy
Sponsor: University of North Carolina, Chapel Hill

 
 
CONFIDENTIAL 
 
0 
 
 
Effect of tACS Stimulation on Alpha Oscillations 
   
 
 
 
 
NCT number NCT03178344 
Document Date 11 April 2017 
 
 
 
 
 
 
 
 
 
 
 

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Effect of tACS Stimulation on Alpha Oscillations 
   
 
Funding Mechanism: 
R01 
Principal Investigator: 
Flavio Frohlich, PhD 
Co-Investigator: 
N/A 
Protocol Number: 
16-1911a 
Version Number: 
1.1 
Date: 
11 April 2017 
 
 
 
 
 
 
 
 
Initial version: 
2/27/17 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ...................................................................................................................... 5 
STUDY SUMMARY ................................................................................................................................ 6 
1 
KEY ROLES ..................................................................................................................................... 7 
1.1 
INDIVIDUALS .................................................................................................................................. 7 
1.2 
INSTITUTIONS ................................................................................................................................. 7 

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1.3 
OPTIONAL ..................................................................................................................................... 7 
1.4 
FUNDING SOURCES ......................................................................................................................... 8 
2 
INTRODUCTION ............................................................................................................................. 9 
2.1 
BACKGROUND ................................................................................................................................ 9 
2.2 
INVESTIGATIONAL AGENT ................................................................................................................. 9 
2.3 
DOSE RATIONALE ............................................................................................................................ 9 
2.4 
STUDY AIMS/HYPOTHESES ............................................................................................................. 10 
3 
SUBJECT SELECTION AND WITHDRAWAL ...................................................................................... 11 
3.1 
INCLUSION CRITERIA ...................................................................................................................... 11 
3.2 
EXCLUSION CRITERIA ..................................................................................................................... 11 
3.3 
STRATEGIES FOR RECRUITMENT AND RETENTION ................................................................................. 12 
3.3.1 
RECRUITMENT ................................................................................................................................... 12 
3.3.2 
RETENTION ....................................................................................................................................... 12 
4 
BASIC STUDY DESIGN ................................................................................................................... 13 
4.1 
TREATMENT ASSIGNMENT PROCEDURES ............................................................................................ 13 
4.1.1 
RANDOMIZATION PROCEDURES ............................................................................................................ 13 
5 
STUDY SCHEDULE ........................................................................................................................ 15 
5.1 
SCREENING .................................................................................................................................. 15 
5.2 
STIMULATION SESSIONS ................................................................................................................. 15 
5.4.1 
SESSION 1 ........................................................................................................................................ 15 
5.4.2 
SESSION 2 ........................................................................................................................................ 15 
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 
6.4.2 
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 

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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 .................................................. 21 
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 ..................................................................................................................... 29 
11.1 
STATISTICAL ANALYSIS STRATEGIES ................................................................................................. 29 
11.2 
SAMPLE SIZE DETERMINATION ....................................................................................................... 29 
11.3 
DATA MANAGEMENT ......................................................................... ERROR! BOOKMARK NOT DEFINED. 
12 
DATA HANDLING AND RECORD KEEPING ................................................................................... 31 
12.1 
PHI AND HIPAA ........................................................................................................................ 31 
12.2 
CONFIDENTIALITY ....................................................................................................................... 31 
12.2.1 
ACCESS TO SOURCE DOCUMENTS ....................................................................................................... 31 
12.2.2 
SENSITIVE INFORMATION .................................................................................................................. 31 
12.2.3 
OTHER ........................................................................................................................................... 31 
12.3 
SOURCE DOCUMENTS .................................................................................................................. 32 
12.4 
DATA MANAGEMENT RESPONSIBILITIES ........................................................................................... 32 
12.5 
DATA CAPTURE METHODS ............................................................................................................ 33 
12.6 
PROTOCOL DEVIATIONS ............................................................................................................... 33 

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12.7 
RECORD RETENTION .................................................................................................................... 33 
13 
ETHICAL CONSIDERATIONS ........................................................................................................ 34 
13.1 
ETHICAL STANDARD .................................................................................................................... 34 
13.2 
INSTITUTIONAL REVIEW BOARD (IRB) ............................................................................................. 34 
13.3 
INFORMED CONSENT PROCESS ...................................................................................................... 34 
13.4 
EXCLUSION OF WOMEN, MINORITIES, AND CHILDREN (SPECIAL POPULATIONS) ....................................... 35 
13.5 
PARTICIPANT CONFIDENTIALITY ..................................................................................................... 35 
13.6 
STUDY DISCONTINUATION ............................................................................................................ 35 
14 
PUBLICATION POLICY ................................................................................................................ 36 
15 
LITERATURE REFERENCES .......................................................................................................... 37 
APPENDIX A: SCHEDULE OF EVENTS ................................................................................................... 39 
APPENDIX B: AE REPORT FORM ......................................................................................................... 39 
APPENDIX C: IRB AMENDMENT TRACKING LOG ................................................................................. 42 
APPENDIX D: AE REPORT FORM ......................................................................................................... 43 
APPENDIX F: NOTE TO FILE ................................................................................................................. 47 
APPENDIX G: TELEPHONE SCRIPT ....................................................................................................... 49 
APPENDIX H: TRAINING LOG .............................................................................................................. 51 
 
 
 

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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 
Hertz 
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 
A pilot, randomized, double-blind, crossover study investigation the effects of 10Hz 
transcranial alternating current stimulation on the immune response to psychological 
stress 
Short Title 
AIMS 
Protocol Number 
Version 1.1 
Phase 
Pilot 
Methodology 
Double-blind, randomized, active sham controlled 
Study Duration 
This study will take two 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 explore the effects of alpha oscillations on the 
relationship between the immune system and stress response.  
Number of Subjects 
20 
Diagnosis and Main 
Inclusion Criteria 
Eligible participants will be healthy adults between the ages of 18-35 with no history 
of autoimmune disease or mental or psychiatric disorder.   
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 10 Hz tACS while in a relaxed, yet experimentally controlled 
state, by watching a nature movie such as “Reefscape” during stimulation. 
Related IRB Applications 
N/A 
 
 
 

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1 
KEY ROLES 
1.1 
INDIVIDUALS 
Principal Investigator 
Flavio Frohlich, PhD 
Co-Investigator 
N/A 
Medical Monitor 
N/A 
 
Flavio Frohlich, PhD – Principal Investigator 
UNC – Chapel Hill Department of Psychiatry 
Email: flavio_frohlich@med.unc.edu 
Office: 4109F Neuroscience Research Building 
Phone: (919) 966-4584 
 
Jhana Parikh – Project Manager/Study Coordinator 
UNC – Chapel Hill  
Email:  jhana@live.unc.edu 
Office: Medical School Wing C – Room 221 
Phone:  (919) 802-6873 
 
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 
The University of North Carolina – Chapel Hill 
Medical School Building 52 
Mason Farm Road 
CB #7097 
Chapel Hill, NC 27599-7097 
(919) 966-3113 
 
 
 
 
 
 

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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 field of psychoneuroimmunology investigates to the interaction between the brain and the immune system, 
regulated by psychological and behavioral factors (Kiecolt-Glaser et al, 2002). There are two components of the 
immune system: innate immunity, which generally responds to threats, and adaptive immunity, which forms 
specific responses to invaders up to days after the target is recognized (Segerstrom & Miller, 2004). Studies in 
psychoneuroimmunology have found decreased adaptive immune functioning in individuals subjected to ongoing 
stress, such as medical students who are administered vaccinations during ongoing periods of high stress (Kiecolt-
Glaser et al, 2002). However, lab-induced stressors produce a quick change in markers of innate immunity.  
Upon encountering an acute psychological stressor, such as a scary movie or difficult exam, the sympathetic 
nervous system activates to ready the body for action. Often called the “fight or flight” response, this activation 
includes heart rate elevation, increased sweat secretion, and vasoconstriction of blood vessels (Segerstrom & 
Miller, 2004). These effectors are stimulated by norepinephrine, a neurotransmitter that binds to adrenergic 
receptors on target cells to carry out the sympathetic response. Natural killer (NK) cells – one of the primary 
components of innate immunity – also have adrenergic receptors; therefore, a sympathetic response to a stressor 
also stimulates NK activity. Studies involving lab-induced stressors have demonstrated this relationship through a 
correlation between norepinephrine and NK activity (Schedlowski et al, 1993). Immediately after the stressor, NK 
levels rise to almost double the baseline value, a peak that is accompanied by a similar rise in norepinephrine 
levels. Within an hour, NK activity drops to a level significantly below baseline, as the effects of the stressful event 
and sympathetic activation returns to normal. If this process is repeated, such as during exams or other periods of 
prolonged acute stress, the fluctuations in NK activity can lead to issues in immune functioning (Kiecolt-Glaser et 
al, 2002).   
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). Alpha oscillations, which occur in frequencies between 8-12Hz, have 
been correlated with a relaxed emotional state, and EEG recordings of individuals who are meditating show an 
increase in alpha in the frontal lobe (Lagopoulos et al, 2009; Takahashi et al, 2005). Additionally, this increase in 
alpha during meditation has been negatively correlated with sympathetic activation, further supporting a 
relationship between alpha oscillations and decreased stress.  
2.3 
DOSE RATIONALE 
10Hz tACS will be applied because this frequency corresponds with the alpha band of 8-12Hz and will therefore 
increase alpha oscillations. This increase should produce a decreased sympathetic stress response, as indicated by 
the previously mentioned relationship between alpha and the sympathetic nervous system. 
 

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2.4 
STUDY AIMS/HYPOTHESES 
 
NULL HYPOTHESIS. 10Hz tACS does not decrease immune response compared to active sham. 
ALTERNATIVE HYPOTHESIS. 10Hz tACS decreases immune response compared to active sham.  

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3 
SUBJECT SELECTION AND WITHDRAWAL 
A total of 20 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 the following criteria: 
• 
Between the ages of 18 and 35 years 
• 
Capacity to understand all relevant risks and potential benefits of the study (informed consent) 
• 
Willing to comply with all study procedures and be available for the duration of the study 
• 
Speak and understand English 
3.2 
EXCLUSION CRITERIA 
A potential participant who meets any of the following criteria will be excluded from participation in the study: 
• 
Diagnosis of eating disorder (current or within the past 6 months) 
• 
Diagnosis of OCD (lifetime) 
• 
ADHD (currently under treatment) 
• 
Neurological disorders and conditions, including, but not limited to: 
o 
History of epilepsy 
o 
Seizures (except childhood febrile seizures and ECT-induced seizures) 
o 
Dementia 
o 
History of stroke 
o 
Parkinson’s disease 
o 
Multiple sclerosis 
o 
Cerebral aneurysm 
o 
Brain tumors 
• 
Medical or neurological illness or treatment for a medical disorder that could interfere with study 
participation (e.g., unstable cardiac disease, HIV/AIDS, malignancy, liver or renal impairment) 
• 
Prior brain surgery 
• 
Any brain devices/implants, including cochlear implants and aneurysm clips 
• 
Traumatic brain injury 
• 
(For females) Pregnancy or breast feeding 
• 
Personal or family history of mental/psychiatric disorder (e.g., anxiety, major depressive disorder, 
schizophrenia, etc.) 
• 
Diagnosis of an autoimmune disorder 
• 
Failure to pass a urinary drug test at the first session. 
• 
Anything that, in the opinion of the investigator, would place the participant at increased risk or preclude 
the participant’s full compliance with or completion of the study 
Justifications for any exclusions based on race, gender, or ethnicity: 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. 

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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 
The target population of this study includes healthy individuals between the ages of 18 to 35 pulled from 
UNC Chapel Hill and the surrounding area, including approximately 30,000 candidates for participation. 
Recruitment will occur via two methods: flyers to be distributed at major locations on the campus 
(libraries, gyms, classroom buildings, etc.) and a mass email to all individuals with a UNC-affiliated email 
address.  
3.3.2 
RETENTION 
The retention strategy includes a payment schedule of two times per participant, corresponding with the 
two sessions. The second session will involve a bonus payment for completion of the study. Research staff 
will send participants a reminder text the day before each session, and will be available by email and 
phone at all times.  
 

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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 20 healthy participants, both male 
and female, between the ages of 18-65. 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 2 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 with 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. 10 Hz tACS 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 peak-to-peak amplitude of 2 mA. 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 total of 2 visits, each lasting approximately 3 hours and separated by at least 1 
week. Total participation will include about 6 hours over the course of two weeks. 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 research will know which treatment the participant is receiving, if any. 
4.1.1 
RANDOMIZATION PROCEDURES 
Charles Zhou will randomize 40 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 10 Hz tACS) 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 
Visit 1: Sham tACS 
Visit 2: 10Hz tACS 
Visit 1: 10 Hz tACS 
Visit 2: 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.  
5.2 
STIMULATION SESSIONS 
Participants will undergo two sessions with the same procedure; the only change will be the stimulation condition. 
5.4.1 
SESSION 1  
In the initial session, participants will be explained the procedure and reminded of their expectations and 
rights (informed consent). After obtaining consent, a urine drug test and pregnancy screening will be 
administered. Once they are both determined to be negative, the stimulation, EEG, and heart rate 
electrodes will be applied. Participants will then undergo a ten-minute resting state block to record EEG 
activity. Participants then provide a baseline saliva sample and receive 40 minutes of either 10Hz tACS or 
sham stimulation (depending on the randomized condition) while watching the ‘Reefscape’ video. After 
the stimulation, the participant will complete the stimulation adverse effects questionnaire, and will then 
provide a final saliva sample. The study coordinator will remove all equipment, and the participant will fill 
out the final two questionnaires and receive $20 in compensation. 
5.4.2 
SESSION 2 
The procedure for the second session will follow the same timeline as the first, with the exclusion of 
informed consent, urine drug test, and pregnancy screening processes. Participants will receive $40 in 
compensation at the end of this session. 
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 PERCEIVED STRESS SCALE (PSS) is a 10-item self-report assessment using a 5-level Likert scale to assess the 
degree to which an individual perceives life events as stressful in the past month. This scale is the most 
commonly used measure of self-reported stress, and produces results that are valid for 4-8 weeks after 
administration (Cohen & Williamson, 1988).  
B. 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). 
C. 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).  
D. THE CONNOR-DAVIDSON RESILIENCE SCALE (CD-RISC) is a 25-item self-report assessment using a 5-level Likert 
scale to assess the degree of resilience an individual displays to stressful events. This scale has been 
shown to be a reliable measure of resilience, correlating with improvement during treatments designed to 
improve anxiety disorders (Connor & Davidson, 2003).  
E. 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).  
6.2 
SPECIAL ASSAYS OR PROCEDURES 
Each participant will receive two days of stimulation, separated by a week. One session will involve 10Hz tACS, and 
the other will involve active sham; the order of stimulation condition will be randomized for each participant. 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.  
 
6.4 
LABORATORY EVALUATIONS 

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6.4.1 
SCREENING LABORATORY EVALUATIONS 
A urine pregnancy test will be performed for any female participant who is unable to confirm pregnancy 
status. 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. 
6.4.2 
SALIVA SAMPLES 
We will be collecting a saliva sample at the first session. This sample will be used 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. 
We will also be collecting two saliva samples at each session to test for a cytokine panel, salivary alpha-
amylase, and cortisol as measures of immunity and stress.  
INSTRUCTIONS FOR SPECIMEN PREPARATION, HANDLING, AND STORAGE. The saliva samples for BDNF testing 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. 
Saliva samples at each session will be collected using the Passive Drool collection kit from Salimetrics. 
These samples will be labeled with the study name and participant ID, and frozen immediately after 
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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 stimulation 
questionnaire.  
7.4 
ASSESSMENT OF PARTICIPANT COMPLIANCE WITH STUDY INVESTIGATIONAL PRODUCT 
Compliance for this study includes attending both sessions. Individuals who miss a session and are unable to 
reschedule within one week will be dropped from the study.  
 
 

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8 
POTENTIAL RISKS AND BENEFITS 
8.1 
BENEFITS TO SUBJECTS AND SOCIETY 
The results of this study have major implications for the use of tACS as a treatment method for alleviating stress 
and symptoms of stress. One such symptom is compromised immune functioning, which has been demonstrated 
as detrimental especially in students and other individuals experiencing high levels of acute stress. The results of 
this study may also prompt further investigation into the relationship between cortical oscillations and immune 
functioning.  
This study is not designed to benefit the individual participants. However, participants may experience some acute 
or even chronic stress relief as a result of the treatment. There are no serious risks to the participant from the 
treatment used in this study.  
8.2 
POTENTIAL RISKS 
8.2.1 
PSYCHOLOGICAL 
Emotional Distress: As part of data collection, participants will undergo a timed mental arithmetic task 
designed to induce psychological stress. This task is meant to induce a short-term stress response via 
enhanced secretion of catecholamines. Such a response occurs naturally in the body and has not shown 
any long-term negative side effects. In order to protect the integrity of results, participants will not be 
made aware of the purpose of the task until after completion of the final session.  
8.2.2 
PHYSICAL 
Risk of Injury and Discomfort: Transcranial current stimulation has been used without any reports of 
serious side-effects for more than a decade. This stimulation made 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 cause super-threshold activation of neurons 
(Frohlich and McCormick, 2010). In particular, tACS has been used without reports of any serious side-
effects. Some participants report a transient mild tingling, burning, or itching underneath the electrodes 
and headache, but no other side effects have been noted. Importantly, it remains unclear if these mild 
side-effects were caused by the transcranial brain stimulation. In order to monitor these side-effects, we 
will be administering an adverse effects stimulation questionnaire after each stimulation session to 
determine whether these effects were experienced. Research personnel present during these sessions 
will also check in with the participant periodically during the stimulation to see whether they are 
comfortable. If any side-effect occurs (rated by the participant as stronger than “moderate”) or the 
participant is experiencing severe discomfort, the stimulation will be immediately stopped. 
 
8.3 
REFERRALS FOR MEDICAL FOLLOW-UP OR PSYCHOLOGICAL COUNSELING 
There is a purely theoretical likelihood that stimulation of neuronal circuits can lead to epileptic discharge. To 
minimize this occurrence, we screen and exclude patients with personal and family history of neurological 
conditions from the study. If abnormalities or a seizure is witnessed during the course of the study, a referral will 
be made to the UNC Department of Neurology for follow-up. In the theoretical event that a seizure is witnessed 

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that involves the loss of consciousness, the patient will be told not to operate a motor vehicle until cleared by the 
DMV. 
To ensure participant comfort, a study coordinator or research assistant will periodically check in with the 
participant about any side-effects he/she may be experiencing during each stimulation session. Following the 
conclusion of the stimulation session, the participant will receive an Adverse Effects Questionnaire to report on 
any of the side-effects he/she may have experienced. This questionnaire reports side-effects on a likert scale 
(1=Absent, 2=Mild, 3=Moderate, 4=Severe). If the participant reports side-effects of Moderate to Severe intensity, 
a study coordinator or research assistant will discuss the side-effects experienced and note this response. The PI 
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 PI, who will review AEs in real time and make decisions 
regarding a participant’s continuation of the clinical trial.  
9.3 
EARLY WITHDRAWAL OF PARTICIPANTS 
9.3.1 
REASONS FOR WITHDRAWAL 
A study participant will be discontinued from further participation if: 
• 
The participant fails to adhere to rules, including stress, exercise, and sleep restrictions 
• 
The participant meets any exclusion criteria (either newly developed or not previously 
recognized). 
• 
Anything that, in the opinion of the investigator, would place the participant at increased risk or 
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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-I, 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-I*), 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 will determine whether an AE is associated with the study 
treatment. The event will be labeled associated if the event is temporally related to the administration of 
a therapy and no other factors can explain the event. The event will be labeled as not associated if the 
event is temporally independent of the study treatment and can be explained by external factors, such as 
major life events. 
10.2.1 SERIOUS ADVERSE EVENTS 
Serious Adverse Event (SAE): An SAE, as defined by the NIH, consists of adverse events that result in 
death, require either inpatient hospitalization or the prolongation of hospitalization, are life-threatening, 
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. 
10.4 
TYPES AND DURATION OF FOLLOW-UP OF PARTICIPANTS AFTER ADVERSE EVENTS 
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11 
STATISTICAL PLAN 
The statistician for this study is Dr. Flavio Frohlich.   
11.1 
STATISTICAL ANALYSIS STRATEGIES 
11.1.1 MEASURES OF INTEREST 
The primary outcomes of this study will be the quantified changes in cytokine, alpha-amylase, and cortisol 
activity.  
EEG changes will be quantified and analyzed as secondary outcomes. 
11.1.2 AIMS 
AIM 1: Characterize and compare the sham and tACS stimulation conditions in terms of the measures of 
interest, stated above. These outcomes will be used to decide whether the tACS regimen should be 
evaluated in a larger controlled trial. 
AIM 2: Obtain statistical estimates needed to plan a future, large-scale clinical trial. 
11.1.2 ANALYSIS 
Statistical analyses will be performed to test the null hypothesis indicated in section 2.4 Study 
Aims/Hypothesis. Data from the saliva samples will be compared within and between the two treatment 
sessions for each participant. Within sessions, the post-treatment sample will be compared to both the 
post-stress and the baseline, to determine the changes in biomarker levels as a result of the stimulation. 
Then, these two differences will be compared to the same differences from the corresponding treatment 
session for the participant, in order to determine if the tACS treatment had a significant effect on NK cell 
count. Biomarkers will also be correlated with each other to confirm the previously established 
relationship between sympathetic activation and immune response.  
A significant difference (p-value less than or equal to 0.05) between the treatment conditions in within-
session activity of any of the biomarkers will constitute a rejection of the null hypothesis. Any outcome 
with a p value > 0.05 will be regarded as inconclusive. Confidence intervals of 95% will be reported for all 
statistical estimates. Additionally, interpretation of outcomes will focus on estimated changes in levels of 
biomarkers, rather than just significance. Data will be represented in a mixed linear model to account for 
correlated data and unequal variances. In the event that the primary outcomes do not produce significant 
results, exploratory analyses will be conducted on the existing data to determine new hypotheses.  
Any incomplete or missing data will be excluded from analysis; if time permits, further data collection will 
be conducted to account for the loss.  
 
11.2 
SAMPLE SIZE DETERMINATION 
This clinical trial represents a pilot study. A pilot study is a clinical trial that is conducted to decide whether a new 
treatment should be tested in a large controlled trial; therefore, we do not calculate sample size. This study can be 

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considered a pilot study, as it is the first time this specific treatment will be performed on this clinical population. 
The results from this study will be used to determine sample sizes for future, large-scale clinical trials. 
In addition, we have to restrict the number of included participants to a small sample size due to limited funding 
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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 
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. Source documents (i.e. 
paper forms) will be kept in a locked file cabinet in a locked office. 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.  
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.  
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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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 
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 
Buysse, D. J., Reynolds, C. F., Monk, T. H., Berman, S. R., & Kupfer, D. J. (1989). The Pittsburgh sleep quality index: A 
new instrument for psychiatric practice and research. Psychiatry Research, 28(2), 193-213. doi:10.1016/0165-
1781(89)90047-4 
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. 
Cohen, S & Williamson, G. (1998). Perceived Stress in a Probability Sample of the United States. Social Psychology 
of Health, ed. S. Spacapan & S. Oskamp  
Connor, K. M., & Davidson, J. R. (2003). Development of a new resilience scale: the Connor-Davidson Resilience 
Scale (CD-RISQ). Depression and Anxiety 18(2), 76-82. Doi:10.1002/da.10113 
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 
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. 
Kiecolt-Glaser, J. K., McGuire, L., Robles, T. F. & Glaser, R. (2002). Psychoneuroimmunology: psychological 
influences on immune function and health. Journal of Consulting and Clinical Psychology 70, 537-547. 
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 
Lagopoulos, J., Xu, J., Rasmussen, I., Vik, A., Malhi, G.S., Eliassen, C. F., Arnsten, I. E., Saether, J. G., Hollup, S., 
Holen, A., Davanger, S., & Ellingson, O. (2009). Increased theta and alpha EEG activity during nondirective 
meditation. Journal of Alternative and Complementary Medicine, 15, 1187-1192, doi:10.1089/acm.2009.0113. 
Lustenberger, C., Boyle, M. R., Foulser, A. A., Mellin, J. M., & Fröhlich, F. (2015). Functional role of frontal alpha 
oscillations in creativity. Cortex, 67, 74-82. doi:10.1016/j.cortex.2015.03.012  
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. 
Schedlowski, M., Jacobs, R., Stratmann, G., Richter, S., Hadicke, A., Tewes, U., Wagner, T. O., & Schmidt, R. E. 
(1993). Changes of natural killer cells during acute psychological stress. Journal of Clinical Immunology 13, 119-126. 
Segerstrom, S. C. & Miller, G. E. (2004). Psychological stress and the human immune system: a meta-analytic study 
of 30 years of inquiry. Psychological Bulletin 130, 601-630, doi:10.1037/0033-2909.130.4.601. 

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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. 
Takahashi, T.,  Murata, T., Hamada, T., Omori, M., Kosaka, H., Kikuchi, M., Yoshida, H., & Wada, Y. (2005). Changes 
in EEG and autonomic nervous activity during meditation and their association with personality traits. International 
Journal of Psychophysiology 55, 199-207, doi:10.1016/j.ijpsycho.2004.07.004. 
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 
Day 1 of 
Stimulation 
Day 2 of 
Stimulation 
Provide Verbal Consent 
x 
 
 
Signed Consent Form 
 
x 
 
Assessment of Eligibility Criteria 
x 
x 
 
Urine Pregnancy Test 
 
x 
 
Urine Drug Test 
 
x 
 
Baseline Assessments (PSS, CD-RISQ, PSQI) 
 
x 
 
Saliva Sample 
 
x 
x 
Stimulation 
 
x 
x 
Stimulation Questionnaire 
 
x 
x 
Saliva Sample 
 
x 
x 
Final Questionnaires (PANAS, STAI) 
 
x 
x 
 
 
 
 
 
 
 
 
 
 
APPENDIX B: AE REPORT FORM 
 

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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___________