Pilot Clinical Trial for the Evaluation of Feedback Transcranial Alternating Current Stimulation for the Treatment of Major Depressive Disorder
Phase: NA
Conditions: Major Depressive Disorder, MDD
Sponsor: University of North Carolina, Chapel Hill

1 
 
PILOT CLINICAL TRIAL FOR THE EVALUATION OF TRANSCRANIAL ALTERNATING 
CURRENT STIMULATION FOR THE TREATMENT OF MAJOR DEPRESSIVE DISORDER 
IRB # 14-1622 
 
NCT02339285 
 
Funding Mechanism: National Alliance for Research on Schizophrenia and Depression 
(NARSAD) - The Brain and Behavior Research Foundation  
Principal Investigator: Dr. Flavio Frohlich, PhD  
Co-Investigator: Dr. David Rubinow, MD 
Draft or Version Number: 5.0 
04 January 2016 
 
 
 
 

2 
 
STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following  
 United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312) 
 ICH E6; 62 Federal Register 25691 (May 9, 1997)  
All key personnel (all individuals responsible for the design and conduct of this study) have 
completed Human Participants Protection and HIPAA Training. 

3 
 
SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICH guidelines. 
 
Signed: 
 
Date: 
 
 
 
 
 
 

4 
 
TABLE OF CONTENTS 
 
Page 
Statement of Compliance .................................................................................................................2 
Signature Page .................................................................................................................................3 
Table of Contents .............................................................................................................................4 
List of Abbreviations .......................................................................................................................7 
Protocol Summary ...........................................................................................................................9 
1 
Key Roles ..............................................................................................................................13 
2 
Introduction: Background Information and Scientific Rationale ..........................................15 
2.1 
Background Information ...........................................................................................15 
2.2 
Rationale ...................................................................................................................15 
2.3 
Potential Risks and Benefits .....................................................................................16 
2.3.1 Potential Risks ..............................................................................................16 
2.3.2 Known Potential Benefits .............................................................................17 
3 
Objectives .............................................................................................................................19 
3.1 
Study Objectives .......................................................................................................19 
3.2 
Study Outcome Measures .........................................................................................19 
3.2.1 Primary Outcome Measures ..........................................................................19 
3.2.2 Secondary Outcome Measures ......................................................................19 
4 
Study Design .........................................................................................................................20 
5 
Study Enrollment and Withdrawal........................................................................................21 
5.1 
Participant Inclusion Criteria ....................................................................................21 
5.2 
Participant Exclusion Criteria ...................................................................................21 
5.3 
Strategies for Recruitment and Retention .................................................................22 
5.4 
Treatment Assignment Procedures ...........................................................................23 
5.4.1 Randomization Procedures ...........................................................................23 
5.4.2 Reasons for Withdrawal ................................................................................23 
5.4.3 Handling of Withdrawals ..............................................................................23 
5.4.4 Termination of Study ....................................................................................24 
6 
Study Intervention/Investigational Product ..........................................................................25 
6.1 
Study Product Description ........................................................................................25 
6.1.1 Device Description .......................................................................................25 
6.1.2 Operation.......................................................................................................26 
6.1.3 Safety Percautions .........................................................................................27 
6.2 
Preparation and Administration of Study Investigational Product ...........................28 
6.3 
Assessment of Participant Compliance with Study Investigational Product ............29 
7 
Study Schedule......................................................................................................................30 
7.1 
Screening...................................................................................................................30 

5 
 
7.2 
Enrollment/Baseline ..................................................................................................31 
7.3 
Stimulation Sessions .................................................................................................31 
7.4 
Follow-up ..................................................................................................................33 
7.5 
Final Study Visit .......................................................................................................33 
8 
Study Procedures/Evaluations ..............................................................................................34 
8.1 
Clinical Evaluations ..................................................................................................34 
8.2 
Laboratory Evaluations .............................................................................................35 
8.2.1 Clinical Laboratory Evaluations ...................................................................35 
8.2.2 Special Assays or Procedures .......................................................................36 
9 
Assessment of Safety ............................................................................................................37 
9.1 
Specification of Safety Parameters ...........................................................................37 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters .................................................................................................................37 
9.2.1 Adverse Events .............................................................................................37 
9.2.2 Expected Adverse Reactions.........................................................................39 
9.2.3 Serious Adverse Events ................................................................................39 
9.2.4 Unanticipated Problems ................................................................................40 
9.3 
Reporting Procedures ................................................................................................40 
9.3.1 Reporting of Pregnancy ................................................................................41 
9.4 
Type and Duration of Follow-up of Participants after Adverse Events ....................41 
9.5 
Halting Rules ............................................................................................................41 
9.6 
Safety Oversight........................................................................................................42 
10 
Clinical Monitoring ...............................................................................................................43 
10.1 
Frohlich Lab Monitoring Plan ..................................................................................43 
11 
Statistical Considerations ......................................................................................................44 
11.1 
Study Hypotheses......................................................................................................44 
11.1.1 Primary Objective…………………………………………………..............44 
11.1.2 Secondary Objective………………………………………………..............44 
11.2 
Sample Size Considerations ......................................................................................44 
11.3 
Final Analysis Plan ...................................................................................................44 
12 
Source Documents and Access to Source Data/Documents .................................................45 
13 
Ethics/Protection of Human Participants ..............................................................................47 
13.1 
Ethical Standard ........................................................................................................47 
13.2 
Institutional Review Board .......................................................................................47 
13.3 
Informed Consent Process ........................................................................................48 
13.4 
Exclusion of Women, Minorities, and Children (Special Populations) ....................48 
13.5 
Participant Confidentiality ........................................................................................49 
13.6 
Study Discontinuation ...............................................................................................49 
14 
Data Handling and Record Keeping .....................................................................................50 
14.1 
Data Management Responsibilities...........................................................................50 
14.2 
Data Capture Methods ..............................................................................................50 

6 
 
14.3 
Types of Data ............................................................................................................50 
14.4 
Timing/Reports .........................................................................................................51 
14.5 
Study Records Retention...........................................................................................51 
14.6 
Protocol Deviations ...................................................................................................52 
15 
Publication Policy .................................................................................................................53 
16 
Literature References ............................................................................................................54 
Supplements/Appendices ...............................................................................................................57 
Appendix A: Schedule of Events .....................................................................................................57 
Appendix B: Study Start Up Checklist  ....................................................................... ..................58 
Appendix C: Documentation of Informed Consent Process ........................................ ..................59 
Appendix D: Consent Amendment Tracking Log ........................................................ ..................61 
Appendix E: Informed Consent Evaluation Feedback. ............................................... ..................62 
Appendix F: IRB Amendment Tracking Log ............................................................... ..................63 
Appendix G: Note to File ............................................................................................ ..................64 
Appendix H: Inclusion/Exclusion Criteria Checklist with signature of PI for participant 
eligibility. .................................................................................................................... ..................65 
Appendix I: Telephone Contact Log ........................................................................... ..................66 
Appendix J: Adverse Event Tracking Log  .................................................................. ..................67 
Appendix K: Unexpected/Serious Adverse Event Tracking Log................................. ..................68 
Appendix L: Adverse Event Report Form ................................................................... ..................69 
Appendix M: Serious Adverse Event Report Form ..................................................... ..................71 
Appendix N: Delegation of Authority Log  ................................................................. ..................75 
Appendix O: Protocol Deviation ................................................................................ ..................76 
Appendix Q: Enrollment Log ...................................................................................... ..................77 
Appendix R: Training Log  ......................................................................................... ..................78 
Appendix S: Participant Off Study .............................................................................. ..................79 
Appendix T: Telephone Recruitment Script ................................................................ ..................81 
 
 
 
 
 
 
 
 

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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
BDI 
Beck Depression Inventory  
CAPA 
Corrective and Preventative Action 
CFR 
Code of Federal Regulations 
CGI 
Clinical Global Interview 
CNS 
Central Nervous System 
Co-I 
Co-Investigator 
CRF 
Case Report Form 
CRMS 
Clinical Research Management System 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
dl-PFC 
Dorso-lateral Prefrontal Cortex 
DMV 
Department of Motor Vehicles  
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders (Version IV) 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EEG 
Electroencephalogram  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HDRS17 
Hamilton Depression Rating Scale (17 item) 
HIPAA 
Health Insurance Portability and Accountability Act 
HSD 
Honest Significant Difference  
Hz 
Hertz 
ICF 
Informed Consent Form 
IDE 
Investigational Device Exemption 
IRB 
Institutional Review Board 
JAMA 
Journal of the American Medical Association 
LAR 
Legally Authorized Representative  
MADRS 
Montgomery-Asberg Depression Rating Scale 
MDD 
Major Depressive Disorder 
MINI 
Mini International Neuropsychiatric Interview 
MOCA 
Montreal Cognitive Assessment 
NAMI 
National Alliance on Mental Illness 
NARSAD 
National Alliance for Research on Schizophrenia and Depression  
NIH 
National Institutes of Health 
NIMH 
National Institute of Mental Health  

8 
 
NRB 
Neurosciences Research Building 
OHRE 
Office of Human Research Ethics 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SB 
Suicidal Behavior 
SI  
Suicidal Ideation  
SMC 
Safety Monitoring Committee 
SPI 
Serial Peripheral Interface 
SOP 
Standard Operating Procedure 
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 
YMRS 
Young Mania Rating Scale 

9 
 
PROTOCOL SUMMARY 
 
Title: 
Pilot Clinical Trial for the Evaluation of Transcranial Alternating 
Current Stimulation for the Treatment of Major Depressive 
Disorder 
Précis: 
 
The purpose of this clinical trial is to investigate the effects of 
non-invasive transcranial alternating current stimulation (tACS) 
on patients who suffer from Major Depressive Disorder (MDD). 
We will recruit 60 males and females with unipolar, non-
psychotic MDD.  Eligible participants will have 5 daily (one 
week Monday through Friday), 40 minute stimulation sessions. 
Participants will be randomly assigned to one of three groups; 
sham stimulation, 10 Hz (alpha) tACS or 40 Hz (gamma) tACS. 
Participation will include 1 to 8 visits. At the initial session, 
consent will be given and eligibility will be determined. Eligible 
participants will undergo 5 daily stimulation sessions (40 
minutes duration) with daily assessment of suicide risk, mania, 
and stimulation side-effects. Clinical assessments will be 
performed at baseline, 5th day of stimulation, the 2 week follow-
up and the 4 week follow-up using the Montgomery-Asberg 
Depression Rating Scale (Attachment 8). Neurophysiological 
(EEG) and cognitive assays will be performed before and after 
stimulation. Please see Appendix A for a detailed schematic 
describing all visits and assessments. 
 
Objectives: 
 
Our primary objective is to conduct a pilot clinical trial to 
establish the feasibility and collect first effectiveness data for the 
treatment of patients with MDD with tACS. The treatment 
rationale is to down-regulate pathological alpha oscillations in 
left dl-PFC of unmedicated patients with MDD. The primary 
outcome measure of this study is the change in Montgomery-
Asberg Depression Rating Scale (MADRS) between initial 
assessment and assessment at the 4 week follow-up. In addition, 
we will also assess the change in MADRS between week 2 and 
week 5.Changes in alpha power between the first and the last day 
of stimulation is the secondary outcome of this study.  In 
addition, we will perform explorative analysis of the EEG data 

10 
 
from all three time points as a pilot study for the future 
development of EEG-based biomarkers.  
 
 
Population: 
 
We will recruit 60 males and non-pregnant females ages 18-65 
with a diagnosis of unipolar, non-psychotic MDD, who have 
been free of medication for the treatment of MDD for at least 6 
months, including antipsychotic and anticonvulsant medications. 
Eligible participants will have a Hamilton Depression Rating 
Scale > 17 and low suicide risk.  Participants will be recruited 
from the Chapel Hill, Durham and Raleigh areas. 
Phase: 
Pilot Study 
Number of Sites: 
This is a single site study performed at University of North 
Caroline- Chapel Hill. 
Study Duration: 
This study will take 2 years to complete 
Participant Participation 
Duration: 
Eligible participants who complete this clinical trial will have a 
total of 8 visits; an initial session, 5 days of stimulation, a 2 and a 
4 week follow up visit  (Follow up sessions are measured from 
first day of stimulation).  The initial session will take 
approximately 2 hours, the first and last day of stimulation will 
take approximately 5 hours. Days 2 through 4 of stimulation will 
take 1.5 hours each day.  The one week follow up will take 
approximately 2 hours and the four week follow up will take 
approximately 4 hours.  We estimate that total participation to be 
approximately 22.5 hours. 
Description of Agent or 
Intervention: 
We will be using an active sham, 10 Hz and 40 Hz tACS. 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. Both 10 Hz and 40 Hz will 
also 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.  
Participants will stay in a relaxed yet experimentally controlled 
state by watching a nature movie such as “Reefscape” during 
stimulation. 

11 
 
 
Estimated Time to 
Complete Enrollment: 
 
We estimate that it will take 2 years to complete enrollment of 
participants. 

12 
 
*Schematic of Study Design: 
Table 1. The 60 participants will be randomized into one of three of the following arms 
ARM 1 
20 participants 
Sham 
ARM 2 
20 participants 
10 Hz tACS 
ARM 3 
20 participants 
40 Hz tACS 
 
 
 
 
*Weeks are based on time from initial stimulation session 
 

13 
 
1 
KEY ROLES 
Individuals: 
Principal Investigator:  Flavio Frohlich, Ph.D. 
 
Co-Investigator: David Rubinow M.D. 
Medical Monitor: Asa Cordle, M.D. 
 
 
Flavio Frohlich Ph.D. – Principal Investigator   
 
 
UNC - Chapel Hill Department of Psychiatry 
Email: flavio_frohlich@med.unc.edu  
 
 
     
Office: 4109F Neuroscience Research Building 
Phone: (919) 966-4584 
 
David Rubinow M.D. – Co-Investigator 
UNC - Chapel Hill Department of Psychiatry 
 
 
E-mail:  drubinow@med.unc.edu 
Office: 304 MacNider Hall 
 
 
 
Phone: (919) 445-0208 
 
Courtney Lugo MPH. – Project Manager/Study Coordinator 
UNC - Chapel Hill Department of Psychiatry 
E-mail: courtney_lugo@med.unc.edu  
 
 
Office: Medical School Wing C-233 
Phone: (919) 962-5271 
 
Juliann Mellin B.A. – Study Coordinator 
UNC - Chapel Hill Department of Psychiatry 
E-mail: juliann_mellin@med.unc.edu  
 
Office: Medical School Wing C-233 
Phone: (919) 966-9929 
 
Morgan Alexander B.S/BA – Study Coordinator 
UNC_ Chapel Hill Department of Psychiatry 
E-Mail: Morgan_Alexander@med.unc.edu  
Office: Medical school Wing C- 233 
Phone: (919) 966- 5271 
 
Michael Boyle B.S. – Graduate Research Assistant  
 
UNC - Chapel Hill Department of Biomedical Engineering 
Email: mrboyle@live.unc.edu 
 
 
 

14 
 
Office: 4129 Neuroscience Research Building 
 
Phone: (919)-966- 2682  
 
 
 
Bradley Vaughn M.D. – Other 
 
 
 
 
UNC - Chapel Hill Department of Neurology 
 
 
 
E-mail: vaughnb@neurology.unc.edu 
 
 
Office: 2122 Physician Office Building 
 
 
Phone:(919) 966-8178 
 
Asa Cordle M.D. – Medical Monitor  
 
 
 
UNC - Chapel Hill Department of Psychiatry 
 
 
Email: cordle@email.unc.edu 
 
 
 
Office: UNC Hospitals CB# 7160 
 
 
 
Phone: (919) 966-5217 
 
Institutions: 
University of North Carolina- Chapel Hill 
 
Other: 
IRB 
University of North Carolina-Chapel Hill 
Medical School Building 52 
Mason Farm Road 
CB #7097 
Chapel Hill, NC 27599-7097 
(919) 966-311 
Brain & Behavior Research Foundation 
90 Park Avenue, 16th Floor 
New York, NY 10016 
(646) 681-4888 

15 
 
2 
INTRODUCTION: BACKGROUND INFORMATION AND 
SCIENTIFIC RATIONALE 
2.1 
Background Information 
 
Major depressive disorder (MDD) is a common, severe psychiatric illness that is associated with 
pathological dynamics of large-scale neuronal networks.  More effective and safe therapies for 
MDD are desperately needed. Brain research has recently begun to uncover the biological 
substrate of depression: impaired ability of the brain to organize its electric activity into 
meaningful patterns that enable effective information processing.  
 
Patients with MDD exhibit elevated oscillatory activity in left dorso-lateral prefrontal cortex (dl-
PFC) in the alpha (8-12 Hz) frequency band (Henriques and Davidson, 1990). Alpha oscillations 
represent a fundamental state of neuronal hypoactivity that actively mediates suppression of 
information processing in thalamo-cortical circuits (Laufs et al., 2003; Palva and Palva, 2007). 
Transcranial magnetic stimulation to treat MDD has been recently approved by the FDA and is 
based on stimulation with a 10 Hz pattern. Importantly, bifrontal stimulation in the alpha 
frequency band with low-amplitude electric fields have recently been found to reduce symptoms 
in a multicenter, double-blind, sham-controlled study (personal communication, Dr. Linda 
Carpenter, Brown University). However, it has remained unknown if transcranial alternating 
current stimulation (tACS), a safe and non-invasive brain stimulation modality, is also an 
effective modulator of the network dynamics that mediate symptoms of depression. Addressing 
this lack in knowledge is critical for advancing our understanding of the network-level substrate 
of MDD and for the rational design of novel brain stimulation paradigms that directly target 
pathological network dynamics.  
 
2.2 
Rationale 
 
Hypoactivity in the left dorso-lateral prefrontal cortex is a hallmark of MDD (Brunoni et al., 
2010). Increasing activity levels by transcranial direct current stimulation (tDCS) that utilizes a 
constant current to increase cortical excitability has recently been demonstrated to be effective 
for the treatment of MDD (Brunoni et al., 2013). However, previous studies were more equivocal 
and recent meta-reviews came to differing conclusions (Berlim et al., 2013; Kalu et al., 2012). 
Our approach aims to use more targeted stimulation that directly modulates oscillatory activity. 
Specifically, we use non-invasive brain stimulation to target pathologically increased levels of 
alpha oscillations in left dl-PFC in depressed patients (e.g. Henriques and Davidson, 1990). 
tACS utilizes sine-wave stimulation waveforms that likely enhance specific oscillations (Ali et 
al., 2013; Herrmann et al., 2013). In contrast, suppressing oscillations with tACS, such as for the 
downregulation of pathologically enhanced alpha oscillations, is a more challenging task. The 
proposed work is the first study of its kind to evaluate the feasibility and effectiveness of two 

16 
 
different tACS-based stimulation paradigms. We will use 10 Hz stimulation motivated by the 
recent success in 10 Hz stimulation for treatment of depression with transcranial magnetic 
stimulation and we will use 40 Hz stimulation in order to indirectly modulate alpha oscillations 
due to endogenous antagonistic coupling of alpha and gamma frequency activity.  
 
2.3 
Potential Risks and Benefits 
 
2.3.1 
Potential Risks 
 
Risk of Confidentiality Breach: In the unlikely event of a breach of confidentiality, people 
might discover that an individual was involved in this research study. This is especially 
sensitive because the clinical population recruited for this study may be subjected to 
negative consequences caused by the stigma of mental disorders. Furthermore, some 
might not agree with the principle of participating in research or of changing natural brain 
activity. To avoid breaches in confidentiality, study documents that contain personal 
information, including the informed consent document, and the document that links study 
ID numbers to personal identifying information are kept in locked filing cabinets in 
locked rooms, separate from any source documents containing participant dummy 
identifiers. All data is stored in locked cabinets inside locked offices; electronic data will 
be stored only on password-protected computers, and data encryption methods will be 
used during communication between investigators. Only study personnel will have access 
to these data. All study staff participate in annual human participant training that includes 
education about responsibilities to the minimize risk of confidentiality breach.  
 
Risk of Embarrassment: Self-report assessments contain questions regarding sensitive 
personal information. This risk is necessary in order to assess mood symptoms and 
associated psychopathology. Participants will be assured upon intake that only study 
personnel will see any clinical ratings.  
 
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 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 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 (Attachments 6 &7) after each stimulation session to determine whether 

17 
 
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.  
 
There is a purely 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. If abnormalities or 
a seizure is witnessed during the course of the study, a referral will be made to the UNC 
Department of Neurology for follow-up. In the theoretical event that a seizure is 
witnessed that involves the loss of consciousness, the patient will be told not to operate a 
motor vehicle until cleared by the DMV.  
 
Patients with MDD have an about 20 times higher rate of suicide than average. We have 
no evidence that our treatment paradigms will in any way increase this likelihood. 
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 UNC 
Psychiatry will be made. Dr. Rubinow, Co-I, will facilitate this process. 
 
We will be using the Suicidality Module included in the M.I.N.I 7.0 to assess suicide risk. 
Inclusion criteria states that the patient must be low suicide risk, potential participants 
that have an above “low risk” designation will not be eligible for the study. We will 
administer a daily questionnaire to assess suicide risk. In the case suicide risk increases 
during participation in the study, the participant will be asked to stop the study and will 
be provided with a referral to UNC Department of Psychiatry and their mental health care 
or family medical doctor will be contacted.  
 
2.3.2 
Known Potential Benefits 
 
Major depressive disorder is a common, severe psychiatric illness. Patients with 
MDD exhibit elevated oscillatory activity in left dorso-lateral prefrontal cortex. Our 
novel approach introduces non-invasive brain stimulation for mental illnesses and has 
the potential to treat symptoms not only in depression but also schizophrenia, and 
anxiety disorders.  
 
This study has not been 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. There are no serious risks to the participant from the 
treatment used in this study. The chance to understand and develop a new treatment 

18 
 
for a wide range of psychiatric disorders is an important step in helping the millions 
of people in the world who suffer from mental illness.  

19 
 
3 
OBJECTIVES 
3.1 
Study Objectives 
 
Our primary objective is to conduct a pilot clinical trial to establish feasibility and to collect first 
effectiveness data for the use of tACS to renormalize pathological alpha oscillations in dl-PFC of 
unmedicated patients with MDD by comparing MADRS scores from baseline and 5 week follow 
up visit. 
 
3.2 
Study Outcome Measures 
 
3.2.1 
Primary Outcome Measures 
 
The Montgomery-Asberg Depression Rating Scale (Attachment 8) will be the primary 
outcome measures for this study.  This measurement will be taken at baseline (first day of 
stimulation), last day of stimulation, at the 2 week and at the 4 week follow up visits.   
We will compare the MADRS scores between baseline and 4 week follow up as our 
primary outcomes measure. 
 
3.2.2 
Secondary Outcome Measures 
 
As a secondary outcomes measure, we will compare alpha oscillation power from resting 
state EEG recordings on the first and last day of stimulation. We will also collect EEG 
data at the 4 week follow up visit. We will use these data to analyze alpha frequency 
activity as a pilot study for derivation of EEG biomarkers.  

20 
 
4 
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 recruiting from a clinical population.  For this clinical trial we are seeking 60 males and 
non-pregnant females ages 18-65 with unipolar, non-psychotic MDD, free of benzodiazepine and 
anticonvulsant medication, who have a Hamilton Depression Rating Scale > 8 and are at a low 
risk for suicide according to the Hamilton Depression Rating Scale.  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. These individuals will be outpatients and may seek mental health care 
from a family practitioner, therapist or psychiatrist. 
 
This is a single site, pilot clinical trial with 3 arms.  We estimate 2 years to complete study 
enrollment.   
 
Participants will be randomly assigned to one of three arms; active sham stimulation, 10 Hz 
(alpha) tACS or 40 Hz (gamma) tACS. 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 total 
stimulation.  The choice of an active sham is motivated to enhance success of patient blinding by 
mimicking skin sensations associated with tACS.  10 Hz and 40 Hz tACS will have a 10 second 
ramp in and ramp out with 40 minutes of stimulation for a total of 2420 seconds. Stimulation 
waveform is a sine-wave with a peak-to-peak amplitude of 2 mA. In each arm, participants will 
stay in a relaxed and yet controlled state by watching a nature movie such as “Reefscape” during 
stimulation.  
 
Eligible participants who complete this clinical trial will have a total of 8 visits; an initial 
session, 5 days of stimulation, a 2 and a 4 week follow up visit.  The initial session will take 
approximately 3 hours, the first and last day of stimulation will take approximately 6 hours and 
days 2 through 4 of stimulation will take 1.5 hours each.  The one week follow up will take 
approximately 2 hours and the four week follow up will take approximately 4.5 hours.  We 
estimate that total participant participation duration will be approximately 26 hours.  
  
Our primary objective is to conduct a pilot clinical trial to establish the feasibility and to collect 
first effectiveness data for the use of tACS to renormalize pathological alpha oscillations in dl-
PFC of unmedicated patients with MDD comparing MADRS scores from baseline to 4 week 
follow up visits. As a secondary objective we will assess the differential clinical effects of sham, 
10 Hz and 40 Hz tACS on EEG measures of alpha oscillations. 
 

21 
 
5 
Study Enrollment and Withdrawal 
 
5.1 
Participant Inclusion Criteria 
 
In order to be eligible to participate in this study, a participant must meet all of the following 
criteria: 
 
 
Provide signed and dated informed consent form 
 
Male or female, aged 18-65 years 
 
DSM-IV diagnosis of MDD; unipolar, non-psychotic 
 
Hamilton Depression Rating Scale score >8 
 
Capacity to understand all relevant risks and potential benefits of the study (informed 
consent) 
 
Meet criteria for low suicide risk 
 
Willing to comply with all study procedures and be available to do so for the duration of the 
study 
 
Women of reproductive potential must use highly effective contraception 
 
At least 6 months since their last ECT session  
 
5.2 
Participant Exclusion Criteria 
 
A potential participant who meets any of the following criteria will be excluded from 
participation in this study: 
 
 
DSM-IV diagnosis of alcohol of substance abuse (other than nicotine) within the last month 
or a DSM-IV diagnosis of alcohol or substance dependence (other than nicotine) within the 
last 6 months 
 
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 sequelae 
 
Prior brain surgery 
 
Any brain devices/implants, including cochlear implants and aneurysm clips 
 
Co-morbid neurological condition (i.e. seizure disorder, brain tumor) 
 
Non English speakers 
 
Pregnancy, nursing, or if female and fertile, unwilling to use appropriate birth control 
measures during study participation 
 
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  

22 
 
 
Current axis I mood, anxiety, or psychotic disorder other than major depressive disorder.    
 
Lifetime comorbid psychiatric bipolar or psychotic disorder.                                             
 
Eating disorder (current or within the past 6 months)                                                             
 
Obsessive-compulsive disorder (lifetime)                                                                                
 
PTSD (current or within the last 6 months)                                                                             
 
ADHD (currently under treatment)          
 
Current use of benzodiazepines and/or antiepileptic drugs                                                         
                         
 
5.3 
Strategies for Recruitment and Retention 
 
This clinical trial will utilize multiple recruitment strategies in order to communicate this 
opportunity to as many potential participants as possible.  Our first means is through a referral 
process.  Participants can be referred to the study through their primary mental health care 
provider or family doctor during routine visits. This type of recruitment will take place in 
doctors’ offices throughout Chapel Hill, Carrboro, Durham and Raleigh areas. We estimate that 
approximately 20 participants will be enrolled from the Chapel Hill/Carrboro area and 10 
between Durham and Raleigh. Clinicians will be informed of inclusion criteria through email and 
listserv announcements and be asked to mention this clinical trial to appropriate patients and 
offer them a flyer/ brochure with contact information. Interested individuals can than call or 
email the secure line/address in order to set up a phone prescreening.  
 
We will also be posting ads in the local newspapers including, the Independent Weekly. In 
addition to newspapers we will have postings on websites such as ClinicalTrials.gov and NAMI. 
We will have contact information and a brief summary of the clinical trial posted on the Frohlich 
Lab Facebook and Twitter pages.  These strategies will assist in recruiting medication free 
patients. Finally, with permission from Jennifer Rothman, the NIMH Outreach Partner for North 
Carolina, we will speak about our study and hand out fliers at NAMI Family to Family meetings. 
In addition to these recruitment strategies, we will also be utilizing advertisements through 
Facebook and Craigslist, and have information about our study with study coordinator contact 
information on Join the Conquest, ClinicalTrials.gov, and Studypages.com. Interested 
individuals need simply to read the information about the study and contact the study coordinator 
to complete the phone screening. 
 
Our retention strategy includes a payment schedule of four times per participant. The participant 
will receive payment at the initial session, the 5th day of stimulation, and both follow up sessions, 
at the final follow up session will include a completion bonus of $20.00. The research staff will 
also give each participant a reminder call for the initial session, the first day of stimulation, and 
each follow up session. Each research staff member will be easily available for the participants to 
contact via email or phone. The inclusion criteria state that each participant must be able to 

23 
 
understand all risks and benefits associated with this study. We will be asking each participant to 
answer questions about the consent form to determine that the study process and the duration of 
participation are completely understood by all participants. We will aim to have a specific 
research team member assigned to complete all sessions with the same participant. However we 
will not require the same researcher to be present during stimulation sessions 2 through 4.  The 
study team will work hard at forming a professional relationship with the participant so they feel 
comfortable and willing to discuss what may be sensitive information. Retention will be 
quantified by the fraction of participants coming to each scheduled session (the data from each 
session will be scored and documented the day of the session). Participants will no longer be 
eligible to continue the study if they miss any stimulation session. 
5.4 
Treatment Assignment Procedures 
 
Participants will be randomized into one of three arms.  This is a double blind study, so neither 
the participant nor the researcher will know which treatment the participant is receiving, if any.   
 
5.4.1 
Randomization Procedures 
 
Kristin Sellers will randomize 60 codes which will be used by the study coordinator and 
research assistants.  These codes are directly linked to which treatment participants 
receive (sham, 10Hz tACS or 40 Hz tACS).  Kristin Sellers has no other responsibility in 
the study other than providing these randomized codes.   
 
5.4.2 
Reasons for Withdrawal 
 
A study participant will be discontinued from further participation if: 
 
 A participant answers yes to any of the daily suicide questionnaires.  
 A participant has a YMRS score greater than or equal to 12. 
 The participant has missed any day of stimulation. 
 Any clinical adverse event (AE), laboratory abnormality, intercurrent illness or other 
medical condition, or situation occurs such that continued participation in the study 
would not be in the best interest of the participant. 
 The participant meets any exclusion criteria (either newly developed or not previously 
recognized). 
 A participant wishes to withdraw from further participation for any reason. 
 

24 
 
5.4.3 
Handling of Withdrawals 
 
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-specified safety follow-up 
procedures.  If voluntary withdrawal occurs, the participant will be asked to continue 
scheduled evaluations and complete an end-of-study evaluation.  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 and Co-I.  In the case of an early withdrawal, the 
researcher will complete a Participant Off Study form to document the withdrawal reason 
(Appendix S). 
 
5.4.4 
Termination of Study  
 
This study may be prematurely terminated if, in the opinion of the investigator, there is 
sufficient reasonable cause.  Circumstances that may warrant termination include, but are 
not limited to: 
 
 Determination of unexpected, significant, or unacceptable risk to participants. 
 Insufficient adherence to protocol requirements. 
 Data those are not sufficiently complete and/or evaluable.  
 Plans to modify suspend or discontinue the development of the study device. 
 
The IRB will be informed promptly and provided the reason(s) for the termination or 
suspension by the sponsor or by the investigator/institution, as specified by the applicable 
regulatory requirement(s). 

25 
 
6 
STUDY INVESTIGATIONAL PRODUCT 
6.1 
Study Product Description 
  
We will be using a transcranial current stimulator designed in the Frohlich Lab for 
investigational research purposes and the Neuroconn devices used in pervious IRB approved 
studies.  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 
use of transcranial brain stimulation. Previous studies in the Frohlich Lab that used comparable 
devices have always been classified as “non-significant risk” by the UNC IRB. 
 
In addition, some participants will be stimulated with the commercial, CE-certified Neuroconn 
Plus stimulator (for purely logistic reasons of device availability). The use of this device in this 
study has previously received a NSR designation on initial review by the full UNC IRB. Both 
devices are electrically equivalent and provide the same stimulation. The NeuroConn device 
description is as follows: 
 
The DC-STIMULATOR is a CE-certified medical device for conducting non-invasive 
transcranial direct-current stimulation (tDCS) in humans. DC stimulation is used in clinical 
practice and in the research of stroke, epilepsy, migraine, tinnitus, depression, multiple sclerosis, 
dementia and chronic headache. The DC-STIMULATOR is a micro-processor-controlled 
constant current source. It meets the highest safety standards thanks to (hardware- and software-
based) multistage monitoring of the current path. By continuously monitoring electrode 
impedance it can detect insufficient contact with the skin and automatically terminate 
stimulation, maximising patient safety. 
The device's alphanumeric display and the 4 touch keys allow various stimulation modes to be 
selected and stimulation parameters such as current strength, duration, fade-in and fade-out to be 
set. 
 
DC-STIMULATOR features: 
• 
1 channel (anodal and cathodal stimulation possible) 
• 
Adjustable current up to 5,000 µA * 
• 
Adjustable application time up to 30 minutes * 
• 
2 standard modes - single (continuous stimulation) and - pulse (cyclical stimulation 
activation/deactivation) with fade in and fade out 
• 
Customer-specific programs possible (optional) 
• 
"Study mode" for blind processing of genuine and 'pseudo' stimulation (optional) 
• 
External trigger input (optional) 
 
 
6.1.1 Device Description 
 
The device consists of the following main components/subsystems: 

26 
 
 
1. Tablet with user interface application (App) 
2. Microprocessor 
3. Function generator chip 
4. Voltage controlled current source 
5. Safety circuitry 
 
First, the stimulation parameters are specified by the user through the app.  The 
parameters are: 
 
1. tDCS/tACS 
2. Number of channels 
3. Amplitude 
4. Test duration 
5. Frequency (for tACS) 
6. Password. 
 
Next, the parameters are sent via Bluetooth to the microprocessor.  The microprocessor 
interprets these parameters, and programs the function generator chip accordingly.  The 
function generator then creates the programmed waveform, which is ultimately a voltage 
signal.  The voltage signal is applied to a voltage controlled current source, which 
generates the specified amount of current through an arbitrary load resistance. 
 
 
 
6.1.2 Operation 
 
A. The desired current value is scaled to a register value and stored in the function 
generator. 
 
B. The value in the register determines the percent of full scale output current, generated 
by the function generator. 
 
C. The generated current waveform from the function generator is driven through a 
specified resistance.  The resulting voltage drop is amplified by an instrumentation 
amplifier.  
 
D. The voltage waveform from the output of the instrumentation amplifier is applied to a 
voltage controlled current source. 
 

27 
 
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 
generates 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 overcurrent 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 sensor output is then shifted 
before it is read by the microprocessor using the same level shifting circuit described in 
the current sensor section.   
 
6.1.3 Safety Precautions 
 
The device is equipped with 4 different stages of safety protection, all of which protect 
the stimulant 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 +/-3mA peak.  If the 
current exceeds these limits, 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 +/-4.5mA.  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 successful hardware cutoff function 
 

28 
 
 
 
 
3. Permanent hardware current cutoff.  A 5mA fast-acting fuse is in series with the 
electrode connector.  If the above two over-current detection methods fail, the fuse will 
blow, and the stimulant will no longer be electrically connected to the device. 
 
4. Power supply fuse.  Finally, if for any 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. 
 
6.2 
Preparation and Administration of Study Investigational Product 
 
After participants have completed the daily 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 day, for 40 minutes.  In the 10 Hz and 40 Hz groups 
stimulation 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 
Yellow: Relay control line 
Green: Current through 
electrode (goes from 
negative current to zero) 
Blue: Current sensor 
output (has lowpass filter) 
Purple: SR latch output 
 

29 
 
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 three 
experimental arms. Researchers will enter the participant-specific code into the App that controls 
the simtulation 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 R for an example of the training documentation log. To monitor 
side effects of stimulation a daily questionnaire will be administered after each stimulation 
session.  Please see Attachment 6 for an example of the daily stimulation questionnaire, and 
Attachment 7 for an example of the endpoint stimulation questionnaire.  
 
6.3 
Assessment of Participant Compliance with Study Investigational 
Product 
 
Compliance for this study includes making all 5 stimulation sessions. Follow up periods will be 
able to take place ±3 days of scheduled visits.  

30 
 
7 
STUDY SCHEDULE 
Dr. Cordle or other approved clinician will be present during the 1st day of stimulation, the 5th 
day of stimulation, the 2 week and the 4 week follow ups to administer the CGI (Attachment 3) 
until research personnel are comfortable and certified to do so (will be determined by 
accompanying clinician). In order to increase data quality, the assessments for an individual 
participant at the initial session, the 1st day of stimulation, the 5th day of stimulation, the 2 week 4 
week follow ups will be administered by the same researcher. Protocol for this study will not 
require the same researcher to be present during days 2 through 4 of stimulation although the 
team will strive to schedule the same researcher for every session.  
 
7.1 
Screening 
 
Screening Telephone Call 
 
Individuals who are referred by a mental health care provider will be contacted by a research for 
an initial phone screening.  Researchers will keep a Telephone Contact log for each telephone 
conversation with a participant throughout the study. There will be a log for each participant and 
will be filed in the participant binder (Appendix I).  
 
During the telephone screening, researchers will provide a brief background about MDD and 
tACS.  Any initial questions will be answered at this point. The timeline of visits will then be 
explained; there will be 1 to 8 sessions, with 1 initial session, 5 consecutive week days of 
stimulation, 2 follow up sessions 2 weeks after the final stimulation and another 4 weeks after 
final stimulation. The participant will be informed that compensation for their participation will 
be received at 3 sessions throughout the study; the initial session, last day of stimulation, and at 
the 4 week follow up. The participant will be asked if they have any additional questions.  Once 
all questions have been answered, the participant will be asked if he/she is still interesting in 
participating in the study.  If yes, the researcher will begin the initial phone screening which will 
determine eligibility for the initial session. The screening questions are shown below. If the 
required answers are given for each question, the initial session will be scheduled and a reminder 
call will be given at least 24 hours before initial session. We will use the telephone script 
provided in Appendix T for all telephone screenings.  
 
 
Are you 18 years old or older?  (Yes) 
 
Have you ever, or are you currently being treated for a neurological condition (i.e. 
epilepsy, migraines, etc)? (No) 
 
Are you currently taking medication for the treatment of depression or any other 
psychiatric illness? (No) 
o 
Have you ever taken medication for a mood disorder?  
o 
If yes, has it been at least 6 months since then? 

31 
 
 
How long have you been depressed?  
 
What steps have you taken to treat this depression? 
 
Have you ever had brain surgery? (No) 
 
Do you have any brain devices or implants, including a cochlear implant or aneurysm 
clip? (No) 
 
Have you ever been diagnosed with a traumatic brain injury? (No) 
 
For females only, is there a chance you may be pregnant? (No) 
Follow-up Questions 
 
Have you been diagnosed with Major Depressive Disorder by a professional (i.e. a 
psychiatrist or other licensed clinician)? 
 
Have you ever been hospitalized? 
o 
If yes, was it in anyway related to a mood disorder or psychiatric condition?  
o 
If yes, when did this occur? 
 
7.2 
Enrollment/Baseline 
 
Initial Session Visit (Visit 1, Day 0) 
 
At the initial session participants will sign both a HIPAA authorization form and the consent 
form. Each form will be read to the participant by the researcher, and the participant will be 
given the time to ask any questions about the information discussed. Each participant will be 
asked a series of questions (Appendix E) to ensure that the consent form is fully understood.  
 
Once consent is obtained, the researcher will verify that the participant meets inclusion criteria. 
If the participant is female, and unsure of pregnancy status, she will be asked to complete a urine 
pregnancy test to verify status. Next, demographic information will be collected, which will 
include a history of medication, alcohol, and drug use. This information is used to verify that the 
participant does not have an existing alcohol or drug dependency or disorder. A short handedness 
questionnaire will also be administered. Once the questionnaires and tasks are complete, the 
researchers will perform an 8 minute EEG recording. Participants will be asked to keep eyes 
open for 4 minutes and then keep eyes closed for 4 minutes during the recording. After the 
resting state EEG recording, the participant will be administered the “n-back” working memory 
task for a total of 20 minutes while a second EEG is being recorded. The n-back will be 
administered during each EEG recording following the resting state EEG. The following 
questionnaires will then be administered to further check eligibility; The Mini International 
Neuropsychiatric Interview (MINI) to confirm diagnosis and suicide risk, and the Hamilton 
Depression Rating Scale 17 item (HDRS17) will be used to assess the severity of depression 
(Attachment 5).  At the end of the initial session, and once eligibility has been confirmed, a 
saliva sample will be collected (for testing of BDNF allele), the week of stimulation will be 
scheduled, and the participant will be paid.  
 

32 
 
7.3 Stimulation Sessions 
 
Day 1 of Stimulation (Visit 2) 
 
At the first day of stimulation, several questionnaires will be administered. First, the suicide 
assessment (Attachment 4), and YMRS (Attachment 10) will be administered to assess safety. 
These assessments will be administered at the beginning of each study visit. If the participant 
shows any development of SI, SB or manic symptoms, their participation will be stopped and 
their primary mental health care provider or family physician will be contacted.  In the case that 
they do not see anyone for their depression, Dr. Cordle will assist the participant in seeking 
medical care.  
 
Next, the HDRS17 (Attachment 5), MADRS (Attachment 8), BDI (Attachment 1), and CGI 
(Attachment 3) will be administered. These tools are used to collect information on the 
participant’s symptom severity and are administered multiple times throughout the study. 
Baseline cognitive function tests will follow the symptom scale and include; the MOCA 
(Attachment 9) and the n-back working memory task.  
 
Once the questionnaires and tasks are complete, the researchers will perform an 8 minute EEG 
recording. Participants will be asked to keep eyes open for 4 minutes and then keep eyes closed 
for 4 minutes during the recording. After the resting state EEG recording, the participant will be 
administered the “n-back” working memory task for a total of 20 minutes while a second EEG is 
being recorded. The n-back will be administered during each EEG recording following the 
resting state EEG. Then the participant will undergo either a sham, 10 Hz or 40Hz tACS 
treatment for 40 minutes. Participants will stay in a relaxed yet experimentally controlled state 
by watching a nature movie such as “Reefscape” during stimulation.  
 
Finally, to assess any side effects of stimulation, the stimulation adverse effects questionnaire 
will be administered. This questionnaire will be administered at the end of each stimulation 
session (Attachment 6).  
 
Days 2 – 4 of Stimulation (Visit 3 – 5) 
 
The Suicide Assessment (Attachment 4) and the YMRS (Attachment 10) will continue to be 
administered at the beginning of each session. Once safety is assessed, and it is determined to be 
safe to continue, the participant will receive 40 minutes of sham, 10 Hz or 40Hz tACS (as per the 
initial randomization) while watching the assigned movie.  The stimulation session will be 
followed by the stimulation adverse effects questionnaire ending the session.  If the participant 
shows any development of SI, SB or manic symptoms, their participation will be stopped and 
their primary mental health care provider or family physician will be contacted.  In the case that 

33 
 
they do not see anyone for their depression, Dr. Cordle will assist the participant in seeking 
medical care.  
 
Day 5 of Stimulation (Visit 6) 
 
The Suicide Assessment (Attachment 4) and the YMRS (Attachment 10) will be administered at 
the beginning of the session. Once safety is assessed and it is determined to be safe to continue, 
the participants will receive 40 minutes of either sham, 10 Hz or 40Hz tACS (as per the initial 
randomization) while watching the assigned movie, followed the stimulation adverse effects 
questionnaire. The HDRS17 (Attachment 5), MADRS (Attachment 8), BDI (Attachment 1), and 
CGI (Attachment 3) data collection assessments will be administered during this session. After 
the assessments are completed, an 8 minute EEG will be administered, with 4 minutes of eyes 
open and 4 minutes of eyes closed. Following this, the participant will perform the “n-back” 
working memory test for a total of 20 minutes. The participant will be paid at the end of this 
session for the completion of 5 stimulation sessions.  
 
 
7.4 
Follow-up  
 
2 Week Follow-up Visit (Visit 7, 2 weeks after final day of stimulation) 
 
The Suicide Assessment (Attachment 4) and the YMRS (Attachment 10) will be administered at 
the beginning of this session. The HDRS17 (Attachment 5), MADRS (Attachment 8), BDI 
(Attachment 1), and CGI (Attachment 3) assessments will be administered after safety has been 
assessed. 
 
7.5 
Final Study Visit 
 
4 Week Follow-up Visit (Visit 8, 3 weeks after first follow up visit) 
 
The Suicide Assessment (Attachment 4) and the YMRS (Attachment 10) will be administered at 
the beginning of this session.  The participant will be asked to recall their experience of 
stimulation and answer the final stimulation adverse effects questionnaire (Attachment 7).  This 
questionnaire will ask the participant whether they believed they received treatment (answer 
options include yes, no, and I don’t know) and whether they think their symptoms have 
improved.  The HDRS17 (Attachment 5), MADRS (Attachment 8), BDI (Attachment 1), and 
CGI (Attachment 3) assessments will be administered, followed by the MOCA (Attachment 9) 
and n-back working memory task. After the cognitive assessments, a final 10 minute EEG will 
be administered, with 5 minutes of eyes open and 5 minutes of eyes closed. The participant will 
be paid at the end of this session including the study completion bonus. 

34 
 
8 
STUDY PROCEDURES/EVALUATIONS 
8.1 
Clinical Evaluations 
 
During the initial session, researchers will collect demographics. Participant demographics 
include medical history and medication history.  This information is used to confirm inclusion 
criteria; CNS medications free for at least 6 months, and no current alcohol and drug abuses or 
disorder exist. 
 
Several clinical evaluations will be used throughout this study. These assessments are listed 
below and can be found in the attached documents. 
 
i. The Mini International Neuropsychiatric Interview (MINI) is a short, structured interview 
that will be used during the initial session to confirm diagnosis of MDD, unipolar and non-
psychotic with a low suicide risk. This scale has been validated as being a reliable diagnostic 
tool (Sheehan et al. 1998). 
 
ii. The Hamilton Depression Rating Scale 17-item (HDRS17) (Williams 2001; Khan et al 2002; 
Leentjens et al. 2000) will be administered during the initial session, day 1 of stimulation 
(baseline), day 5 of stimulation and at the 3 and 5 week follow ups. This scale is used to 
determine patient eligibility and to monitor the severity of the participant’s depression 
symptoms. (Attachment 5) 
 
iii. The Beck Depression Inventory (BDI) (Beck et al. 1988; Dozois et al. 1998) will be 
administered at baseline, day 5 of stimulation and at week 3 and 5 follow up. The BDI is a 
21-item, self-report rating inventory that measures characteristic attitudes and symptoms of 
depression and will be used to monitor the severity of the patient’s depression throughout the 
study. (Attachment 1) 
 
iv. The Clinical Global Impression scale (CGI) (Khan et al. 2001) will be administered at 
baseline, day 5 of stimulation and at week 3 and 5 follow up. The CGI will be used to 
monitor the severity of the patient’s symptoms and also as a measure of treatment response 
and efficacy. Dr. Cordle or other approved clinician will be present during the 1st day of 
stimulation, the 5th day of stimulation, the 2 week follow up and the 4 week follow up to 
administer the CGI until research personnel are comfortable and certified to do so. 
(Attachment 3) 
 
v. The Montgomery-Asberg Depression Rating Scale (MADRS) (Khan et al. 2001; Leentjens et 
al. 2001) will be administered at baseline, day 5 of stimulation and at week 3 and 5 follow 
up. This scale will be used as a primary outcome of this study and will be used to measure 

35 
 
the severity of depressive episodes experienced by participants. (Attachment 8) 
 
We will be monitoring the safety of our participants throughout the study with the following 
assessments. These assessments can also be found in attachments. 
 
i. 
A suicide questionnaire previously used in IRB # 14-0600 will be used at each session of 
this study. This questionnaire tracks suicidal ideation and behavior.  Participants will be 
asked to answer whether they have had any thoughts of hurting themselves within the 
past 24 hours and whether they have hurt themselves within the past 24 hours. If a 
participant admits to experiencing either SI or SB their participation will be stopped 
immediately and their primary mental health care provider or family physician will be 
contacted.  In the case that they do not see anyone for their depression, Dr. Cordle will 
assist the participant in seeking medical care. (Attachment 4) 
 
ii. 
A stimulation adverse effects questionnaire will be administered at the end of each 
stimulation session and at the 5 week follow visit. This questionnaire will be used as a 
safety measure and to collect data on participant experience. A similar questionnaire was 
used in IRB 13-2995 to determine ability to successfully blind using transcranial current 
stimulation.  (Attachment 6 and Attachment 7) 
 
iii. 
The Young Mania Rating Scale (YMRS) (Young et al. 1978) was designed to assess the 
severity of manic symptoms at baseline, with the ability to reassess the individual’s 
symptoms over time. When undergoing treatment for depression, a possible effect of 
treatment is to alter the serotonin levels, potentially causing a manic episode. Although 
we do not expect such an event to occur since we are not using a medication that targets 
serotonin levels, we will be conducting this assessment at each evaluation as a 
precautionary measure. In the case a participant develops any sign of mania their 
participation in the study will be stopped and their primary mental health care provider or 
family physician will be contacted.  In the case that they do not see anyone for their 
depression, Dr. Cordle will assist the participant in seeking medical care. (Attachment 10) 
8.2 
Laboratory Evaluations 
 
8.2.1 
Clinical Laboratory Evaluations 
 
During the initial session, a urine pregnancy test will be performed for any female 
participant who is unable to confirm pregnancy status. This information will be recorded 
on the inclusion/exclusion criteria checklist (Appendix H) to be completed by the 
researcher. 
 

36 
 
8.2.2 
Special Assays or Procedures 
 
Two cognitive assays will be administered in order to assess cognitive abilities at 
baseline and again at the study endpoint. The Montreal Cognitive Assessment (MOCA) 
(Attachment 9) will be used to monitor changes in cognition since it has been developed 
to detect changes in cognition. In addition, an n-back working memory task will be 
administered during each EEG recording.  This task is designed to detect changes in 
working memory performance that has been associated with overall functional integrity 
of neuronal circuits in the prefrontal cortex. 
 
There will be two procedures used throughout this study. Each participant will attend 5 
consecutive weekdays of stimulation for this study. Each participant will be randomly 
assigned to one of three treatment arms for this study (sham, 10HZ active tACS or 40 Hz 
active tACS). Electrodes with measurement 5x5cm will be placed over F3 and F4, and a 
return electrode, 5x7cm, will be placed over Cz. In order to detect any change(s) at the 
neurophysiological level, an EEG will be performed during the 1st day of stimulation, the 
5th day of stimulation, and at the 5 week follow up session. This measurement will 
contribute to the design of novel network-level biomarkers of MDD and of treatment 
response.   
In addition to the above procedures, we will be collecting a saliva sample at the initial 
visit.  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 
polymorphism in the BDNF gene, has functional 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 treatments (TMS) with expected changes 
whereas individuals expressing the 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. 
  

37 
 
9 
ASSESSMENT OF SAFETY 
9.1 
Specification of Safety Parameters 
 
There will be three different assessments used to ensure participant safety. First, the Suicide 
Assessment (Attachment 4) will be administered at the beginning of each session.  This 
assessment is used to determine SI and SB within the past 24 hours. If the participant answers 
“Yes” to either question, participation in the study will be stopped and their primary mental 
health care provider or family physician will be contacted.  In the case that they do not see 
anyone for their depression, Dr. Cordle will assist the participant in seeking medical care.  
 
Immediately following the Suicide Assessment, the YMRS (Attachment 10) will be 
administered.  This assessment is used to detect any emergence of manic symptoms. If any 
manic symptoms become apparent, participation in the study will be stopped and their primary 
mental health care provider or family physician will be contacted.  In the case that they do not 
see anyone for their depression, Dr. Cordle will assist the participant in seeking medical care.  
 
After each stimulation session, a stimulation adverse effects questionnaire (Attachment 6) will be 
administered.  This tool is used to document any side effects experienced during stimulation. The 
researcher will also check with the participant throughout the 40 minute stimulation sessions to 
make certain no discomfort is felt.  The stimulation session will be terminated if the participant 
reports having unmanageable discomfort or pain (more than “moderate”).  Additionally, this 
information will be reported on an AE report form (Appendix L) and an AE log (Appendix J). 
 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
 
9.2.1 
Adverse Events 
 
Adverse Event:  An AE, as defined by the NIH, is any unfavorable changes in health, 
including /abnormal laboratory findings that occur in trial participants during the clinical 
trial or within a specified period following the trial.  
 
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 L).  The AE report form 
includes the follow; what is known about the therapy and 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 a worsening of baseline 
symptoms or related to a concurrent medical condition or medication use. Once complete, 

38 
 
this form will be given to the PI and the Co-I who will review, comment and sign this 
form.  Completed forms will be placed in the participant’s folder.  
 
The study coordinator will document any AE occurrence on the AE log (Appendix J) 
which includes information such as the date of the AE, severity, relationship to the 
treatment (assessed by the PI), actions taken, and outcome(s). The log will be reviewed 
and initialed by the PI 72 hours after being completed. All AEs 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 the study treatment.  Any medical condition noted at the initial session 
will be considered as baseline and not reported as an AE. 
 
 
 
All AEs will be graded for severity using the following guidelines. 
 
 
Asymptomatic: the participant is exhibiting no symptoms due to the event; no 
treatment needed.  
 
Mild Adverse Event– 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 Adverse Event – 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 adverse event the medical 
advisor may recommend an over the counter medication. 
 
Severe and undesirable Adverse Event – Event results in significant symptoms that 
prevents 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 G) and will be filed in the participant’s folder.  
 
Relationship to Study Products:  The PI and Co-I 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 the 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. 
 

39 
 
9.2.2 
Expected Adverse Reactions 
 
Transcranial current stimulation has been used without reports of any serious side-effects. 
Some subjects 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. During the stimulation, the researcher will ask the participant about their 
comfort.  Stimulation will immediately be stopped if any discomfort (more than 
“moderate”) is reported. In theory, there is a possibility that application of weak 
stimulation current could induce a seizure.  
 
These adverse reactions will be monitored with the stimulation adverse effects 
questionnaire (Attachment 6). The following scale reflects the scoring of severity for any 
possible side effects.  
 
1 = Absence of the indicated symptom 
2 = Mild (awareness of a symptom but the symptom is easily tolerated) 
3 = Moderate (discomfort enough to cause the researcher to be informed) 
4 = Severe (incapacitating; the stimulation is terminated due to extreme discomfort) 
 
All expected adverse reactions questionnaires are a daily source document that will be 
placed in each individual’s folder.  Additionally, this data is imported directly into the 
RECap secure data base. Should the DSMB ask to see a complete report of this 
information we can generate a report using REDCap.   
 
9.2.3 
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 M), 
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 

40 
 
participant’s binder at the resolution of the event. The study coordinator will complete the 
UE/SAE log (Appendix K ) 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 has been 
notified, and the date that the SAE Form was completed.  
 
9.2.4 
Unanticipated Problems. 
 
Unexpected Events (UE) will be recorded on the UE/SAE log (Appendix K ) 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 considers unanticipated problems involving 
risks to participants or others to include, in general, any incident, experience, or outcome 
that meets all of the following criteria: 
 
 
Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the participant 
population being studied; 
 
Related or possibly related to participation in the research  
 
Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
 
If an UE occurs the IRB will be notified and the study will be adjusted as needed to 
protect the health and safety of the participants. Depending on the nature of the UE, the 
research protocol, inclusion/exclusion criteria, and informed consent will be changed to 
reflect the possibility of this event reoccurring. Please see Appendix D for an example of 
the Consent Amendment Tracking log. 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.  
 
9.3 
Reporting Procedures 
 
We will be adopting the follow table for reporting procedures:  
 
What Event is Reported 
When is Event Reported 
By Whom is Event 
Reported 
To Whom is Event 
Reported 

41 
 
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 
Investigator3 
 External IRBs 
 
9.3.1 
Reporting of Pregnancy 
 
Pregnancy tests will be administered at the initial session 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 Co-I and medical monitor.   
 
9.4 
Type and Duration of Follow-up of Participants after Adverse Events 
 
Medical monitors and Co-I will follow up with participants with in one week of an AE. 
 
9.5 
Halting Rules 
 
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 (Berlin 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 

42 
 
subjects, either short-term or long-term. 
 
9.6 
Safety Oversight 
 
Safety oversight will be under the direction of a DSMB composed of Dr. Ross Simpson, an 
epidemiologist, a biostatistician and one or more clinical researchers. The DSMB will review 
AEs every 6 months whereas the medical monitor will review AEs in real time and make 
decisions as of participant’s continuation of the clinical trial. The PI will review AEs weekly 
with research team and may request additional review by Co-I on a case-by-case basis. The 
medical monitor will also be present at weekly meetings in order to discuss/explain any event(s) 
that may occur. 
 
Every 6 months DSMB will review blinded AE reports, scores from suicide questionnaires and 
any cognitive changes. If there is reason to view unblinded information, the DSMB will directly 
receive the list of participants’ identification numbers from Kristin Sellers.  Participant 
identification number will be displayed in a table according to the three arms of the study; 
however the specific treatment of that arm will not be disclosed.  This will allow the DSMB to 
compare the three treatment groups. 
 
Reasons for stopping the study and asking for further investigation include; increased suicide 
risk due to treatment (>25% of participants asked to seek mental health care), decrease in 
cognitive abilities based on baseline and end of study data (>25% decrease in scores in >15% of 
participants).  In addition, as mentioned above, if a seizure occurs during a study visit, the 
clinical trial will be temporarily be placed on hold for further investigation.   
 
 
  

43 
 
10 
CLINICAL MONITORING 
The Purpose of the monitoring plan is to present the Frohlich Lab’s approach to monitoring 
clinical trials.  The plan facilitates compliance with good clinical practice. 
 
(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. 
 
10.1 Frohlich Lab Monitoring Plan 
 
The latest version of the approved IRB application for this clinical trial will be followed at all 
times. This responsibility falls in the hands of the study coordinator and research assistants.  If at 
any time there is a deviation from protocol, the deviation from protocol log (Appendix O) 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 at the Clinical Trials desk in Rm 4109 of the NRB. 
Deviations will be sent to IRB every 4-6 weeks (if necessary). 
 
At the end of the month clinical trials meeting with the PI, 3 randomly selected informed consent 
forms will be chosen. The PI will verify that (1) these forms have been filled out appropriately, 
and (2) the consent form process described in the SOP 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 the Master Protocol.  Documents of AE and SAE can be 
found in the study binder on file at the Clinical Trials desk in Rm 4109 of the NRB.  It is 
responsibility of the study coordinator to report all events to the PI.  In all weekly meetings with 
the PI, all AE and SAE are discussed.  For our practices we have adapted the decision tree 
provided by UNC-CH IRB to assist with reporting of such events (Attachment 1).  
 
At all weekly clinical trial team meetings, the study coordinator will chose one CRF and Source 
Document to assess for completion and maintenance. At weekly clinical trials meeting, with the 
PI will assess completeness of data on REDCap (data site). The PI has read-only access.  This 
allows the PI to view reports that provide information on any missing data on an individual 
participant basis, but does not allow them to add, change or input any data. 

44 
 
11 
STATISTICAL CONSIDERATIONS 
11.1 Study Hypotheses 
 
11.1.1 Primary Objective 
 
Null hypothesis: There is no difference baseline and the 4 week follow up in MADRS 
score between treatment groups. 
 
Alternative hypothesis: There is a difference between baseline and the 4 week follow up 
MADRS score between treatment groups.  
 
11.1.2 Secondary Objective 
 
Null hypothesis: There is no difference in changes of alpha frequency power between 
baseline EEG and EEG at completion of stimulation between treatment groups. 
 
Alternative hypothesis: There is a difference in changes of alpha frequency power 
between baseline EEG and EEG at completion of stimulation between treatment groups. 
 
11.2 Sample Size Considerations 
 
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.  It is difficult to recruit a large number of patients diagnosed with MDD to 
participate in a single site extensive study.  However, we expect with 20 participants in each 
group that we have enough power to detect significance if there is a clear effect of tACS on 
depression and/or the underlying biomarkers.   
 
11.3 Final Analysis Plan 
 
We will perform spectral analysis of resting state EEG before and after stimulation treatment and 
use a mixed ANOVA with the within subject factor session (day one of stimulation and 4 week 
follow up) and between subject factor treatment (sham, 10Hz tACS or 40Hz tACS). Spectral 
analysis will be performed with multi-tapered estimation of the frequency spectrum followed by 
integration over the classical alpha EEG band (8-12 Hz).  We will apply the same statistical 
analysis procedure for our primary outcome of MADR scale. 
 
We will also use post-hoc paired or unpaired Student’s t-test to identify the group or groups that 
differed. We will further control for multiple comparisons by using Bonferroni corrections.  

45 
 
12 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
Partners Human Research Committee (IRB): 
 All IRB Correspondences are on file. 
 The study staff is IRB approved prior to performing any study procedures. 
 Adverse events and deviations are reported to IRB per current guidelines. 
 All versions of the IRB protocols and informed consent forms are on file. 
 
Informed Consent: 
 Ensure that participant identification is on all pages of the ICF 
 There is documentation that the participant is given a copy of the consent form (Appendix C) 
 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 G) made for any informed consent deviations.   
 Ensure a valid (current version date) copy of the consent form was used. 
 
Protocol: 
 Confirm that the study staff is conducting the study in compliance with the protocol approved 
by IRB  
 The protocol deviations (exceptions and violations) are documented in the participant chart and 
reported to IRB as required. 
  
Source Documents: 
 Each participant binder will contain a checklist to ensure that each binder has each source 
document. The checklist will be dated by the researcher for each time an assessment is 
administered. (Appendix P) 
 Review participant charts 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 G) are made for missing or incomplete data and to explain any 
discrepancies or additional comments.  
 
Electronic Case Report Forms (eCRF)  
 Ensure the data reported on the eCRF is consistent with the source documents.  
 Discrepancies between the source documents and eCRF are explained in a note to file 
(Appendix G) or captured in a comment in the eCRF.  

46 
 
 
 
DNA  
 
Participant names will not be on any of the samples collected at the initial session. DNA testing 
is performed within the University of North Carolina at Chapel Hill and the samples are not 
shared with or processed by any third party outside the university. 
 
The research coordinator, research assistants, and PI will have access to all of the above 
information.  CO-I 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.  The key 
linking dummy identifiers with subject information will be securely destroyed after completion 
of data acquisition. 
 
 

47 
 
13 
ETHICS/PROTECTION OF HUMAN PARTICIPANTS 
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 
 
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 
 
1. The rights and welfare of human participants are paramount in the research process; 
2. The highest standards of ethical conduct are employed in all research involving human 
participants; 
3. Research investigators are properly trained in the ethical and regulatory aspects of 
research with human participants; 
4. 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 

48 
 
5. Research using human participants at UNC-Chapel Hill conforms to all 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 and their families. 
Consent forms describing, in detail, the study intervention, device, procedures, and risks are 
given to the participant and written documentation of informed consent is required prior to the 
administration of any treatment or assessments used in this study.  Please see Appendix C for an 
example of the Documentation of Informed Consent Process form. All consent forms will be 
IRB-approved and updated with any new information as modifications are made throughout the 
study (Appendix D). 
 
Together, the researcher and potential participants will review the clinical trial in its entirety. At 
several intervals during the consent review, the researcher will ask the participant questions that 
will assess the comprehension of the information in the consent. If the participant is unsure or 
does not know, the researcher will return to that section and more carefully explain the 
information. Participants must sign the informed consent document prior to any procedures 
taking place.  If needed, the participants will have the opportunity to discuss the study with their 
surrogates or think about it prior to agreeing to participate.  Participants may withdraw consent at 
any time throughout the course of the trial.  A copy of the signed informed consent document 
will be given to the participants for their records.  The rights and welfare of the participants will 
be protected by emphasizing to them that the quality of their medical care will not be adversely 
affected if they decline to participate in this study. 
 
13.4 Exclusion of Women, Minorities, and Children (Special Populations) 
 
Non-English speaking individuals are excluded because the ability to accurately and completely 
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. 

49 
 
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. 
 
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. 

50 
 
14 
DATA HANDLING AND RECORD KEEPING 
The study coordinator and research assistants are responsible for the accuracy, completeness, 
legibility, and timeliness of the data reported. During weekly meetings, the data will be reviewed 
by the PI to check for completeness and continued safety of the participants and research staff.  
Any changes made to the data will involve crossing out the original data, documenting the new 
data with the initials and date of the researcher making the change.  
 
14.1 Data Management Responsibilities 
 
The responsibilities designated to each member of the research team are documented on the 
Delegation of Authority SOP (Appendix N).  The study coordinator and research assistants will 
be responsible for the informed consent process, review for eligibility, questionnaire 
administration, data entry, device administration, EEG administration, and CRF entries. The 
study coordinator will be responsible for AE/SAE documentation and reporting, while the PI will 
be responsible for the AE assessment, review of the AE documentation forms and overview of 
the research staff. Dr. Asa Cordle will be the medical monitor for the study.        
 
REDCap will serve as a secure data management tool for this study. The study coordinator and 
research assistants will have complete access to the REDCap system, while the PI and Co-I will 
have read only ability. This will enable the researchers to enter the data and the PI and Co-I to 
review. 
 
14.2 Data Capture Methods 
 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and 
clinical laboratory data will be entered into a data capture system provided by REDCap.  The 
data system includes password protection and internal quality checks, such as automatic range 
checks, to identify data that appear inconsistent, incomplete, or inaccurate.  Clinical data will be 
entered directly from the source documents. 
 
14.3 Types of Data 
 
Data will be collected to determine eligibility. During the initial session, the MINI, and the 
HDRS17 will be administered. In order to participate in this study, the participant must have a 
diagnosis of MDD (unipolar, non-psychotic), have a low suicide risk, and have a score of greater 
than 8 on the HDRS.  
 
We will also be collecting data to assess cognitive abilities at baseline and endpoint (5 week 
follow up). The MOCA and n-back working memory task will be administered as two separate 

51 
 
measurements of cognition.   
 
The Suicide Assessment and the YMRS will be administered at the beginning of each session to 
monitor the safety of the participant. The Suicide Assessment will be administered in order to 
evaluate whether the participant has experienced any SI or SB in the past 24 hours. The YMRS 
will assess the development of any manic symptoms throughout the study. The stimulation 
adverse effects questionnaire will be administered after each stimulation session in order to 
monitor any side effects the participant may experience from the stimulation treatment.  
The MADRS will be our primary outcome for this study. We will administer this questionnaire 
on the 1st day of stimulation, the 5th day of stimulation, and the 2 and 4 week follow up. As our 
primary outcome, the data we collect with the MADRS will be used to determine effectiveness 
of treatment.  
 
The HDRS17 will be used not only to determine eligibility, but also to collect additional data 
throughout the study. This questionnaire will also be administered on the 1st day of stimulation, 
the 5th day of stimulation, and the 2 and 4 week follow up, in addition to during the initial 
session.  
 
The remainder of the assessments will collect data to monitor depressive symptoms throughout 
the study, as extra safety assessments. The BDI (Attachment 1) and CGI (Attachment 3) will be 
administered the 1st day of stimulation, the 5th day of stimulation, and at the 2 and 4 week follow 
ups. An EEG will be administered the 1st day of stimulation, the 5th day of stimulation and at the 
end of the 4 week follow up session. The EEG data will enable assessment of neurophysiological 
changes induced by stimulation.  
 
14.4 Timing/Reports. 
 
The stimulation adverse effects questionnaire will be administered at the end of each stimulation 
session. Any AE will be reported to the PI within 72 hours and medical monitor within 24 hours. 
 Reports will be run at the end of each week and any unusual activity that could be a cause of 
concern will be reported to the PI at weekly meetings.  
 
14.5 Study Records 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.  
 

52 
 
14.6 Protocol Deviations 
 
All deviations from the protocol will be addressed in study participant source documents. The 
researcher will complete a Protocol Deviation Log (Appendix O) 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. 

53 
 
15 
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. 

54 
 
16 
LITERATURE REFERENCES 
 
Ali, M.M., Sellers, K.K., and Frohlich, F. (2013). Transcranial alternating current stimulation 
modulates large-scale cortical network activity by network resonance. J Neurosci 33, 11262-
11275.  
 
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 
 
Beck, A. T., Steer, R. A., & Garbin, M. G. (1988). Psychometric properties of the Beck 
Depression Inventory: Twenty-five years of evaluation. Clinical Psychology Review, 8(1), 77-
100. doi:10.1016/0272-7358(88)90050-5 
 
Berlim, M.T., Van den Eynde, F., and Daskalakis, Z.J. (2013). Clinical utility of transcranial 
direct current stimulation (tDCS) for treating major depression: a systematic review and meta-
analysis of randomized, double-blind and sham-controlled trials. Journal of psychiatric research 
47, 1-7.  
 
Brunoni, A.R., Teng, C.T., Correa, C., Imamura, M., Brasil-Neto, J.P., Boechat, R., Rosa, M., 
Caramelli, P., Cohen, R., Del Porto, J.A., et al. (2010). Neuromodulation approaches for the 
treatment of major depression: challenges and recommendations from a working group meeting. 
Arq Neuropsiquiatr 68, 433-451.  
 
Brunoni, A.R., Valiengo, L., Baccaro, A., Zanao, T.A., de Oliveira, J.F., Goulart, A., Boggio, 
P.S., Lotufo, P.A., Bensenor, I.M., and Fregni, F. (2013). The sertraline vs. electrical current 
therapy for treating depression clinical study: results from a factorial, randomized, controlled 
trial. JAMA Psychiatry 70, 383-391.  
 
Dozois, D. A., Dobson, K. S., & Ahnberg, J. L. (1998). A psychometric evaluation of the Beck 
Depression Inventory–II. Psychological Assessment, 10(2), 83-89. doi:10.1037/1040-
3590.10.2.83 
 
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., & McCormick, D. A. (2010). Endogenous electric fields may guide neocortical 
network activity. Neuron, 67(1), 129-43.  
 
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 

55 
 
Human Memory-Related Hippocampal Activity and Predicts Memory Performance. The Journal 
Of Neuroscience, 23(17), 6690-6694. 
 
Henriques, J.B., and Davidson, R.J. (1990). Regional brain electrical asymmetries discriminate 
between previously depressed and healthy control subjects. J Abnorm Psychol 99, 22-31.  
 
Herrmann, C.S., Rach, S., Neuling, T., and Struber, D. (2013). Transcranial alternating current 
stimulation: a review of the underlying mechanisms and modulation of cognitive processes. 
Front Hum Neurosci 7, 279.  
 
Kalu, U.G., Sexton, C.E., Loo, C.K., and Ebmeier, K.P. (2012). Transcranial direct current 
stimulation in the treatment of major depression: a meta-analysis. Psychol Med 42, 1791-1800. 
 
Khan, A., Khan, S. R., Shankles, E. B., & Polissar, N. L. (2002). Relative sensitivity of the 
Montgomery-Asberg Depression Rating Scale, the Hamilton Depression rating scale and the 
Clinical Global Impressions Rating Scale in antidepressant clinical trials. International Clinical 
Psychopharmacology, 17(6), 281-285. doi:10.1097/00004850-200211000-00003 
 
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 
  
Laufs, H., Krakow, K., Sterzer, P., Eger, E., Beyerle, A., Salek-Haddadi, A., and Kleinschmidt, 
A. (2003). Electroencephalographic signatures of attentional and cognitive default modes in 
spontaneous brain activity fluctuations at rest. Proc Natl Acad Sci U S A 100, 11053-11058.  
 
Leentjens, A. G., Verhey, F. J., Lousberg, R., Spitsbergen, H., & Wilmink, F. W. (2000). The 
validity of the Hamilton and Montgomery-Åsberg depression rating scales as screening and 
diagnostic tools for depression in Parkinson's disease. International Journal Of Geriatric 
Psychiatry, 15(7), 644-649. doi:10.1002/1099-1166(200007)15:7&lt;644::AID-
GPS167&gt;3.0.CO;2-L 
 
National Institute of Health. (2011). Further resources for NIH grantees. Retrieved from: 
http://grants.nih.gov/clinicaltrials_fdaaa/definitions.htm 
Palva, S., and Palva, J.M. (2007). New vistas for alpha-frequency band oscillations. Trends in 
neurosciences 30, 150-158. 
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. 
Sheehan, D. V., Lecrubier, Y., Sheehan, K., Amorim, P., Janavs, J., Weiller, E., & ... Dunbar, G. 
C. (1998). The Mini-International Neuropsychiatric Interview (M.I.N.I): The development and 

56 
 
validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. Journal Of 
Clinical Psychiatry, 59(Suppl 20), 22-33. 
Williams, J. W. (2001). Standardizing the Hamilton Depression Rating Scale: past, present, and 
future. European Archives Of Psychiatry And Clinical Neuroscience, 251(Supl2), 6-12. 
doi:10.1007/BF03035120 
Young, R. C., Biggs, J. T., Ziegler, V. E., & Meyer, D. A. (1978). A rating scale for mania: 
Reliability, validity and sensitivity. The British Journal Of Psychiatry, 133429-435. 
doi:10.1192/bjp.133.5.429 
 
 

 ____________________________________________________________________________________________ 
57 
SUPPLEMENTS/APPENDICES 
APPENDIX A: SCHEDULE OF EVENTS 
A detailed schematic describing all visits and assessments. 
 
MDD Study Outline 
Procedures 
Initial Session 
Day 1 of 
Stimulation 
Days 2 –4 of 
Stimulation 
Day 5 of 
Stimulation 
Week 2  
Follow Up 
Week 4  
Follow Up 
Signed Consent Form 
X 
 
 
 
 
 
Assessment of Eligibility 
Criteria 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medications 
X 
 
 
 
 
 
BDNF test 
X 
 
 
 
 
 
MINI 
X 
 
 
 
 
 
HDRS 
X 
X 
 
X 
X 
X 
 
YMRS 
X 
X 
X 
X 
X 
Suicide Assessment 
 
X 
X 
X 
X 
X 
MADRS 
 
X 
X 
X 
X 
BDI 
 
X 
 
X 
X 
X 
CGI 
 
X 
 
X 
X 
X 
MOCA 
 
X 
 
X 
n-back working memory 
 
X 
 
X 
 
X 
Stimulation 
 
X 
X 
X 
 
EEG 
X 
X 
X 
 
X 
Stimulation Adverse 
Events Questionnaire 
 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 

 ____________________________________________________________________________________________ 
58 
APPENDIX B: STUDY START UP CHECKLIST 
 
Study Start Up Checklist 
Study Title: ______________________________________________________    
 
Funding Source: 
_______________________________________________________________ 
 
 
Date Completed 
 
CRMS Recorded Created 
______________________ 
 
IRB Application Submitted  
______________________ 
Approved 
Date : 
___________ 
CVs/Certifications/Medical 
License 
______________________ 
 
IRB Roster 
______________________ 
 
IRB Statement of Compliance 
______________________ 
 
PI Signature of Protocol 
______________________ 
 
HD-974 Forms 
______________________ 
 
                                                                Date Completed 
Study Binders Created 
______________________ 
______________________ 
______________________ 
______________________ 
______________________ 
______________________ 
______________________ 
______________________ 
______________________ 
 
 
 
______________________ 
______________________ 
______________________ 
______________________ 
 
Regulatory Documents Filed 
Protocol Deviation Tracking Log 
Filed 
Completion of Site Training, 
Filed 
Delegation Log Completed 
Develop Recruitment Plan 
Begin Pre-Screening 
Source Documents Created  
Participant Folders Created 
 
 
 
Schedule Study Start Up 
Meeting 
Lab Kits Received 
Participant Supplies Received 
Investigational Device Received 
 
 

 ____________________________________________________________________________________________ 
59 
 
APPENDIX C: DOCUMENTATION OF INFORMED CONSENT PROCESS 
Abbreviated Study Title:  
 
 
 
 
 
 
Participant Name:  
 
 
 
____      Date of Birth:  
 
 
 
 
 
Medical Record #: __________________________ 
 
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 CO-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). 
 
 
 
 
 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 

 ____________________________________________________________________________________________ 
60 
  
 
 
(date) at  
 
(time). 
 
Notes:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Person Obtaining Consent 
 
 
Date 
 
 
 
Time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 ____________________________________________________________________________________________ 
61 
APPENDIX D: CONSENT AMENDMENT TRACKING LOG 
Study Title: 
 
 
 
Change Initiated 
by: 
Adjustments made  
to consent form   
Date 
Submitted 
to IRB 
Date of 
IRB 
Answer 
Requires 
Stipulations? 
(Y/N) 
Stipulation 
Submission 
Date 
IRB 
Approval 
Date  
Initials  Reference 
ID 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 ____________________________________________________________________________________________ 
62 
APPENDIX E: INFORMED CONSENT EVALUATION FEEDBACK 
 
Name of Research Study:  
 
 
You have been asked to be in a research study. This sheet will help you think 
of questions to ask but you may have other questions.  This is not a test.  We 
want to be sure you understand what it means to be in this research study.  
You should understand the research before you decide whether or not to 
participate. 
 
 
1. What is the purpose of the research? 
 
 
2. What are the possible benefits of the research? 
 
 
3. What are the possible risks of the research? 
 
 
4. Will everyone receive the same treatment? 
 
 
5.   How is this research different than the care or treatment I would get if I wasn’t in 
the research study?  
 
 
6.  Does in the research cost me anything extra? 
 
 
7. Can you stop being in the research once you’ve started? 
 
 
8.  Who will view your medical records? 
 
 
9. Who do you call if I have questions about being a research subject? 
 
10.  Any questions? 

 ____________________________________________________________________________________________ 
63 
APPENDIX F: IRB AMMENDMENT TRACKING LOG 
Study Title: 
 
 
 
Change Initiated by: 
Description of IRB: Type and Brief Summary  
Date 
Submitted 
to IRB 
Date of 
IRB 
Answer 
Requires 
Stipulations? 
(Y/N) 
Requires 
Updated 
Consent 
Form? 
(Y/N) 
Stipulation 
Submission 
Date 
IRB 
Approval 
Date  
Initials  
Reference 
ID 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 ____________________________________________________________________________________________ 
64 
APPENDIX G: NOTE TO FILE 
 
IRB#: 14-1622 
 
 
 
 
 
 
 
PI: Flavio Frohlich 
Study Title: 
________________________________________________________________ 
Date of Occurrence: ________________ 
Research Name: ____________________________________ 
Participant ID: _________________ 
Reason for Note: 
________________________________________________________________ 
________________________________________________________________ 
Note: 
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________ 
 
Corrective action (if applicable): 
______________________________________________________________________ 
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________ 
 
Signature: ______________________________  
     Date: _______________ 
 
 

 ____________________________________________________________________________________________ 
65 
APPENDIX H: INCLUSION/EXCLUSION CRITERIA CHECKLIST 
(WITH PI SIGNATURE FOR PARTICIPANT ELIGIBILITY) 
 
Participant ID: ____________________________ 
Date: ____________ 
 
Inclusion Criteria 
Ages 18-65 years 
 
 
 
 
 
 
 
 
 
Yes  
 
No 
DSM-IV diagnosis of MDD; unipolar, non-psychotic 
 
 
 
 
 
Yes  
 
No 
Hamilton Rating Depression Rating Scale score >8 
 
 
 
 
 
Yes  
 
No 
Low suicide risk                                                                                                                               Yes                No  
If the responses to all the inclusion criteria are YES and all the exclusion criteria are NO, the 
participant is able to participate in the trial. 
Is the participant eligible to participate in the trial?   
 
YES 
 
NO 
If NO, discontinue subject. 
If YES, I have reviewed the inclusion and exclusion criteria and have determined that the 
participant is eligible for participation in the trial. 
 
Investigator Signature: ____________________________  
 
Date: _____________ 
 
Exclusion Criteria 
DSM-IV diagnosis of alcohol of substance abuse (other than nicotine)  
within the last month or a DSM-IV diagnosis of alcohol or substance  
 
 
  
Yes  
 
No 
dependence (other than nicotine) within the last 6 months 
Medical or neurological illness (unstable cardiac disease, AIDS,  
malignancy, liver or renal impairment) or treatment for a medical disorder  
 
 
 Yes  
 
No 
that could interfere with study participation 
History of traumatic brain injury, reoccurring seizures or later cognitive   
 
  
Yes  
 
No 
rehabilitation or causing cognitive sequelae 
Prior brain surgery 
 
 
 
 
 
 
 
 
 
 Yes  
 
No 
Any brain devices/implants, including cochlear implants and aneurysm clips 
 
 
 Yes  
 
No 
Co-morbid neurological condition (i.e. seizure disorder, brain tumor) 
 
 
 
 Yes  
 
No 
Non English speakers 
 
 
 
 
 
 
 
 
 
 Yes  
 
No 
Pregnancy, nursing, or if female and fertile, unwilling to use  
 
 
 
  
Yes  
 
No 
appropriate birth control measures during study participation 
Capacity to understand all relevant risks and potential  
 
 
 
 
 
Yes  
 
No 
benefits of the study (informed consent) 
Current axis I mood, psychotic disorder other than MDD 
Lifetime comorbid psychiatric bipolar or psychotic disorder 
Eating disorder (current or with the past 6 months) 
Obsessive-compulsive disorder (lifetime) 
PTSD (current or with the past 6 months) 
ADHD (current or with the past 6 months) 
Current use of benzodiazepines and/or antiepileptic drugs 

 ____________________________________________________________________________________________ 
66 
APPENDIX I: TELEPHONE CONTACT LOG 
 
Protocol Title: ___________________________________________ 
           Subject #: ______________________ 
 
 
Date/Time 
 
 
Incoming/Outgoing 
 
Message/Conversation 
 
Reason for calling 
 
Comments/Researcher Initials 
 
 
 
 
Incoming 
Outgoing 
 
 
Message 
Conversation 
 
 
 
 
Incoming 
Outgoing 
 
 
Message 
Conversation 
 
 
 
 
Incoming 
Outgoing 
 
 
Message 
Conversation 
 
 
 
 
Incoming 
Outgoing 
 
 
Message 
Conversation 
 
 
 
 
Incoming 
Outgoing 
 
 
Message 
Conversation 
 
 
 
 
Incoming 
Outgoing 
 
 
Message 
Conversation 
 
 

 ____________________________________________________________________________________________ 
67 
APPENDIX J: ADVERSE EVENTS TRACKING LOG 
 
 
Participant ID 
 
 if AE meets 
definition of 
serious* 
 
Was this an 
Expected or 
Unexpected 
Event? 
 
Grade / Intensity 
 
1. Asymptomatic 
2. Mild 
3. Moderate 
4. Severe 
 
 
Date of 
Incident 
 
Relationship 
to study 
device 
 
1. Related 
2. Possibly 
3. Not Likely 
4. Not Related 
 
 
Was 
Action 
Taken? 
 
 
 
 
 
Action(s) Taken: 
 
 
 
Outcome: 
 
1. Recovered 
2. Not Recovered 
3. Recovered 
w/Sequel 
4. Fatal 
5. Unknown 
 
PI Initials / 
Date 
 
 
Expected/ 
Unexpected 
 
 
 
Yes  /  
No 
 
 
 
 
 
Expected/ 
Unexpected 
 
 
 
Yes  /  
No 
 
 
 
 
 
Expected/ 
Unexpected 
 
 
 
Yes  /  
No 
 
 
 
 
 
Expected/ 
Unexpected 
 
 
 
Yes  /  
No 
 
 
 
 
 
Expected/ 
Unexpected 
 
 
 
Yes  /  
No 
 
 
 
 
 
Expected/ 
Unexpected 
 
 
 
Yes  /  
No 
 
 
 
 
 
Expected/ 
Unexpected 
 
 
 
Yes  /  
No 
 
 
 
 
 
Expected/ 
Unexpected 
 
 
 
Yes  /  
No 
 
 
 
 
 
Expected/ 
Unexpected 
 
 
 
Yes  /  
No 
 
 
 
 
 
Expected/ 
Unexpected 
 
 
 
Yes  /  
No 
 
 
 

 ____________________________________________________________________________________________ 
68 
APPENDIX K: UNEXPECTED/SERIOUSADVERSE EVENT TRACKING LOG 
 
 
Participant ID 
  
 
 
Date Event 
Occurred 
 
Was this an 
Expected or 
Unexpected 
Event? 
 
Date Study 
Team Notified 
of Event 
 
 
Event 
 
 
Date Reported to 
IRB 
 
 
Study SAE Form 
Completed 
 
 
Expected/ 
Unexpected 
 
 
 
Yes     
No      
N/A      
 
 
Expected/ 
Unexpected 
 
 
 
Yes     
No      
N/A      
 
 
Expected/ 
Unexpected 
 
 
 
Yes     
No      
N/A      
 
 
Expected/ 
Unexpected 
 
 
 
Yes     
No      
N/A      
 
 
Expected/ 
Unexpected 
 
 
 
Yes     
No      
N/A      
 
 
Expected/ 
Unexpected 
 
 
 
Yes     
No      
N/A      
 
 
Expected/ 
Unexpected 
 
 
 
Yes     
No      
N/A      
 
 
Expected/ 
Unexpected 
 
 
 
Yes     
No      
N/A      
 
 
Expected/ 
Unexpected 
 
 
 
Yes     
No      
N/A      
 
 
Expected/ 
Unexpected 
 
 
 
Yes     
No      
N/A      
 
 
Expected/ 
Unexpected 
 
 
 
Yes     
No      
N/A      
 
 
Expected/ 
Unexpected 
 
 
 
Yes     
No      
N/A      

 ____________________________________________________________________________________________ 
69 
APPENDIX L: ADVERSE EVENT 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) 
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
____________________________________________________________ 
CI signature 
_______________________________________________________Date___________ 
 
PI Comments:  
______________________________________________________________________
______________________________________________________________________

 ____________________________________________________________________________________________ 
70 
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________ 
 
Steps to be taken (if applicable) 
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________ 
 
PI signature 
__________________________________________________Date______________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 ____________________________________________________________________________________________ 
71 
 
 
 
APPENDIX M: SERIOUS ADVERSE EVENT REPORT FORM 
 
Serious Adverse Event Form 
Participant ID: _______________ 
 
1. Location of SAE (e.g., clinic, home): __________________________________________ 
 
2.   Age: ______  
 
3.  Gender: Male Female 
 
4. SAE term (provide diagnosis): _____________________________________________________ 
 
4a. If diagnosis is not known, symptoms: ____________________________________________ 
 
5. Date of onset: ________________________ (dd/mm/yyyy) 
 
6. What is the severity grade of the serious adverse event?  
 
Grade: 1: Mild  
Grade 2: Moderate  
Grade 3: Severe  
Grade 4: Life-threatening  
Grade 5: Death 
 
7. Did the participant receive the investigational product or study intervention prior to this SAE? 
   Yes  
 No  
 
N/A 
 
7a. If yes, identify the investigational product or study intervention received prior to the SAE: 
Investigational Product/Study Intervention 
 
Dose_______ 
Units_______ 
Frequency________ 
 
Start Date _____/_____/______(dd/mm/yyyy) 
Stop Date _____/_____/______( (dd/mm/yyyy) 
Check if Ongoing 
      8. Action taken with investigational product/study intervention: 
 
Continued 
Lowered 
Interrupted 
Discontinued 
Increased 
N/A 
 
9. Outcome of SAE: 
 

 ____________________________________________________________________________________________ 
72 
Ongoing at this time 
Resolved without sequelae 
Resolved with sequelae 
Death 
Present at death, not contributing to death 
 
 
10. Date of resolution: ________________________ (dd/mm/yyyy) or  
 Ongoing at end of study 
 
11. Seriousness criteria? (Check all that apply) 
 
Life-threatening 
Required hospitalization or 
Prolongation of existing hospitalization 
Congenital anomaly 
Disabling/incapacitating 
Important medical event 
Fatal 
If fatal: 11a. Date of death: ________________________ (dd/mm/yyyy) 
11b. Primary cause of death: _______________________________________________ 
11c. Was an autopsy performed?  
 
Yes  
No 
 
12. Relationship to investigational product/study intervention: 
 
Related (Associated with the use of the study intervention. There is a reasonable 
possibility that the experience may have been caused by the study intervention.) 
Unrelated 
 
13. If SAE is unrelated to investigational product/safety intervention, select all possible etiologies: 
Concurrent illness, disease, or other external factors, specify: 
_____________________________________________________________________________
_____________________________________________________________________________ 
 
Concurrent medication, specify: 
_____________________________________________________________________________ 
 
Secondary study procedure, specify: 
_____________________________________________________________________________ 
 
Accident, trauma, or other external factors, specify: 
_____________________________________________________________________________ 
 
Other, specify: 
_____________________________________________________________________________ 
 
14. Did the participant receive any relevant concomitant medications in response to the SAE?  
Yes 
 No 
 
 
14a. If yes, please specify: Name, Start and Stop date or On going  
 
_____________________________________________________________________________ 
 

 ____________________________________________________________________________________________ 
73 
 
 
15. Did the participant receive any treatments/procedures in response to the SAE?  
 
Yes  
No  
 
15a. If yes, please specify 
 
_____________________________________________________________________________ 
 
_____________________________________________________________________________ 
 
16. Did the participant receive relevant laboratory or diagnostic tests in response to the SAE?  
 
Yes  
No  
 
16a. If yes, provide the name of the test and results with normal ranges and/or supplemental 
 
 exams below:  
 
____________________________________________________________________________ 
 
____________________________________________________________________________ 
 
_____________________________________________________________________________ 
 
 
17. Narrative/Comments (provide a description of the serious adverse event including chronological 
clinical presentation and evolution of the serious adverse event and associated signs/symptoms):  
 
____________________________________________________________________________________ 
 
____________________________________________________________________________________ 
 
____________________________________________________________________________________ 
 
____________________________________________________________________________________ 
 
____________________________________________________________________________________ 
 
____________________________________________________________________________________ 
 
____________________________________________________________________________________ 
 
____________________________________________________________________________________ 
 
____________________________________________________________________________________ 
 
____________________________________________________________________________________ 
 
____________________________________________________________________________________ 
 
____________________________________________________________________________________ 
 

 ____________________________________________________________________________________________ 
74 
 
18. Completion of form: printed names, signatures and date of signature  
 
Person Completing Form 
(print name)  
           Person Completing Form  
                   (signature)  
Date  
 
 
 
______________________________________________________________________________ 
 
Investigator (print name)  
Investigator (signature)  
Date 
 
______________________________________________________________________________ 

 ____________________________________________________________________________________________ 
75 
APPENDIX N: DELEGATION OF AUTHORITY 
 
 
 
USE ONE VERTICAL COLUMN FOR EACH DESIGNEE 
Designee (full 
name) 
Courtney 
Lugo 
Juliann Mellin 
Dr. Asa Cordle  Michael Boyle  
Dr. David 
Rubinow  
Dr. Flavio 
Frohlich 
Title & Position 
 
 
 
 
 
 
Delegated Activity 
(see codes) 
 
 
 
 
 
 
Designee 
Signature & Dates 
 
 
 
 
 
 
Designee Initials 
(signed) 
 
 
 
 
 
 
 
Activity Codes: 
01:  Informed Consent                                 04:  CRF Entries                           07:  Data Entry 
02:  Initial Session Review for Eligibility   05:  Device Administration           08: Adverse Event Assessment 
03:  Questionnaire Administration              06:  EEG Administration              09: Adverse Event 
Documentation/Reporting 
10: Medical Monitor   
 
Investigator’s Authorization: I hereby delegate the above significant research-related duties to the following 
persons and understand that the overall responsibility for conduct of the research remains with me. 
 
1Investigator’s Signature: 
Date:  

 ____________________________________________________________________________________________ 
76 
APPENDIX O: PROTOCOL DEVIATION LOG 
 
 
Participant ID 
 
Date Occurred 
 
Description 
 
CAPA* 
 
Date PI Notified 
 
Date IRB 
Notified 
 
PI Initial/Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 ____________________________________________________________________________________________ 
77 
APPENDIX P: ENROLLMENT LOG 
 
Subject ID 
Date Consent 
Signed 
Gender 
Race 
Ethnicity 
Treatment 
Arm / 
Group 
Explanation if subject did not complete 
study / Comment 
1 
 
 
M 
 F 
  
 
 
 
2 
 
 
M 
 F 
 
 
 
 
 
3 
 
 
M 
 F 
 
 
 
 
 
4 
 
 
M 
 F 
 
 
 
 
 
5 
 
 
M 
 F 
 
 
 
 
 
6 
 
 
M 
 F 
 
 
 
 
 
7 
 
 
M 
 F 
 
 
 
 
 
8 
 
 
M 
 F 
 
 
 
 
 
9 
 
 
M 
 F 
 
 
 
 
 
10 
 
 
M 
 F 
 
 
 
 
 
11 
 
 
M 
 F 
 
 
 
 
 
12 
 
 
M 
 F 
 
 
 
 
 
13 
 
 
M 
 F 
 
 
 
 
 
14 
 
 
M 
 F 
 
 
 
 
 
15 
 
 
M 
 F 
 
 
 
 
 
 
 
 

 ____________________________________________________________________________________________ 
78 
 
APPENDIX Q: TRAINING LOG 
Title of Training:______________________________ 
 
DATE:__________________________ 
(e.g., Protocol; Amendment; IRB [include version #/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):_____________________________ 
(Please print) 
Trainer Signature (if relevant):___________________________________
Training Date 
(if different than 
above) 
Trainee Name 
(please print) 
Trainee Signature 
Training Format 
(ie Presentation; Self-Study) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
APPENDIX R: PARTICIPANT OFF STUDY FORM 
Participant Initials                            ID 
 
 
           Date:             /               / 
                         Month         Day            Year 
 
 
Participant Off Study 
 
Date participant went Off Study:             /               / 
             
 
                         Month         Day            Year 
 
INDICATE OFF STUDY REASON:  
  Study Activities Completed  
  Side effects of study intervention (complete applicable SAE form or AE Tracking Log) 
  Death 
 
  Participant lost to follow-up* (provide comments below) 
 
  Participant refused follow-up* (provide comments below) 
 
  Other* (provide comments below) 
  Participant withdrew (complete Early Withdrawal section below) 
 
Was treatment unblinded? 
1 Yes    
2 No    
3 Not Applicable 
 
Early Withdrawal  
 
Last Visit Completed:  
 
 
 
 
  Early Withdrawal form not completed
 
  Screening Visit  
  Visit 1 
 
  Visit 3 
  Visit 4 
 
  Visit 6 
  Visit 7    
      
  Visit 2                                            
  Visit 5 
Indicate the primary reason the participant has withdrawn from the study (select only one): 
  Participant deemed eligible but declined participation 
  Participant deemed inappropriate for study participation by the PI 
  Participant was determined to be ineligible after enrollment* (provide comments 
below) 
 
 
 
 
 
 
 
 
  Identification of disease/condition after enrollment that warrants withdrawal* 
 
  Unable to continue due to personal constraints* 
  Side effects of study intervention * (complete UWI-02-007 Adverse Event Tracking 
Log) 
  Other * 
 
 
                                       

 
80 
 
*Additional explanation required:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FORM COMPLETED BY:    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
81 
 
APPENDIX S: TELEPHONE RECRUITMENT SCRIPT 
 
Hello, my name is _________. Are you contacting me in regards to the non-invasive brain 
stimulation study?  
 
If ‘No’, redirect them as necessary) 
(If ‘Yes’, proceed) 
Do you have time now to hear about the study, answer a few screening questions, and schedule 
your first visit?  
 
(If ‘No’, ask for a good time to call back) 
(If ‘Yes’, proceed) 
 
Great! This study is looking at abnormal rhythms of brain activity in Major Depressive Disorder 
(and how they) respond to very weak applied electric currents. Findings from this study will help 
the development of treatments for the symptoms of depression.  In the study, a very weak electric 
current will be applied to your scalp. Some people report a mild tingling because of this 
stimulation, but no other side effects have been found. It is not a shock and should cause no pain.  
 
Participation in this study includes one to eight sessions, with one session being an initial 
information session, then 5 stimulation sessions, followed by a 2 and 4 week follow up session. 
The stimulation sessions need to be over a consecutive week. You will be compensated for each 
hour of your time spent participating in the study, with a $20 completion bonus for finishing the 
study. Therefore, the maximum compensation for this study is $280 for completing all of the 
sessions. Are you still interested in participating? 
 
(If ‘No’, thank them for their time) 
(If ‘Yes’, proceed) 
 
Great! In order to make sure you’re eligible for the study, I need to ask you a few questions. 
Please answer yes or no. You do not need to provide any further details.  
(If the answer given is not the same as the answer shown, thank the individual for his or her 
interest and say unfortunately, they do not qualify for the current study) 
 
 
Are you 18 years old or older?  (Yes) 
 
Have you ever, or are you currently being treated for a neurological condition (i.e. 
epilepsy, migraines, etc)? (No) 
 
Are you currently taking medication for the treatment of depression or any other 
psychiatric 
illness? (No) 
o 
Have you ever taken medication for a mood disorder?  
o 
If yes, has it been at least 6 months since then? 
 
How long have you been depressed?  
 
 
What steps have you taken to treat this depression? 

 
82 
 
 
 
 
Have you ever had brain surgery? (No) 
 
Do you have any brain devices or implants, including a cochlear implant or aneurysm 
clip? (No) 
 
Have you ever been diagnosed with a traumatic brain injury? (No) 
 
For females only, is there a chance you may be pregnant? (No) 
 
Follow-up Questions 
 
Have you been diagnosed with Major Depressive Disorder by a professional (i.e. a 
psychiatrist or other licensed clinician)? 
 
Have you ever been hospitalized? 
o 
If yes, was it in anyway related to a mood disorder or psychiatric condition?  
o 
If yes, when did this occur? 
 
Do you wear glasses/contact lenses? 
o 
Could you bring your contact lenses for the study visits instead of wearing your 
glasses? 
 
(If answered according to all indicated responses, continue) 
 
You are eligible for participation in the first session of the study. At the first session we will 
determine your eligibility for the remainder of the sessions.  I’d like to schedule your first 
session now. It will last approximately 3 hours. All testing will be conducted at either UNC 
Hospital or the NCPRC in Raleigh.  (Specify time). 
 
(Schedule a time for first session) 
 
I will send you an email or letter by mail, depending on your preference,  confirming this time, 
and providing directions on how to find the specific location of you session. We will also send 
you an email, if you chose this form of communication to confirm your appointment 24 hours 
beforehand. Please respond to this email so we know you are still coming. If you have any 
questions before then, please don’t hesitate to contact us at this phone number or at 
Courtney_lugo@med.unc.edu  
 
Thank you for your time.