Augmenting Single-session Behavioral Activation (BA) With Delta-beta Transcranial Alternating Current Stimulation (tACS) for the Treatment of Depression
Phase: NA
Conditions: Major Depressive Disorder
Sponsor: University of North Carolina, Chapel Hill

 
Augmenting single-session behavioral activation (BA) with delta-beta 
transcranial alternating current stimulation (tACS) for the treatment 
of depression 
 
 
 
NCT number NCT05693922 
Document Date 09/19/2022 
 

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Master Protocol Document 
 
Title 
Augmenting single-session behavioral activation (BA) with delta-beta 
transcranial alternating current stimulation (tACS) for the treatment of 
depression        
 
Sub-Title 
 
Augmenting Behavioral Activation with tACS       
 
Principal Investigator 
Flavio Frohlich, Ph.D. 
919-966-4584 
 
Co-Investigators 
 
Justin Riddle, Ph.D. 
Crystal Schiller, Ph.D.  
Erin Bondy, M.A. 
Stacey Daughters, Ph.D. 
Medical Monitor 
Crystal Schiller, Ph.D. 
 
Statistical  Co-Investigator 
Justin Riddle, Ph.D.  
Research Sites 
University of North Carolina at Chapel Hill 
Carolina Center for Neurostimulation 
77 Vilcom Center Drive 
Suite 170 
Chapel Hill, NC 27514 
 
Version Number  2 
19 SEPTEMBER 2022    
 
 
 
 
I have read, understood, and approved this version of the protocol.    
 
Principal Investigator:      
_ Date: ____9/19/2022________ 
 
Statistical Co-investigator:       
 
 
________ 
_ 
Date: ____9/19/2022____  
 
 
Statement of Confidentiality and Nondisclosure     This document is a confidential communication.  Acceptance of this document 
constitutes agreement by the recipient that no unpublished information contained herein will be published or disclosed without 
prior written approval of the Principal Investigator or other participating study leadership, except that this document may be 

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disclosed in any medium to appropriate investigators, Institutional Review Boards, Scientific Review Committees, and others who 
are directly involved in the study specified herein under the condition that they keep the information confidential. 
Table of Version Changes 
 
Previous 
Version No. 
Affected 
Sections 
Summary of the Changes 
to the Protocol 
Reason for Changes 
1 
 
AUGUST 
19 
2022 
1, 2, 3, 4, 5, 7, 
8, 9, 12, 13 
CLARIFIED TIMELINE FOR SESSIONS, REVISED STATISTICAL 
PLAN, INCLUDED RATIONALE FOR STUDY DESIGN 
INCORPORATED 
SRC 
FEEDBACK. 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
Table of Version Changes ..................................................................................................................................... 2 
Statement of Compliance ..................................................................................................................................... 5 
Table of Abbreviations ......................................................................................................................................... 6 
1. 
Protocol Synopsis ..................................................................................................................................... 7 
2. 
Introduction ............................................................................................................................................. 9 
2.1. 
Background Information ...................................................................................................................... 9 
2.2. 
Scientific Rationale ............................................................................................................................. 10 
3. 
Specific Aims .......................................................................................................................................... 11 
3.1. 
Aim 1 .................................................................................................................................................. 11 
3.2. 
Aim 2 .................................................................................................................................................. 11 
3.3. 
Aim 3 .................................................................................................................................................. 11 
3.4. 
Aim 4 .................................................................................................................................................. 11 
4. 
Study Design........................................................................................................................................... 13 
4.1. 
Treatment Design ............................................................................................................................... 14 
4.2. 
Experimental Design ........................................................................................................................... 15 
4.3. 
Measurement Design ......................................................................................................................... 15 
5. 
Study Participants .................................................................................................................................. 16 
5.1. 
Numbers of Participants ..................................................................................................................... 16 
5.2. 
Eligibility Criteria ................................................................................................................................ 16 
5.3. 
Enrollment/Selection Strategies ........................................................................................................ 16 
5.4. 
Strategies for Retention ..................................................................................................................... 17 
5.5. 
Matching and Stratification ................................................................................................................ 17 
5.6. 
Randomization  and  Concealment .................................................................................................... 17 
5.7. 
Blinding ............................................................................................................................................... 18 
6. 
Treatment Design: Procedures .............................................................................................................. 19 
7. 
Schedule of Activities and Procedures .................................................................................................. 19 
7.1. 
Table of Events ................................................................................................................................... 19 
7.2. 
Screening ............................................................................................................................................ 19 
7.3. 
Enrollment .......................................................................................................................................... 20 
7.4. 
Study Visits ......................................................................................................................................... 20 
7.5. 
Final Visit ............................................................................................................................................ 20 
7.6. 
Phone Contacts .................................................................................................................................. 20 
7.7. 
Follow-Up Contact .............................................................................................................................. 20 
7.8. 
Early Discontinuations ........................................................................................................................ 20 
7.9. 
Enrollees May Drop Out ..................................................................................................................... 21 
8. 
Statistical Analysis Plans ........................................................................................................................ 21 
8.1. 
Strategies that Apply to all the Aims .................................................................................................. 21 

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8.2. 
Sample Description ............................................................................................................................ 22 
8.3. 
Aim-Specific Plans .............................................................................................................................. 22 
8.4. 
Planned Interim Analyses ................................................................................................................... 23 
9. 
Sample Size Rationale ............................................................................................................................ 25 
10. 
Data Capture and Database Management ........................................................................................... 25 
10.1. 
Software for Data Capture ................................................................................................................. 25 
10.2. 
Responsibilities for Data Capture and Database Management ......................................................... 26 
10.3. 
Study Records Retention .................................................................................................................... 26 
11. 
Collection and Management of Tissue Specimens ............................................................................... 26 
11.1. 
Use in Current and Future Studies ..................................................................................................... 26 
11.2. 
Sample Preparation ............................................................................................................................ 26 
11.3. 
Record Keeping and Monitoring ........................................................................................................ 26 
11.4. 
Storage and Security .......................................................................................................................... 26 
12. 
Safety Monitoring and Management .................................................................................................... 26 
12.1. 
Risk / Benefit Assessment .................................................................................................................. 26 
12.2. 
Assessment of Safety ......................................................................................................................... 27 
12.3. 
Unanticipated Problems, Adverse Events, Serious Adverse Events ................................................... 28 
12.4. 
Safety Monitoring ............................................................................................................................... 30 
12.5. 
Study Suspension / Early Termination of the Study ........................................................................... 31 
13. 
Regulatory, Ethical, and Study Oversight Specifications ...................................................................... 31 
13.1. 
Informed Consent Process ................................................................................................................. 31 
13.2. 
Study Discontinuation and Closure .................................................................................................... 32 
13.3. 
Confidentiality and Privacy ................................................................................................................. 32 
13.4. 
Future Use of Stored Specimens and Data ......................................................................................... 33 
13.5. 
Key Roles and Study Governance ....................................................................................................... 33 
13.6. 
Safety Oversight ................................................................................................................................. 33 
13.7. 
Clinical Monitoring Plan (CMP) .......................................................................................................... 33 
13.8. 
Quality Assurance and Quality Control .............................................................................................. 34 
13.9. 
Protocol Deviations ............................................................................................................................ 34 
13.10. Publication and Data Sharing Policy ................................................................................................... 34 
13.11. Conflict of Interest Policy ................................................................................................................... 35 
14. 
Additional Considerations ..................................................................................................................... 36 
15. 
References .............................................................................................................................................. 36 
16. 
Appendices ............................................................................................................................................. 37 
 
 
 

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Statement of Compliance 
This study will be conducted as specified in the protocol and in accordance with the International Conference on 
Harmonisation Guidelines for Good Clinical Practice (ICH E6) and the Code of Federal Regulations on the Protection 
of Human Subjects (45 CFR Part 46).  
The protocol, informed consent form(s), recruitment materials, and all participant materials will be submitted to 
the Institutional Review Board (IRB) for review and approval.  Approval of both the protocol and the consent form 
must be obtained before any participant is enrolled.  Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study.  In addition, all changes to the consent form 
will be IRB-approved; a determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
If required by the IRB, the master protocol document, informed consent form(s), recruitment materials, and all 
participant materials will be submitted to the Scientific Review Committee (SRC) prior to IRB review 
(research.unc.edu/clinical-trials/src). 
The statistical analysis plans will be consistent with guidance in CONSORT Statement [1] or STROBE Statement [2], 
ICMJE recommendations [3], the 2016 and 2019 statements of the American Statistical Association [4,5], and 
recommendations in Nature [6,7].*  
All personnel involved in the conduct of this study have completed human subjects protection training. 
 
 
 
 
 
 
 
 
 
 
*  [1]   www.consort-statement.org  
   [2]  www.strobe-statement.org  
   [3]  www.icmje.org  
   [4]  Wasserstein RL, et al. (2016), The ASA's Statement on p-Values, The American Statistician, 70:2, 129-133  
   [5]  Wasserstein RL, et al. (2019), Moving to a World Beyond p < 0.05, The American Statistician, 73:sup1, 1-19  
   [6]  Amrhein, et al. (2019) Scientists rise up against statistical significance, Nature 567, 305-307  
   [7]  Editorial (2019) It’s time to talk about ditching statistical significance: Looking beyond a much used and abused measure 
          would make science harder, but better. Nature 567, 283-283. 

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Table of Abbreviations 
AE / SAE 
adverse event / serious adverse event 
ANOVA 
analysis of variance 
BA 
Behavioral activation 
BADS 
Behavioral Activation for Depression Scale 
BIS/BAS 
Behavioral Inhibition System / Behavioral Activation System questionnaire 
CFR 
U.S. Code of Federal Regulations (www.eCFR.gov) 
CT.gov 
ClinicalTrials.gov website 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DSMB 
data and safety monitoring board 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders (5th Edition) 
ECT 
Electroconvulsive therapy 
EEG 
Electroencephalography 
FDA 
U.S. Food and Drug Administration   (www.fda.gov) 
GCP 
good clinical practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GLMM 
Generalized linear mixed model 
GVS 
galvanic vestibular stimulation 
HDRS 
Hamilton Depression Rating Scale 
HIPAA 
U.S. Health Insurance Portability and Accountability Act   (www.hhs.gov/hipaa) 
ICH 
International Council for Harmonization   (www.ich.org) 
ICMJE 
International Committee of Medical Journal Editors   (www.icmje.org) 
IDAS 
Inventory of Depression and Anxiety Symptoms 
IRB 
institutional review board 
MDD 
Major depressive disorder 
MDE 
Major depressive episode 
MINI 
Mini International Neuropsychiatric Interview 
MPD 
master protocol document 
N 
number of enrolled participants 
OCT 
UNC Office of Clinical Trials (research.unc.edu/clinical-trials) 
OHRP 
Office for Human Research Protections 
PHI 
protected health information 
PI 
principal investigator 
RCT 
randomized controlled trial 
REDCap 
Research Electronic Data Capture system 
RRS 
Rumination Response Scale 
SD 
standard deviation 
SE 
standard error 
S-EEfRT 
Streamlined Effort Expenditure for Rewards Task 
SHAPS 
Snaith Hamilton Pleasure Scale – Self-Report 
SHAPS-C 
Snaith Hamilton Pleasure Scale – Clinician Administered 
SOP 
standard operating procedures 
SRC 
UNC Scientific Review Committee   (research.unc.edu/clinical-trials/src) 
STAI 
State-Trait Anxiety Inventory 
tACS 
Transcranial alternating current stimulation 
tDCS 
Transcranial direct current stimulation 
TEPS 
Temporal Experience of Pleasure Scale 
TMS 
Transcranial magnetic stimulation 
TraCS 
N.C. Translational and Clinical Sciences Institute   (tracs.unc.edu) 
tRNS 
transcranial random noise stimulation 
UNC 
The University of North Carolina 
 

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1. Protocol Synopsis 
Title 
 Augmenting single-session behavioral activation (BA) with delta-beta 
transcranial alternating current stimulation (tACS) for the treatment of 
depression           
 
Study Description 
The purpose of this study is to examine whether concurrent transcranial 
alternating current stimulation (tACS) augments the effects of a single 
session behavioral activation (BA) treatment of depression. Following a 
series of clinical assessments, participants will perform a reward-based 
decision-making task while electroencephalography (EEG) is collected. 
Then, all participants will take part in a single-session 90-minute BA 
intervention; half of the participants will receive delta-beta tACS during 
the final 30 minutes of the session and half will receive an active sham 
stimulation. Participants will return two weeks later for another task-
based EEG. Four weeks after the intervention session, they will receive 
self-report questionnaires via email to complete online.  
 
Specific Aims 
(objectives) 
 
Aim 1 (PRIMARY). Evaluate the effects of delta-beta transcranial 
alternating current stimulation (tACS) on depression symptom 
severity from pre- to post-treatment. 
 
Aim 2 (SECONDARY).   Examine changes in goal-directed behavior during 
a reward-based decision-making task from pre- to post-
treatment. 
 
Aim 3 (SECONDARY).  Investigate changes in delta-beta coupling during a 
reward-based decision-making task from pre- to post-treatment. 
 
Aim 4 (EXPLORATORY). Explore the effects of delta-beta transcranial 
alternating current stimulation (tACS) on anhedonia symptom 
severity from pre- to post-treatment. 
 
Target Population 
 
Inclusion Criteria We will recruit individuals 18 years and older who meet 
criteria for current major depressive disorder (MDD) as captured by the 
Mini International Neuropsychiatric Interview (MINI). Participants will be 
recruited from the Chapel Hill and Durham areas. 
 
Exclusion Criteria  
- 
Participants must not have active suicide intent as determined by 
the Columbia Suicide Severity Rating Scale (C-SSRS). Active suicide 
intent will be captured in responses to items 4 and/or 5 on the C-
SSRS. 
- 
Participants must not meet criteria for current severe substance 
use disorder, anorexia nervosa, or active psychosis as captured by 
the MINI. 
- 
Participants may not currently be in psychotherapy and have not 
received any other psychotherapy and/or stimulation (ECT, TMS) 
within the last 4 weeks.  

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- 
Any participants taking psychotropic medication must be on a 
stable dose for at least 4 weeks with no planned dose changes 
within the next 4 weeks.  
- 
(for female participants) Participants must not be pregnant or 
breastfeeding. 
- 
Participants may not have any medical or neurological illness for 
which symptom presentation or treatment could interfere with 
study participation 
- 
Participants may not have undergone prior brain surgery 
- 
Participants may not have any brain devices/implants, including 
cochlear implants and aneurysm clips 
- 
Participants may not have had brain injury or concussion within the 
last three months 
- 
Participants may not have a history of brain injury requiring current 
treatment 
 
Numbers of Enrollees 
Our target sample size is N = 40. 20 participants will be assigned to the BA 
+ delta-beta tACS condition and 20 will be assigned to the BA + active 
sham condition. We conservatively estimate to enroll 80 participants as a 
ceiling for the sake of IRB approval. 
 
We anticipate that at least n = 30  of the enrollees will complete all aspects 
of the protocol and have complete data. 
                                               
Interventions  or  
Exposures/Conditions 
 
Single-session BA: Participants will take part in a 90-minute BA 
intervention tailored to treat depression. This intervention will include 
psychoeducation, activity monitoring, evaluation of values, and activity 
planning and scheduling. 
 
Neurostimulation: We will use the DC-STIMULATOR MC Stimulator Plus for 
investigational purposes to deliver either cross-frequency delta-beta or active 
sham transcranial alternating current stimulation. Active sham treatment will 
include 20 seconds of ramp in to 40 seconds of tACS with a ramp out of 20 
seconds for a total of 80 seconds of stimulation.  
 
Outcome Measures 
For Aim 1 (PRIMARY).   Change in clinician-rated depressive symptoms 
using HDRS between baseline visit and 2-week follow-up visit. 
 
For Aim 2 (SECONDARY).   Phase-amplitude coupling between delta-beta 
oscillations during task performance of the Streamlined Expenditure of 
Effort for Reward Task (S-EEfRT) at baseline visit and 2-week follow-up 
visit. 
 
For Aim 3 (SECONDARY). Behavioral metric, percentage of hard trials 
chosen, during the S-EEfRT at baseline visit and 2-week follow-up visit.  
 
For Aim 4 (EXPLORATORY). Change in clinician-rated anhedonia 
symptoms using SHAPS-C between baseline visit and 2-week follow-up 
visit. 
 
 

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Statistical Analysis Plans  
for Each Aim  
Aim 1 Plans. Repeated-measures ANOVA with one within-participant 
factor (before and after treatment) and one between-participants factor 
(delta-beta, sham) comparing change in clinician-assessed  depressive 
symptoms. 
 
Aim 2 Plans. Repeated-measures ANOVA with one within-participant 
factor (before and after treatment) and one between-participants factor 
(delta-beta, sham) comparing change in delta-beta coupling. 
 
Aim 3 Plans. Repeated-measures ANOVA with one within-participant 
factor (before and after treatment) and one between-participants factor 
(delta-beta, sham) comparing change in goal-directed behavior. 
 
Aim 4 Plans. Repeated-measures ANOVA with one within-participant 
factor (before and after treatment) and one between-participants factor 
(delta-beta, sham) comparing change in clinician-assessed anhedonia 
symptoms. 
 
Study Duration 
1 year  
Participation Duration 
Study participation for each participant will be approximately 4 weeks. 
Completion includes three in-person sessions: a baseline clinical 
assessment and EEG session, an intervention session, and a follow-up 
assessment and EEG session two weeks later. The baseline clinical 
assessment and EEG session will take approximately 3 hours. The 
intervention session will take approximately 2 hours. The follow-up visit 
will take approximately 2.5 hours. Participants will be sent questionnaires 
to complete online 4 weeks after the intervention visit.  These 
questionnaires are expected to take approximately 0.5 hours to complete. 
We estimate that total participation will take approximately 8 hours.  
 
Enrollment Duration 
8 months 
 
2. Introduction 
2.1.  Background Information 
Major depressive disorder (MDD) is a common and debilitating disorder characterized by heterogeneity and 
variability of treatment response (Fava et al., 1997; Friedrich, 2017). Behavioral activation (BA) is a treatment for 
MDD and depressive symptoms aimed at increasing engagement with pleasurable and mastery activities in line with 
an individual’s identified values (Dimidjian et al., 2014; Mazzucchelli et al., 2009). Obstacles to treatment 
engagement, including time and resource limitations, often contribute to worse treatment outcomes and have led 
to consideration of single-session depression interventions (Gawrysiak et al., 2009; Schleider et al., 2022; Parra et 
al., 2019; Read et al., 2016 Wasil et al., 2021), and initial studies have largely found reductions in stress and 
depressive symptoms, as well as increases in self-reported agency following single-session BA interventions.  
 
Additionally, recent findings have emerged that suggest non-invasive brain stimulation may be a particularly 
effective intervention for treatment-resistance. Guided by prior research from our lab, this study will investigate 
the effect of delta-beta transcranial alternating current stimulation (tACS) on response to single-session BA for 
depression. Coupling between low-frequency cognitive control signals in the delta frequency band (1-4 Hz) 

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emanating from prefrontal cortex and the amplitude of beta oscillations (15-30 Hz) in the primary motor cortex was 
found to be positively correlated with goal-directed behavior in our previous experiment (Riddle et al., 2022). 
Furthermore, individual differences in the  strength of delta-beta coupling were negatively correlated with 
depressive symptoms in a sample that included patients within a major depressive episode. 
 
The proposed study will examine whether non-invasive brain stimulation targeted to enhance neural activity related 
to goal-directed behavior will increase the efficacy of BA in patients with major depressive disorder. This approach 
was selected based on literature that found reward-related deficits associated with depression (Admon & Pizzagalli, 
2015; Grahek et al., 2019) and the proposed mechanisms of action for BA (Nagy et al., 2020). In light of the link 
between delta-beta coupling and goal-directed behavior (Riddle et al., 2022), delta-beta tACS will be aligned with 
the timing of the “activity planning and scheduling” phase of BA. Building on the link between specific symptoms of 
depression (e.g., anhedonia) and reward processing (der-Avakian et al., 2012), exploratory analyses will examine 
whether treatment may uniquely target anhedonic symptoms. 
 
We believe that the proposed study will provide an important test of novel treatments particularly tailored to 
depression and the potential role of reward-related pathways. Results may pave the way for larger clinical trials to 
establish a more personalized treatment approach.  
2.2.   Scientific Rationale 
This study is a randomized, sham-controlled interventional parallel-arm clinical trial. All participants will receive the 
same single-session BA intervention. Concurrent with the goal-directed phase of the BA intervention, participants 
will receive either delta-beta tACS or an active sham stimulation. All researchers involved in data collection and the 
participants receiving stimulation will be blind to the stimulation condition to reduce bias in the data collection 
process, i.e., double-blinding. A previous study in the lab found that depressed participants demonstrated reduced 
delta-beta coupling (Riddle et al., Cerebral Cortex 2022), and a study currently ongoing is testing the impact of delta-
beta stimulation on performance during a reward-related decision-making task (NCT05084924). Moreover, another 
previous study recorded EEG during the S-EEfRT in patients with MDD. This study found that participants with MDD 
demonstrated reduced goal-directed behavior and reduced delta-beta coupling. This preliminary data provides strong 
evidence that stimulation delivered in a delta-beta pattern should be beneficial to reward-related behavioral outcomes 
that are the focus of BA. The proposed study will build on these findings to determine whether a BA intervention 
combined with targeted stimulation may lead to improved treatment outcomes in reward-related constructs. 
 
 

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3. Specific Aims 
 
3.1. Aim 1 
(PRIMARY) Evaluate the effects of delta-beta transcranial alternating current stimulation (tACS) on 
depression symptom severity from pre- to post-treatment. 
 
 
3.2. Aim 2 
(SECONDARY) Examine changes in goal-directed behavior during a reward-based decision-making task 
from pre- to post-treatment. 
 
 
 
3.3. Aim 3 
(SECONDARY) Investigate changes in delta-beta coupling during a reward-based decision-making task from 
pre- to post-treatment. 
 
 
 
3.4. Aim 
(EXPLORATORY) Explore the effects of delta-beta transcranial alternating current stimulation (tACS) on 
anhedonia symptom severity from pre- to post-treatment. 
 
 
 
Table 1. Examples of Alignment of the Specific Aims with Measures and Aim-Specific Statistical Analysis 
Plans 
 
Specific 
Aim 
Outcomes  
Measures 
Population Parameters to be Estimated 
(“Estimands”) 
Statistical  
Estimators 
 
Aim 1. (PRIMARY) Evaluate 
the effects of delta-beta 
transcranial 
alternating 
current stimulation (tACS) 
on depression symptom 
severity from pre- to post-
treatment. 
 
Change in clinician-rated 
depressive 
symptoms 
using 
HDRS 
between 
baseline visit and 2-week 
follow-up visit. 
 
 Treatment response 
ANOVA 
 
Aim 
2. 
(SECONDARY)  
Examine changes in goal-
directed behavior during a 
reward-based 
decision-
making task from pre- to 
post-treatment.. 
 
Phase-amplitude coupling 
between 
delta-beta 
oscillations during task 
performance 
of 
the 
Streamlined Expenditure 
of Effort for Reward Task 
(S-EEfRT) at baseline visit 
and 
2-week 
follow-up 
visit.  
  Treatment response 
ANOVA 
Aim 
3. 
 
(SECONDARY) 
Investigate 
changes 
in 
delta-beta coupling during 
a reward-based decision-
Behavioral 
metric, 
percentage of hard trials 
chosen, during the S-
EEfRT at baseline visit and 
2-week follow-up visit. 
 Treatment response 
ANOVA 

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making task from pre- to 
post-treatment. 
Aim 
4. 
(EXPLORATORY) 
Explore the effects of delta-
beta 
transcranial 
alternating 
current 
stimulation 
(tACS) 
on 
anhedonia 
symptom 
severity 
following 
from 
pre- to post-treatment. 
Change in clinician-rated 
anhedonia 
symptoms 
using SHAPS-C between 
baseline visit and 2-week 
follow-up visit. 
 
Treatment response 
ANOVA 
 
 
 

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4. Study Design
This is a single site interventional study evaluating the use of transcranial alternating current stimulation (tACS) to 
augment a single-session behavioral activation (BA) intervention in the treatment of depressive symptoms (Figure 
1). To examine the effects of neurostimulation on treatment response, participants will be randomized to receive 
either cross-frequency transcranial alternating current stimulation (tACS) or an active sham. 
Figure 1. Study schema
Choice of dosage of neurostimulation:
Transcranial alternating current stimulation (tACS) is an extremely safe non-invasive stimulation paradigm without a 
single serious adverse event directly related to stimulation. The same tACS method has been used during performance 
of a task with intermittent resting state EEG in our previous approved UNC IRB protocol 18-0003 (NCT03800030) that 
was overseen by Dr. Riddle. A similar experimental design using a single session with reward-based decision-making tasks 
and tACS in participants with major depressive disorder (MDD) was approved in our previous UNC IRB protocol 21-1321
(NCT03449979) that was overseen by Dr. Riddle. Transcranial alternating current stimulation (tACS) applies a weak 
electric current to the scalp and all previous studies (approximately 15 to date) performed in the Carolina Center for 
Neurostimulation have received a “non-significant risk designation” from the 
UNC IRB. Thus, no direct FDA oversight is required and no investigational 
device application filing is required. Further conversations with the 
regulatory core of the UNC CTSA and the director of the Office of Human 
Research Ethics that administers the UNC IRB over the years have 
consistently confirmed this classification. We will deliver tACS using a delta-
beta stimulation waveform that was designed to mimic the endogenous 
cross-frequency coupling pattern observed by EEG. For the active arm of this 
RCT, the interventional stimulation will be 30 minutes of tACS delivered 
during the second phase of BA. For the placebo arm, participants will receive 
active sham tACS in which  delta-beta tACS is delivered for 1 minute and then 
returns to baseline (approximately 15 second ramp up and ramp down). This 
active sham is designed to mimic the sensation of receiving stimulation 
without delivering a sufficient dose of tACS to influence the efficacy of BA.
The delta-beta waveform was designed based on our previous experiment 
that observed delta-beta coupling between prefrontal and motor cortex in a 
Phone screen
• Obtain informed 
consent (verbal)
• Assess 
inclusion/exclusion 
crieria
• MINI MDE 
questions
Baseline visit
• Overview of study 
and obtain informed 
consent (written)
• MINI
• HDRS
• SHAPS-C
• IDAS
• TEPS
• BIS/BAS
• BADS
• STAI
• RRS
• EEG
• S-EEfRT
Treatment visit
• Single session BA 
(90 minutes)
• tACS group (N=20)
• 30 min 
stimulation 
during second 
half of session
• Sham group (N=20)
• Sham during 
second half of 
session
2 week FU
• HDRS
• SHAPS-C
• IDAS
• TEPS
• BADS
• STAI
• RRS
• EEG
• S-EEfRT
4 week FU - online
Via online 
questionnaires
• SHAPS
• IDAS
• TEPS
• BADS
• STAI
• RRS
Figure 2. Electrical waveform for 
delta-beta tACS. Peak stimulation 
amplitude is 1 mA for target 
electrodes.

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reward-based decision-making task in participants with MDD (Riddle et al., 2022). The timing of the stimulation was 
chosen to align with the “activity planning and scheduling” portion of BA, when goal-directed behaviors are thought to 
be maximal. The stimulation amplitude delivered is standard for tACS studies (Ahn, Mellin et al. 2018, Alexander, 
Alagapan et al. 2019) – stimulation peaks at 1 mA during the peak of the high-frequency component for target electrodes 
(see Y-axis of Figure 2). The high frequency component consists of 3.5 cycles of a sine-wave of the high frequency that is 
centered at 90 degrees of each cycle of the low-frequency component. Stimulation peaks at 2 mA zero-to-peak for the 
return electrode, but the electrode size is 35 cm2 for the return electrode and 20.25 cm2 for each of the target electrodes. 
Thus, the current density is comparable between the two: 0.057 mA/cm2 for the return electrode and 0.049 mA/cm2 for 
the target electrodes. We will use the international 10-20 head measurement system to place the tACS electrodes 
on the scalp. The two target electrodes will be placed anterior and ventral to F3 and posterior and ventral to C3. 
The return electrode will be centered on FCz. This electrode montage is designed to deliver synchronized 
stimulation to the prefrontal cortex and motor cortex to enhance cross-frequency coupling between these brain 
regions. 
 
 
4.1. Treatment Design 
 
Participants will take part in a single-session behavioral activation (BA) intervention. This intervention was adapted from 
standard BA protocols for the treatment of depression to be completed in a single, 90-minute session. This intervention 
will have 4 main components based on prior protocols:  
• 
Treatment overview and rationale 
• 
Tracking of daily activities  
• 
Exploration of values  
• 
Planning/scheduling activities  
 
Participants will be stimulated with the commercial, CE-certified Neuroconn multiple channel (MC) stimulator. The use 
of this device in this study has previously received a NSR designation on initial review by the full UNC IRB. The NeuroConn 
device description is as follows: The DC-STIMULATOR MC is a CE-certified medical device for conducting non-invasive 
transcranial direct current stimulation (tDCS) in humans. Direct current 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 MC 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, maximizing patient 
safety. The device includes a digital display with various stimulation modes to be selected and stimulation parameters 
such as current strength, duration, fade-in and fade-out to be set. 
DC-STIMULATOR MC features: 
• 
4 programmable, micro-processor-controlled constant current sources using inependent channels 
(optional: 16 channels) 
• 
For transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), cranial 
electrical stimulation (CES), galvanic vestibular stimulation (GVS) and transcranial random noise stimulation 
(tRNS) 
• 
4 standard modes - tDCS (continuous stimulation) - pulse (cyclical stimulation activation/deactivation) - 
sinus (sinus wave) - noise (normally distributed) 
• 
Current strength and curve forms adjustable up to ¬±4,000 ¬µA, AC current strength adjustable up to 8,000 
¬µA (peak-to-peak) 
• 
Frequencies adjustable up to 1,000 Hz, phase freely adjustable 

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• 
Various types of stimulation can be selected and combined - continuous stimulation, cyclical switching on 
and off of stimulation, sinusoidal stimulation 
• 
Medical panel PC for the use and programming of stimulation modes and stimulation sequences 
 
4.2.  Experimental Design    
All participants will receive the single-session 90-minute BA intervention. Participants will be randomized to either 
receive either cross-frequency transcranial alternating current stimulation (tACS) or an active sham. 
4.3.  Measurement Design 
Table 2.  Variables of interest: their occasions of evaluation, their uses for the aims, their roles in the study 
Variables within Domains 
Scale1 
Occasions2  Aims3 
Main Roles 
Identifiers 
 
 
 
 
Participant’s unique ID 
nominal 
all 
all 
identifier 
Treatment Regimen (A or B) 
binary 
2 
all 
identifier 
Behavioral Measures 
 
 
 
 
goal-directed behavior (S-EEfRT) 
percentage 
0, 2 
Aim 3 
secondary outcome 
EEG Measures 
 
 
 
 
delta-beta coupling (S-EEfRT) 
continuous 
0, 2 
Aim 2 
secondary outcome 
Clinician Rated Measures 
 
 
 
 
SHAPS-C  
interval 
0, 2 
Aim 4 
exploratory outcome 
MINI  
categorical 
0 
-- 
screening 
HDRS 
interval 
0, 2 
Aim 1 
primary outcome 
Patient-Reported Measures 
 
 
 
 
SHAPS 
interval 
3 
-- 
covariate uses  
IDAS 
interval 
0, 2, 3 
all 
covariate uses 
TEPS 
interval 
0, 2, 3 
all 
covariate uses 
BIS/BAS 
interval 
0 
all 
covariate uses 
BADS 
interval 
0, 2, 3 
all 
covariate uses 
RRS 
interval 
0, 2, 3 
all 
covariate uses 
STAI 
interval 
0, 2, 3 
all 
covariate uses 
Safety Monitoring 
 
 
 
 
AEs and SAEs documentation 
events 
0, 1,2,3 
-- 
safety monitoring 
 
 
1 Units of measurement or the scale. 
 
 
2 Occasions of evaluation or retrieval:     S = screening,   0 = baseline visit, 
 
 
 
 
 
                             1 = treatment visit,     2 = 2 week FU,     3 = 4 week FU. 
 
 
3 The specific aims in which the variable will play a role in data analyses. 
 
 
4 Uses: assess medication adherence, mediation analyses, and exploratory analyses  
 
 
In Table 2, the treatment regimens are:   
 
 
A = BA + delta-beta tACS,   
 
 
B = BA + sham stimulation. 
 

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5. Study Participants 
5.1. Numbers of Participants 
 
5.1.1. Number to be screened:  n  80 
 
 
5.1.2. Number to be enrolled:   Our target sample size is N = 40. 20 participants will be enrolled in the 
BA + tACS condition and 20 will be enrolled in the BA + active sham condition. Conservatively, we may enroll up to 
80 participants, but a potentially substantially high number of people may not meet criteria for MDD as assessed 
by the MINI at the baseline visit. 
5.2. Eligibility Criteria 
Eligibility will be determined based on inclusion and exclusion criteria, defined below. 
 
 
5.2.1. Inclusion Criteria  
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
• 
Between the ages of 18 and 65 
• 
Able to provide informed consent 
• 
Willing to comply with all study procedures and be available for the duration of the study 
• 
Speak and understand English 
• 
DSM-5 diagnosis of major depressive disorder (MDD) as assessed by the MINI 
 
 
5.2.1. Exclusion Criteria  
Any individual who meets one or more of the following criteria will be excluded from participation: 
• 
Participants must not have active suicide intent as determined by the Columbia Suicide Severity Rating Scale 
(C-SSRS). Active suicide intent will be captured in responses to items 4 and/or 5 on the C-SSRS. 
• 
Participants must not meet criteria for current severe substance use disorder, anorexia nervosa, or active 
psychosis as captured by the MINI. 
• 
Participants may not currently be in psychotherapy and have not received any other psychotherapy and/or 
stimulation (ECT, TMS) within the last 4 weeks.  
• 
Any participants taking psychotropic medication must be on a stable dose for at least 4 weeks with no planned 
dose changes within the next 4 weeks.  
• 
(for female participants) Participants must not be pregnant or breastfeeding. 
• 
Participants may not have any medical or neurological illness for which symptom presentation or treatment could 
interfere with study participation 
• 
Participants may not have undergone prior brain surgery 
• 
Participants may not have any brain devices/implants, including cochlear implants and aneurysm clips 
• 
Participants may not have had brain injury or concussion within the last three months 
• 
Participants may not have a history of brain injury requiring current treatment 
5.3. Enrollment/Selection Strategies 
 
5.3.1.  Prospective Recruitment  -or-  Retrospective Selection   
To aid in recruitment, we will advertise the study directly to the public on websites such as ClinicalTrials.gov, 
frohlichlab.org and Carolinaneurostimulation.org. We will have contact information and a summary of the clinical trial 

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posted on the Frohlich Lab social media pages. We may also be launching a social media ad to identify potential patients. 
This ad will also use a pre-screening survey via REDCap to help identify participants. We will also be using the UNC Mass 
email listserv and an IRB-approved registry. All patient identifiers will be stored in REDCap until recruitment is over. When 
recruitment is over, all patients who do not consent or are not eligible for participation in the study will have their 
responses permanently deleted in REDCap.  
 
5.3.2. Screen Failures    
In the design of this study, initial phone screening procedures should identify the majority of participants who could 
potentially become screen failures if consented to participate in the clinical trial. However, the phone screening process 
does not necessarily account for all exclusion criteria. In the case that a participant meets initial criteria, there is still a 
chance that the first interview reveals that they do not meet study criteria. The study personnel completing the 
interviewing process will clearly explain why the participant does not meet criteria. However, in the case that a participant 
does not qualify based on suicide risk, procedures will be followed to ensure participant safety.  
At the first session and after obtaining participant informed consent, the C-SSRS will be administered, which contains 
questions related to suicidal thoughts/actions. If someone indicates intent based on the C-SSRS, their participation in the 
study will be immediately stopped and Dr. Schiller (Co-I, responsible for participant safety) will be contacted for acute 
assessment. In the case that the person does not see anyone for their depression, Dr. Schiller will provide the participant 
with resources for seeking psychological care. 
Assessment may include facilitating contact of the participant with their psychiatrist/primary care physician to establish 
a plan for safety, continued care, and follow-up. If the participant does not have an established provider, Dr. Schiller will 
assist the participant in establishing care. If at any point in the assessment, the participant is deemed to be an imminent 
risk of harm to self or others, study personnel will contact the Emergency Department for further care.  
5.4. Strategies for Retention 
Retention will be primarily achieved by the short duration of participation. Namely, the study includes a single 
intervention session, preceded by and followed by additional study visits. Participants will be paid $45 for 
participation in the initial study visit, $15 for the intervention/stimulation visit, and $30 for the two-week follow up 
visit. Participants will also be sent questionnaires to complete virtually 4 weeks after the intervention visit, and they 
will be paid $10 for completion of these questionnaires. Total payment for completion of all visits in the study totals 
$100. This virtual visit will reduce burden on participants to travel for an additional study visit. The participant will 
receive payment at the end of each session on a payment card that can be loaded. The research staff will also give 
each participant a reminder call or email for upcoming sessions. Each research staff member will be available for 
the participants to contact via email or phone. 
 
5.5.  Matching and Stratification 
N/A 
5.6.  Randomization  and  Concealment 
Mengsen Zhang, a Frohlich Lab member, will oversee the randomization of 40 6-digit codes, which will be used by the 
experimenters. These codes are directly linked to which treatment participants receive (sham/placebo or 10 Hz tACS at 
1 mA) and will be entered into the MATLAB script. In addition, 10 codes will be generated in the event that a participant 
is randomized but discontinues the study. Data will be collected until we reach out target of 40 participants, but there 
will be no bias towards completion for the different arms (in the unlikely event that one of the arms has more dropout 
than the others). The assignment of each participant cannot be determined by looking at the codes (e.g., codes are not 
sequential, code assignment is not based on “odd” or “even” numbers). Thus, the study is both randomized and 
concealed by virtue of using random numbers generated by a computer. Mengsen Zhang has no other responsibility in 
the study other than providing these randomized codes. If Mengsen Zhang leaves the Frohlich Lab, another equivalent 
researcher who does not work with human participants will perform this task.  
 

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5.7.  Blinding 
This study is designed to be double-blind. This means that the participant and the researchers are unaware of each 
participant's assignment until the completion of all data collection. This is accomplished using the randomization codes 
described above. Furthermore, this study utilizes an active sham stimulation. This means that the active sham condition 
includes some stimulation, mimicking the skin sensations associated with tACS. In our previously concluded trial, 
participants in the delta-beta tACS and active sham groups responded similarly to the blinding questionnaire, indicating 
that our active sham stimulation successfully blinded the participants. 
 
 

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6. Treatment Design: Procedures 
Description   All participants will receive the behavioral activation (BA) psychotherapy intervention. This 
intervention occurs in a single 90-minute session. Participants are randomized to receive either an active 
stimulation or sham stimulation using transcranial alternating current stimulation (tACS). 
  
Acquisition   The DC-STIMULATOR MC is a CE-certified medical device is owned and operated by the Carolina Center 
for Neurostimulation / Frohlich lab.    
Concomitant Therapies   Participants will be ineligible to participate in this study if they are currently receiving 
another form of psychotherapy, TMS, and/or ECT. Individuals prescribed psychiatric medication must be on a stable 
dose (>4 weeks).   Concomitant medications will be logged at the first session. Participants will be requested to include 
the dosing for these therapies (i.e., how often per day, how much in each pill, how many pills) as well as when they were 
first prescribed the medication.  
7. Schedule of Activities and Procedures 
7.1. Table of Events 
 
 
 
Table 3. Schedule of activities and procedures for a randomized clinical trial 
Procedure 
Phone 
screening 
Visit 0 
baseline 
Visit 1 
Tx visit 
Visit 2 
2-week 
FU 
Visit 3 
4-week FU 
online 
Recruit a Sample of 
Patients 
Informed consent 
X 
X 
 
 
 
Eligibility assessments 
X 
X 
 
 
 
Enrollment and randomization 
 
X 
 
 
 
Treatment 
Administer regimens 
 
 
X 
 
 
Clinician-Assessed 
Measures 
Depressive symptoms  
 
X 
 
X 
 
DSM-5 Diagnoses 
 
X 
 
 
 
Anhedonia symptoms 
 
X 
 
X 
 
Safety 
Monitoring 
Review concomitant meds. 
 
X 
X 
X 
X 
Suicidality assessment 
 
X 
X 
X 
 
Assessment of AEs 
 
X 
X 
X 
X 
Patient Reported 
Measures 
anhedonia  scores 
 
X 
 
X 
X 
depression and anxiety scores  
 
X 
 
X 
X 
Stress scores  
 
X 
 
X 
X 
Rumination scores 
 
X 
 
X 
X 
1, 2, 3, 4, 5  Footnotes that list and define the measures of interest are used here. 
 
 
 
  Screening 
Participants that request to be in the experiment will provide verbal, documented consent to undergo a phone screening 
to assess that the participant meets exclusion/inclusion criteria. Participants who are initially deemed initially eligible due 
to meeting criteria for 5 or more MDD symptoms within Module A of the MINI will be invited to enroll within two weeks 
of phone screen date.  
At the initial in-person visit, participants will provide written consent before completing additional assessments to 
confirm eligibility and for exploratory analyses. Self-report clinical assessments will be completed on REDCap while being 
monitored: Inventory of Depression and Anxiety Symptoms (IDAS; Watson et al., 2007); Behavioral Activation System and 
Behavioral Inhibition System (BIS/BAS; Carver and White 1994), Temporal Experience of Pleasure Scale (TEPS; Gard, Gard 
et al. 2006), the State-Trait Anxiety Inventory (STAI; Spielberger 2010), and Ruminative Responses Scale (RRS; Nolen-
Hoeksema, Larson et al. 1999). Participants will also undergo clinician-administered assessments that will be entered 
onto REDCap: the Mini International Psychiatric Interview for the DSM-5 (MINI; Sheehan et al., 1998), Hamilton 

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Depression Rating Scale (HDRS; Williams, 1988), Snaith- Hamilton Pleasure Scale – Clinician Administrated (SHAPS-C; 
Ameli et al., 2014), Columbia-Suicide Severity Rating Scale (C-SSRS; Posner et al., 1999). Eligibility for the study is 
determined by a MINI diagnosis of MDD, exclusion based on a present severe substance use disorder, a present diagnosis 
of anorexia nervosa, and meeting criteria for current active psychosis. In addition, participants must not have active 
suicide risk as determined by the C-SSRS (see Inclusion/Exclusion criteria above). In the event that a participant has active 
plans to commit suicide, an adverse event is recorded, an acute psychiatric assessment is conducted by our medical 
monitor, Dr. Crystal Schiller, who is a clinical psychologist at UNC-CH, and participation is terminated. 
 
     
Enrollment  
After providing written informed consent, further clinical assessments will be conducted (e.g., clinician-administered 
depression assessment, MINI diagnostic assessment) to confirm eligibility for enrollment.  
7.2.  Study Visits 
Following an eligible phone screen, participants will be scheduled to come in for the first in-person visit within two 
weeks of the screen. At the session, participants will provide written consent to participate in the study.  They will 
undergo clinician-administered assessments: Hamilton Depression Rating Scale (HDRS), the Snaith-Hamilton 
Pleasure Scale (SHAPS-C), the Mini International Neuropsychiatric Interview for DSM-5 (MINI) and the Columbia-
Suicide severity Rating Scale (C-SSRS).  Exclusion criteria for severe SUD, AN, or current psychotic symptoms will be 
determined from the MINI. In addition, the participant must not have suicide intent as determined by the C-SSRS. 
At this visit, participants will also complete a reward-related decision-making task (S-EEfRT) during EEG collection. 
Participants will also complete self-report questionnaires on psychological symptoms. 
 
At the intervention visit, which will occur within one week of the baseline visit,  all participants will complete a 
single-session 90-minute BA treatment. During the second half of the intervention visit, stimulation will occur for a 
duration of 30 minutes. Participants will be randomized to receive either delta-beta tACS or an active sham 
stimulation. The C-SSRS will also be administered. 
 
The third session occurs approximately two weeks after the intervention session. At the session, the HDRS, SHAPS-
C and C-SSRS will be administered. Participants will complete a behavioral task while EEG data are collected and 
self-report questionnaires on psychological symptoms.  
7.3. Final Visit 
Four weeks after their participation in the intervention visit, participants will be emailed a link to complete self-
report questionnaires to assess clinical outcomes through REDCap, a secure database web-platform.       
7.4.  Phone Contacts  
N/A           
7.5.  Follow-Up Contact  
N/A            
7.6.  Early Discontinuations 
Data to be Collected   If participants elect to withdraw from the study, the reason for discontinuation will be 
documented. No further follow-up data will be collected.    
       

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Criteria for Intervention Discontinuation    
The study intervention (i.e., 90 minutes of BA with final 30 minutes of stimulation) will be discontinued for the 
following reasons: 
• Any clinical adverse event (AE), laboratory abnormality, intercurrent illness or other medical condition, or 
situation occurs such that continued participation in the study would not be in the best interest of the participant. 
• The participant meets any exclusion criteria (either newly developed or not previously recognized).  
 
     
7.7. Enrollees May Drop Out 
Participants are free to withdraw from participation in the study at any time upon request.  
The reason for participant discontinuation or withdrawal from the study will be recorded with the participant files. 
Participants who sign the informed consent form and are not randomized will be replaced. Participants who sign the 
informed consent form, are randomized, and receive the full or part of the study intervention, and subsequently 
withdraw from the study, are withdrawn from the study, or discontinue the study will not be replaced.  
  
   
8. Statistical Analysis Plans 
8.1. Strategies that Apply to all the Aims 
All testing described below assumes a significance threshold of p = 0.05. Analyses will be deemed to be statistically 
significant if the p-value is less than this threshold. An analysis that does not exceed this threshold will be considered 
inconclusive.  
There may be additional covariates included in the analysis. Data will be assessed for normality and, if deemed necessary, 
corrective procedures will be applied (e.g., log normalization). Based on our previous dataset, we expect that the 
variables used here will be approximately Gaussian. However, if the distribution of a variable displays a skewed tail and 
a test for normality fails, then it is justified to use a corrective procedure. This correction will be applied upon 
consideration of the variables themselves, and not based on the result of the intended analysis.  
Human studies are prone to drop-out, missing data, and interval-censored values.  The reasons for drop outs, missing / 
censored data values, and protocol departures will be documented in the database.  Best practices for dealing with 
incomplete data will depend on the documented causes of those occurrences. 
The analysis plans will include outcome-dependent exploratory analyses to generate new hypotheses. 
 
To help ensure replicability of the research, the analysis plans will be reviewed and finalized prior to collection of 
data (a priori). For each specific aim, the analysis plans specify detailed steps for obtaining estimates of the 
population parameters of interest (e.g., treatment effects) and for making inferences.   
• 
Human studies are prone to drop-out, missing data, and interval-censored values.  The reasons for drop-outs, 
missing / censored data values, and protocol departures will be documented in the database.  Best practices 
for dealing with incomplete data will depend on the documented causes of those occurrences.  In the analysis 
plans established a priori, the strategies for coping with incomplete data will be based on anticipated causes. 
Alternative methods for dealing with incomplete data will play important roles in the sensitivity analyses.   
• 
All hypothesis tests yielding large p-values will be reported as being inconclusive. For all sample sizes, all 
hypothesis test procedures are (by design) incapable of establishing that the null hypothesis is true.  
• 
If p-values are computed they should be reported to several decimal places without categorizing or 
dichotomizing the p-value; that is, the words “significant” and “non-significant” should be avoided.  The p-value 
should be reported and interpreted as a continuous measure indicating the availability of information against 

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the (null) hypothesis being tested. The available amount of information against the null hypothesis is equal to 
the Shannon Information S-value, and the p-value = (½) S-value.  Smaller p-values (larger S-values) indicate greater 
amounts of available information.  Larger p-values indicate a lack of information; e.g., if p = 1 then the S = 0.  If 
p = 0.03125 then S = 5 which indicates a result that is as-surprising-as observing 5 ‘heads’ in a row when flipping 
a coin 5 times to test whether it is a fair coin.  Due to lack of information, large p-values cannot be used to draw 
any conclusions as to whether the tested null hypothesis is true or false. Lack of availability of evidence of an 
effect is not evidence of a lack of effect. 
• 
The proposed statistical analysis strategy acknowledges that no p-value can reveal the plausibility, presence, 
truth, or importance of an association or effect --which is consistent with the statements of the American 
Statistical Association [4,5], the recommendations in Nature [6,7], and guidance, such as the CONSORT 
Statement [1], STROBE Statement [2], and ICMJE guidance [3].†] 
 
8.2.  Sample Description 
Continuous data will be described using means, standard deviations, and confidence intervals, while categorical data will 
be described using counts/percentages.  
8.3.  Aim-Specific Plans 
   
 
Plans for Aim 1 (PRIMARY).  
Treatment response will be calculated as the depression (HDRS) scores from pre- to post-treatment. A two-way 
analysis of variance (ANOVA) will be performed using within-participant factor of time (before or after treatment), 
between-participant factor stimulation type (delta-beta tACS, active-sham), and the interaction between time and 
stimulation type. We hypothesize to find an interaction between time and stimulation type. Post hoc differences 
will be investigated. We hypothesize that the predicted interaction will be driven by a decrease in depressive 
symptoms for delta-beta tACS compared to the active-sham. Sensitivity analyses will be conducted to evaluate the 
specificity of these effects: a similar analysis with anxiety symptoms as the dependent variable and we do not expect 
that delta-beta tACS will have any effect on anxiety symptoms. 
 
Further, we will conduct exploratory generalized linear mixed models will be conducted to examine potential 
confounds on treatment effect (e.g., age, sex, baseline depressive symptoms). 
 
 
Plans for Aim 2 (SECONDARY).  
Delta-beta phase amplitude coupling will be calculated between the phase of delta oscillations (2-3 Hz) in 
prefrontal electrodes (FCz and surrounding electrodes) and the amplitude of beta oscillations (15- 25 Hz) 
in left motor electrodes (C3 and surrounding electrodes). The instantaneous phase and amplitude of these 
oscillations will be calculated by averaging the signal in these two regions of interest, band-filtering the 
signal to the specified range, and then performing the Hilbert transform on the signal. Phase-amplitude 
coupling (PAC) is then calculated by creating a hybrid signal using the amplitude of beta oscillations in left 
motor electrodes and the phase of delta oscillations in prefrontal electrodes: 
 
 
†[1] www.consort-statement.org   ,  [2] www.strobe-statement.org,   [3] www.icmje.org  
  [4]  Wasserstein RL, et al. (2016), The ASA's Statement on p-Values, The American Statistician, 70:2, 129-133.  
  [5] Wasserstein RL, et al. (2019), Moving to a World Beyond p < 0.05, The American Statistician, 73:sup1, 1-19.  
  [6] Amrhein,  et al. (2019),  Scientists rise up against statistical significance, Nature 567, 305-307.  
  [7] Editorial (2019) It’s time to talk about ditching statistical significance: … Nature 567, 283-283. 
 

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M is magnitude of beta oscillations, θ is angle of delta oscillations, N is number of time points 
 
The PAC value is normalized by creating a null distribution by randomly shifting the beta timeseries by at 
least 10% of the number of time points. Then, PAC is calculated between the delta-phase timeseries and 
each of these randomly shifted beta-amplitude timeseries. Finally, PACZ is calculated as the z-transformed 
true PAC value relative to the null distribution. 
 
A two-way analysis of variance (ANOVA) will be performed using within-participant factor of time (before or after 
treatment) and between-participant factor stimulation type (delta-beta tACS, active-sham). We hypothesize to find 
an interaction between time and stimulation type. Post hoc differences will be investigated. We hypothesize that 
the predicted interaction will be driven by an increase in delta-beta coupling for delta-beta tACS compared to the 
active-sham. Sensitivity analyses will be conducted to evaluate the specificity of these effects: a similar analysis with 
theta-gamma coupling as the dependent variable and we do not expect that delta-beta tACS will have any effect on 
theta-gamma coupling. 
 
Further, we will conduct exploratory generalized linear mixed models will be conducted to examine potential 
confounds on treatment effect (e.g., age, sex, baseline depressive symptoms). 
 
 
 
Plans for Aim 3 (SECONDARY). 
Goal-directed behavior will be calculated as the average decision to perform the HARD task across blocks.  A two-way 
analysis of variance (ANOVA) will be performed using within-participant factor of time (before or after treatment) 
and between-participant factor stimulation type (delta-beta tACS, active-sham). We hypothesize to find an 
interaction between time and stimulation type. Post hoc differences will be investigated. We hypothesize that the 
predicted interaction will be driven by an increase in goal-directed behavior for delta-beta tACS compared to the 
active-sham. Sensitivity analyses will be conducted to evaluate the specificity of these effects: a similar analysis with 
reward-evaluation as the dependent variable and we do not expect that delta-beta tACS will have any effect on reward-
evaluation. 
 
Further, we will conduct exploratory generalized linear mixed models will be conducted to examine potential 
confounds on treatment effect (e.g., age, sex, baseline depressive symptoms). 
 
 
Plans for Aim 4 (EXPLORATORY).  
Exploratory analyses are planned only if effects are seen on depressive symptoms (Aim 1). If so, we plan to explore 
the potential effects specific to anhedonia symptoms. Treatment response will be calculated as the change in 
anhedonia (SHAPS-C) scores from pre- to post-treatment. A two-way analysis of variance (ANOVA) will be 
performed using within-participant factor of time (before or after treatment) and between-participant factor 
stimulation type (delta-beta tACS, active-sham). We hypothesize to find an interaction between time and 
stimulation type. Post hoc differences will be investigated. We hypothesize that the predicted interaction will be 
driven by a decrease in anhedonia symptoms for delta-beta tACS compared to the active-sham.  
 
Further, we will conduct exploratory generalized linear mixed models will be conducted to examine potential 
confounds on treatment effect (e.g., age, sex, baseline non-anhedonic depressive symptoms). 
 
Exploratory analyses with anhedonia symptoms will not be conducted if effects for overall depressive symptoms 
(Aim 1) are not found. 
 
 
  Planned Interim Analyses 
No interim analyses will be performed.  
 

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9. Sample Size Rationale 
 
The experiment proposed here will utilize a parallel arm design, and primary analyses will use a repeated-measures 
ANOVA with one within-participant factor (before and after treatment) and one between-participants factor (delta-
beta, placebo). With an average effect size of 0.286 partial-eta square estimated from existing literature on single 
session BA, we estimate that we need at least 15 participants per group to achieve 80% statistical power. Using a 
conservative estimate of 0.5 correlation between estimates, we still reach ~99% power with 40 participants (Figure 
3). Data will be collected until we reach 40 participants. Given the similarity in stimulation methodology between 
the current experiment and our previous experiment (Riddle et al., 2021), we anticipate adequate levels of power 
for hypothesis testing with 40 participants. Moreover, other studies of combined psychotherapy and stimulation 
have reported similar sample sizes (Neacsiu et al., 2022). 
 
Figure 3. Power analysis for impact of BA + tACS on depressive symptoms with ANOVA. 
 
10. Data Capture and Database Management 
10.1. 
Software for Data Capture 
The study data will be entered into a REDCap database developed by the study personnel.  REDCap is a 21 CFR Part 
11-compliant data capture system provided by the NC TraCS Institute at UNC. The data system includes password 
protection and internal quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate.  Study data will be entered directly from the source documents. 
 

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10.2. 
Responsibilities for Data Capture and Database Management 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site investigator. 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data 
reported. 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of data.   
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for recording data 
for each participant enrolled in the study.  Data recorded in the electronic case report form (eCRF) derived from 
source documents should be consistent with the data recorded on the source documents.  
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions data) and 
clinical laboratory data will be entered into REDCap, a 21 CFR Part 11-compliant data capture system provided by 
the TraACS. 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.  
 
10.3. 
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, records will be kept for three years after the completion 
of the study or grant end date, whichever is later.  
 
11. Collection and Management of Tissue Specimens 
11.1. 
Use in Current and Future Studies 
N/A 
11.2. 
Sample Preparation 
N/A 
11.3. 
Record Keeping and Monitoring 
N/A   
11.4. 
Storage and Security 
N/A 
12. Safety Monitoring and Management 
12.1. 
Risk / Benefit Assessment 
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 

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brain activity. To avoid breaches in confidentiality, study documents that contain personal information and including 
the informed consent document are kept in locked filing cabinets in locked rooms separate from any source 
documents containing participant dummy identifiers. The document that links study ID numbers to personal 
identifying information is encrypted and protected using a password-protected document on a secure server 
provided by UNC School of Medicine. All data is stored in locked cabinets inside locked offices; electronic data will 
be stored only on password-protected computers, and data encryption methods will be used during communication 
between investigators. Only study personnel will have access to the data. All study staff participate in annual human 
participant training that includes education about responsibilities to the minimize risk of confidentiality breach. Risk 
of Embarrassment: Self-report assessments contain questions regarding sensitive personal information. This risk is 
necessary in order to assess mood symptoms and associated psychopathology. Participants will be assured upon 
intake that only study personnel will see any clinical ratings and that self-identifying information will not be collected 
alongside HIPAA protected information.    
 
Risk of Injury and Discomfort: The side effects of tACS are mild and transient; in fact, low intensity transcranial current 
stimulation, such as tACS, has been used for over a decade without any report of serious side effects (Antal, 
Alekseichuk et al. 2017). Furthermore, 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). However, tACS does have 
some mild side effects, such as transient mild tingling, burning, or itching under the electrode sites. In our previous 
trial, participants from all three groups of stimulation reported either absent or mild side effects, and there was no 
difference between the groups with the exception of “flickering lights” (or phosphenes, p = 0.014) (Alexander, 
Alagapan et al. 2019). To monitor these mild side effects, we will be administering a stimulation questionnaire after 
each stimulation session to determine whether these effects were experienced and at what intensity. Research 
personnel present during these sessions will also check in with the participant periodically during the stimulation to 
see whether they are comfortable. If participant is experiencing severe discomfort (as determined by the 
questionnaire or by self-report), the stimulation will be stopped immediately.   
 
Potential Benefits: This study has not been designed to benefit the individual participants. However, the 
knowledge gained from this study will contribute to understanding about the psychological and biological basis of 
depression. Furthermore, the results from this study might be used to inform future interventions using a 
combination of brief psychotherapy and non-invasive brain stimulation. 
 
12.2. 
Assessment of Safety 
1. The Columbia Suicide Severity Rating Scale (C-SSRS) (Posner, Brown et al. 2011) will be administered by trained 
research personnel at each session to thoroughly assess suicide risk. If a participant reports experiencing either suicidal 
ideation or suicidal behavior, research personnel will collect more information from the participant to deliver to either 
Dr. Schiller. Clinical personnel will decide if an acute assessment is required. Acute assessment may include facilitating 
contact of the participant with their psychiatrist or primary care physician to establish a plan for safety, continued care, 
and follow-up. If the participant does not have an established provider, Dr. Schiller will assist in establishing a care plan. 
If at any point during the assessment, the participant is deemed an imminent risk of harm to self or others, study 
personnel will enlist the aid of campus security to ensure that the participant is safely escorted to the Emergency 
Department for further care. Dr. Schiller will decide if participation should be stopped after the acute assessment. If an 
acute assessment is required, then participation will be halted.  
2. A stimulation side effects questionnaire will be administered at the end of each stimulation session. This tool will be 
used as a safety measure and to collect data on the participant’s experience. A similar questionnaire was used in a 
previous study (IRB# 13-2995) to determine ability to successfully blind the participants using sham transcranial current 
stimulation.  
3. We screen and exclude individuals with any medical or neurological illness for which symptom presentation or 
treatment could interfere with study participation. We further emphasize that there has never been a single report of a 

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seizure that resulted from transcranial alternating current stimulation (Matsumoto & Ugawa, 2016), and existing 
guidelines suggest that both tACS and tDCS are safe (Antal et al., 2017).  
  
12.3. 
Unanticipated Problems, Adverse Events, Serious Adverse Events 
Unanticipated Problems: The Office for Human Research Protections (OHRP) considers unanticipated 
problems involving risks to participants or others to include, in general, any incident, experience, or outcome 
that meets all of the following criteria:  
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are described in 
the protocol-related documents, such as the Institutional Review Board (IRB)- approved research protocol and 
informed consent document; and (b) the characteristics of the participant population being studied;  
• Related or possibly related to participation in the research (“possibly related” means there is a reasonable 
possibility that the incident, experience, or outcome may have been caused by the procedures involved in the 
research); and  
• Suggests that the research places participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
 
Adverse Event (AE) Definitions: Adverse event means any untoward medical occurrence associated with the 
use of an intervention in humans, whether considered intervention-related (21 CFR 312.32 (a)).    
 
Serious Adverse Events (SAE) Definition: An adverse event (AE) or suspected adverse reaction is considered 
"serious" if, in the view of the investigator, it results in any of the following outcomes: death, a life-threatening 
adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth 
defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be 
considered serious when, based upon appropriate medical judgment, they may jeopardize the participant and may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse.     
 
Grading the Severity of Adverse Events and Events of ‘Special Interest’:  
All adverse events (AEs) will be assessed by the principal investigator and/or co-investigator(s) using the 
following guidelines: 
• Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities. 
• Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating. Of note, the term “severe” does not necessarily equate to “serious”.    
 
Relatedness Definition:  
All adverse events (AEs) must have their relationship to study intervention assessed by the principal 
investigator and co-investigator(s) who examines and evaluates the participant based on temporal 
relationship and their clinical judgment. The degree of certainty about causality will be graded using the 
categories below. In a clinical trial, the study product must always be suspect. 
• Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study intervention administration and cannot be 

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explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
study intervention (dechallenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory rechallenge 
procedure if necessary. 
• Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a 
reasonable time after administration of the study intervention, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal (dechallenge). Rechallenge information is not required to fulfill this definition. 
• Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate. 
• Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study intervention administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of the 
study intervention) and in which other drugs or chemicals or underlying disease provides plausible 
explanations (e.g., the participant’s clinical condition, other concomitant treatments). 
• Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. 
 
Expectedness Definition: The principal investigator (Dr. Frohlich), with input from the co-investigators (Dr. 
Schiller, Dr. Riddle) when necessary, will determine whether an adverse event (AE) is expected or unexpected in this 
population. The principal investigator (Dr. Flavio Frohlich) is an expert in non-invasive brain stimulation and will 
provide his expert opinion in regard to this as well. An AE will be considered unexpected if the nature, severity, or 
frequency of the event is not consistent with the risk information previously described for the study intervention. 
 
AE and SAE Assessment, Follow-up Procedures:  
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits, or the study participant may report AE or SAEs outside of a scheduled 
study visit. 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of onset, 
clinician’s assessment of severity, relationship to study product (assessed only by those with the training 
and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs occurring 
while on study must be documented appropriately regardless of relationship. All AEs will be followed to 
adequate resolution. Any medical condition that is present at the time that the participant is screened 
will be considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE. Changes in the severity of an AE 
will be documented to allow an assessment of the duration of the event at each level of severity to be 
performed. AEs characterized as intermittent require documentation of onset and duration of each 
episode. 
Research personnel will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study 
participation. At each study visit, research personnel will inquire about the occurrence of AE/SAEs since 
the last visit. Events will be followed for outcome information until resolution or stabilization. All AEs 
including local and systemic reactions not meeting the criteria for SAEs will be captured on the appropriate 
case report form (CRF). Information to be collected includes event description, time of onset, clinician’s 

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assessment of severity, relationship to study product (assessed only by those with the training and 
authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs occurring while 
on study must be documented appropriately regardless of relationship. All AEs will be followed to 
adequate resolution. 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any time 
during the study, it will be recorded as an AE. 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode.    
Research personnel will record all reportable events with start dates occurring any time after informed consent is 
obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation. At each study 
visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit. Events will be followed for 
outcome information until resolution or stabilization. 
 
Reporting and Documentation Procedures: We will be adopting the following reporting procedures: 
What event is reported 
When is event reported 
By 
whom 
is 
event 
reported 
To 
whom 
is 
event 
reported 
Fatal or life-threatening 
unexpected, 
suspected 
serious adverse reactions 
Within 24 hours of initial 
receipt of information 
Investigator 
Local/internal IRB 
Non-fatal, 
non-life-
threatening unexpected, 
suspected serious adverse 
reactions 
Within 48 hours of initial 
receipt of information 
Research Personnel 
Local/internal IRB 
Unanticipated 
adverse 
devise effects 
Within 7 working days of 
investigator first learning 
of effect 
Investigator 
Local/internal IRB 
Unanticipated 
problem 
that is not an SAE 
Within 7 days of the 
investigator 
becoming 
aware of the problem 
Investigator 
Local/internal IRB 
 
 
Participant Notification of New Information: Any new information gained during the study that may affect a 
participant’s willingness to continue in the study will be reported to all currently enrolled participants. 
12.4. 
Safety Monitoring 
1. The Columbia Suicide Severity Rating Scale (C-SSRS) (Posner, Brown et al. 2011) will be administered by trained 
research personnel at the first session to thoroughly assess suicide risk. If a participant reports experiencing either suicidal 
ideation or suicidal behavior, research personnel will collect more information from the participant to deliver to either 
Dr. Schiller. Clinical personnel will decide if an acute assessment is required. Acute assessment may include facilitating 
contact of the participant with their psychiatrist or primary care physician to establish a plan for safety, continued care, 
and follow-up. If the participant does not have an established provider, Dr. Schiller will assist in establishing a care plan. 
If at any point during the assessment, the participant is deemed an imminent risk of harm to self or others, study 
personnel will enlist the aid of campus security to ensure that the participant is safely escorted to the Emergency 
Department for further care. Dr. Schiller will decide if participation should be stopped after the acute assessment. If an 
acute assessment is required, then participation will be halted.  
2. A stimulation side effects questionnaire will be administered at the end of each stimulation session. This tool will be 
used as a safety measure and to collect data on the participant’s experience. A similar questionnaire was used in a 
previous study (IRB# 13-2995) to determine ability to successfully blind the participants using sham transcranial current 
stimulation.  

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  Study Suspension / Early Termination of the Study 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. If the 
study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform research staff, 
study participants, and the IRB and will provide the reason(s) for the termination or suspension. Study participants 
will be contacted, as applicable, and be informed of changes to study visit schedule.  
 
Circumstances that may warrant termination or suspension include, but are not limited to:  
• 
Determination of unexpected, significant, or unacceptable risk to participants  
• 
Insufficient compliance to protocol requirements  
• 
Data that are not sufficiently complete and/or evaluable  
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and satisfy 
the IRB.    
 
13. Regulatory, Ethical, and Study Oversight Specifications 
 
13.1. 
Informed Consent Process 
 
 
 
 
13.1.1. 
Consent/Assent and Documents Provided to Participants 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the participant 
and written documentation of informed consent is required prior to starting intervention/administering study 
intervention.  
 
 
13.1.2. 
Consent Procedures and Documentation 
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. Verbal consent will be documented prior to conducting the 
phone screenAll consent forms will be IRB-approved and updated with any new information as modifications are 
made throughout the study. 
 
During a phone call, the researcher and potential participants will review the clinical trial in its entirety. At several 
intervals during the consent review, the researcher will ask questions that will assess the comprehension of the 
information in the consent. If the participant is unsure or does not know, the researcher will return to that section and 
more carefully explain the information. 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 will be informed that participation is 
voluntary and that they may withdraw from the study at any time, without prejudice.  
 
At the beginning of the first visit to the lab, participants will sign a physical copy of the consent document witnessed by 
research personnel. A copy of the signed informed consent document will then be given to the participant for their 
records. The rights and welfare of the participant will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study.  
 
 

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13.2. 
Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. If the 
study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform research staff, 
study participants, and the IRB and will provide the reason(s) for the termination or suspension. Study participants 
will be contacted, as applicable, and be informed of changes to study visit schedule.  
 
Circumstances that may warrant termination or suspension include, but are not limited to:  
• 
Determination of unexpected, significant, or unacceptable risk to participants  
• 
Insufficient compliance to protocol requirements  
• 
Data that are not sufficiently complete and/or evaluable  
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and satisfy 
the IRB.    
13.3. 
Confidentiality and Privacy 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their interventions. This confidentiality is extended to cover testing of biological samples and genetic 
tests in addition to the clinical information relating to participants. Therefore, the study protocol, documentation, 
data, and all other information generated will be held in strict confidence. No information concerning the study or 
the data will be released to any unauthorized third party without prior written approval of the sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional Review 
Board (IRB), regulatory agencies or pharmaceutical company supplying study product may inspect all documents 
and records required to be maintained by the investigator, including but not limited to, medical records (office, 
clinic, or hospital) and pharmacy records for the participants in this study. The clinical study site will permit access 
to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use during the 
study. At the end of the study, all records will continue to be kept in a secure location for as long a period as dictated 
by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be 
transmitted to and stored in the TraCS Clinical Research Data Management Service (REDCap). This will not include 
the participant’s contact or identifying information. Rather, individual participants and their research data will be 
identified by a unique study identification number. The study data entry and study management systems used by 
clinical sites and by TraCS research staff will be secured and password protected. At the end of the study, all study 
databases will be de-identified and archived at the Carolina Center for Neurostimulation/Frohlich Lab. 
  
 
 
13.3.1. 
Certificate of Confidentiality 
A certificate of confidentiality will be obtained prior to the start of data collection.  

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13.4. 
Future Use of Stored Specimens and Data 
Data collected for this study will be analyzed and stored within the Carolina Center for Neurostimulation/Frohlich 
Lab. After the study is completed, the data will be fully de-identified and archived within a locked file cabinet or an 
encrypted server maintained by the Carolina Center for Neurostimulation. Biological samples will be stored at the 
Carolina Center for Neurostimulation/Frohlich lab and at UNC’s Neurosciences Hospital. Samples will be not be 
stored for future research. 
 
 
13.5. 
Key Roles and Study Governance 
 
Principal Investigator 
 
Co-Investigator/Medical Monitor 
Flavio Frohlich, Ph.D. 
 
Crystal Schiller, Ph.D. 
University of North Carolina  
 
University of North Carolina  
Department of Psychiatry 
 
Department of Psychiatry 
919-966-4584 
 
919-966-4810 
flavio_frohlich@med.unc.edu 
 
crystal_schiller@med.unc.edu 
 
Co-Investigator/Statistical Co-Investigator 
 
Co-Investigator 
Justin Riddle, Ph.D. 
 
Erin Bondy, M.A. 
University of North Carolina  
 
University of North Carolina  
Department of Psychiatry 
 
Department of Psychiatry 
919-966-2682 
 
919-843-7694 
justin_riddle@med.unc.edu 
 
erin_bondy@med.unc.edu 
 
13.6. 
Safety Oversight 
Safety oversight will be under the direction of the principal investigator and co-investigators composed of three 
clinical researchers. The PI and/or Co-I will review AEs in real time and make decisions as of participant’s 
continuation of the clinical trial. The PI will review AEs as appropriate, every three months at a minimum, with the 
research team. The PI may request additional review by Co-I on a case-by-case basis.  
  
    
13.7. 
Clinical Monitoring Plan (CMP) 
The purpose of the monitoring plan is to present the approach of the Carolina Center for Neurostimulation to 
monitoring clinical trials. The plan facilitates compliance with good clinical practice.  
 
(a) The rights and well-being of human participants are protected.  
(b) The reported trial data are accurate, complete, and verifiable from source documents.  
(c) The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with 
applicable regulatory requirement(s).  
 
This section identifies key monitoring activities and specifies the data to be reviewed over the course of a clinical trial. 
This is a single site, investigator initiated, clinical trial so there will be no site monitoring plan in place.  
 

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The latest version of the approved IRB application for this clinical trial will be followed at all times. This responsibility 
falls in the hands of the trained research personnel. If at any time there is a deviation from protocol, the deviation 
from protocol log will be filled out. All team members will be trained on how and when to use this log. Deviations will 
be sent to IRB every 4-6 weeks (if necessary). 
 
Data will be verified for completeness following every study session and all data will be entered into REDCap, a secure 
online database. After a participant has completed their participation (full completion through the 2-week follow-up 
visit or because they withdrew prior to completion), data will be rereviewed for completeness and accuracy. After all 
data has been collected, data will be re-reviewed by another lab member who was not involved with the data collection 
process.  
 
AE and SAE are clearly defined in the Master Protocol. Documents of AE and SAE can be found in the study binder on 
file within 77 Vilcom Center, Suite 170, Room 110. It is responsibility of trained research personnel to report all events 
to the PI. Reporting of AEs and SAEs is described within Section 12.3.  
 
The PI and Co-I will have read-only access to the REDCap database. This allows the PI and Co-I 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. 
 
13.8. 
Quality Assurance and Quality Control  
The Carolina Center for Neurostimulation will conduct internal quality management of study conduct, data and biological 
specimen collection, documentation and completion. Following written Standard Operating Procedures (SOPs), research 
personnel will verify that the clinical trial is conducted and data are generated, documented (recorded), and reported in 
compliance with the protocol, International Conference on Harmonisation Good Clinical Practice (ICH GCP), and 
applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
 
13.9. 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The noncompliance 
may be either on the part of the participant, the investigator, or the study site staff. As a result of deviations, 
corrective actions are to be developed by the site and implemented promptly.  
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
All deviations from the protocol will be addressed in study participant source documents. The researcher will 
complete a Protocol Deviation Log using the participant code as the identifier. This form will collect information 
such as the date the deviation occurred, details of what the deviation consisted of, any corrective and preventative 
actions that were taken as a result of the deviation, and the date that the PI and IRB were notified. The PI will review 
the information and initial once approved. A completed copy of the Protocol Deviation Form will be maintained in 
the regulatory file, as well as in the participant’s source document. Protocol deviations will be sent to the IRB per 
their guidelines. The site PI/study staff will be responsible for knowing and adhering to their IRB requirements.  
13.10. 
Publication and Data Sharing Policy  
This trial will be registered at ClinicalTrials.gov, and results information from this trial will be submitted to 
ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed journals.  

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13.11. 
Conflict of Interest Policy 
The independence of this study from any actual or perceived influence is critical. Any conflict of interest for any persons 
who have a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and managed by 
the UNC Conflict of Interest Office. If necessary, for persons who have a perceived conflict of interest, management will 
be provided again by the UNC Conflict of Interest office. 
 
 

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14. Additional Considerations 
 
N/A 
 
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16. Appendices 
N/A