Enhancing Neural Synchrony and Affective Cognitive Control in Bipolar Disorder Using Personalized Transcranial Alternating Current Stimulation (tACS)
Phase: NA
Conditions: Bipolar Disorder
Sponsor: University of Michigan

Enhancing Neural Synchrony and Affective Cognitive Control in Bipolar 
Disorder using Personalized Transcranial Alternating Current Stimulation 
(tACS) 
 
Date of IRB Approval: April 12, 2023 
 
NCT05480124 
 
 

tACS Study (HUM00208557) 
 
 
 
 
 
 
Enhancing Neural Synchrony and Affective Cognitive Control in Bipolar 
Disorder using Personalized Transcranial Alternating Current Stimulation 
(tACS) 
 
 
Principal Investigator (PI): Stephan Taylor, MD  
 
 
 
 
University of Michigan 
 
 
 
 
Dept of Psychiatry 
4250 Plymouth Road, Ann Arbor, MI 48109 
Email: sftaylor@med.umich.edu 
 
 
Co-Investigator 
 
Ivy Tso, PhD 
 
 
 
 
Ohio State University 
 
 
 
 
Dept of Psychiatry 
 
 
 
 
 
 
 
 
 
Co-Investigator 
 
Melvin McInnis, MD 
 
 
 
 
University of Michigan 
 
 
 
 
Dept of Psychiatry 
4250 Plymouth Road, Ann Arbor, MI 48109 
 
 
 
 
Email: mmcinnis@med.umich.edu 
 
Investigational Agent:  
Soterix, Medical High-Definition Transcranial Alternating Current  
 
 
 
 
Stimulation device (HD-tACS) 
 
Sponsor: 
 
 
Milken Institute / Baszucki Brain Research Fund 
 
HUM Number: 
 
HUM00208557 
 
IDE Number:  
 
Not Applicable  
 
NCT Number: 
 
05480124 
 
Version: 
 
 
3.03-23-2023  
 
 
 

tACS Study (HUM00208557) 
 
 
Table of Contents 
STUDY SYNOPSIS ....................................................................................................................... 1 
STUDY SCHEMA.......................................................................................................................... 2 
1.0 
BACKGROUND AND RATIONALE ................................................................................ 3 
1.1 
Disease Background ......................................................................................................... 3 
1.2 
Study Agent(s) Background and Associated Known Toxicities ...................................... 3 
1.3 
Rationale........................................................................................................................... 3 
1.4 
Objective .......................................................................................................................... 3 
2.0 
STUDY DESIGN, AIMS AND OUTCOME MEASURES ................................................ 4 
3.0 
SUBJECT ELIGIBILITY .................................................................................................... 4 
3.1 
Inclusion Criteria .............................................................................................................. 4 
3.2 
Exclusion Criteria ............................................................................................................. 5 
4.0 
SUBJECT SCREENING, ENROLLMENT, AND RECRUITMENT ................................ 5 
4.1 
Screen Failures ................................................................................................................. 5 
4.2 
Blinding ............................................................................................................................ 5 
4.3 
Subject Recruitment and Retention .................................................................................. 5 
5.0 
STUDY ASSESSMENTS AND PROCEDURES ............................................................... 6 
5.1 
Assessments ..................................................................................................................... 6 
5.2 
Procedures ........................................................................................................................ 6 
5.3 
Participant Compensation .............................................................................................. 10 
5.4 
Time and Events Table ................................................................................................... 11 
6.0 
ADVERSE EVENTS ......................................................................................................... 11 
6.1 
Adverse Event Reporting Requirements ........................................................................ 11 
6.2 
Definitions ...................................................................................................................... 12 
6.2.1 
Adverse Events ....................................................................................................... 12 
6.2.2 
Serious Adverse Event ............................................................................................ 12 

tACS Study (HUM00208557) 
 
 
6.2.3 
Expected Adverse Events ....................................................................................... 13 
6.2.4 
Unexpected Adverse Event ..................................................................................... 13 
6.3 
Adverse Event Characteristics ....................................................................................... 13 
6.3.1 
Terms and Grading ................................................................................................. 13 
6.3.2 
Attribution of the AE .............................................................................................. 14 
6.4 
Serious Adverse Event Reporting Guidelines ................................................................ 14 
6.5 
Other Reportable Information or Occurrence (ORIO) ................................................... 14 
6.6 
Unblinding Procedures ................................................................................................... 14 
7.0 
STATISTICAL CONSIDERATIONS............................................................................... 14 
8.0 
DATA AND SAFETY MONITORING PLAN ................................................................ 15 
8.1 
Overall framework ......................................................................................................... 15 
8.2 
Roles & responsibilities for regular operations .............................................................. 15 
8.3 
Frequency and type of other study monitoring: ............................................................. 16 
8.4 
Management of withdrawals and drop-outs: .................................................................. 16 
9.0 
BENEFITS/RISKS ............................................................................................................ 17 
9.1 
Benefits........................................................................................................................... 17 
9.2 
Risks ............................................................................................................................... 17 
9.2.1 
Subject Confidentiality ........................................................................................... 17 
9.2.2 
Known Potential Risks and Minimization of Risks ................................................ 17 
10.0 QUALITY ASSURANCE AND AUDITS ........................................................................ 19 
10.1 Audits and Inspections ................................................................................................... 19 
10.2 Event Windows, Missed Assessments, Missed Sessions and Protocol Deviation 
Reporting .................................................................................................................................. 19 
11.0 REGULATORY ................................................................................................................ 19 
11.1 Institutional Review Board (IRB) .................................................................................. 19 
11.2 Subject Information and Consent ................................................................................... 19 
12.0 REFERENCES .................................................................................................................. 20 

tACS Study (HUM00208557) 
 
 
13.0 APPENDIX ........................................................................................................................ 22 
 

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STUDY SYNOPSIS 
Title 
Enhancing Neural Synchrony and Affective Cognitive Control in 
Bipolar Disorder using Personalized Transcranial Alternating 
Current Stimulation (tACS) 
Study Design 
The randomized, double-blind, sham-controlled, cross-over study 
will involve three sessions. The first session will involve a clinical 
interview, questionnaires, and EEG recording during a computerized 
task. The second and third sessions will involve tACS brain 
stimulation (or placebo stimulation) during a computerized task and 
EEG recording.  
 
Study Duration 
Enrollment duration: 12 months 
Subject follow-up duration: 1 month 
Estimated duration until study completion: 12 months 
 
Study Center(s) 
Single center 
 
Aims 
Aim #1: Evaluate the feasibility and acceptance of tACS among 
bipolar patients. 
 
Aim #2: Estimate the preliminary effects of personalizedtACS on 
theta-gamma phase-amplitude coupling (PAC) and cognitive control 
behavior in bipolar disorder (BD). 
 
Number of Subjects 
30 
Disease/condition  
Bipolar Disorder 
Inclusion/Exclusion 
Criteria 
See Section 3.0 for a complete list of inclusion and exclusion criteria 
Description of Study 
Intervention: 
HD-tACS will be used to deliver current (active vs. sham) to the 
electrodes to generate tACS most closely approximate endogenous 
neural activity. Participants will be fitted using a montage consisting 
of 5-9 electrodes placed over the right frontal and temporal scalp.  
Duration of Study 
approximately 6 weeks 
Statistical 
Methodology 
Aim 1: We will compare the percentage of participants requesting to 
discontinue the session and the number of mild and severe adverse 
events reported during and following the tACS vs. sham procedure 
using Bayes factors (BF). 
 
Aim 2: EEG data preprocessing and spectral analyses will be 
conducted using custom MATLAB scripts and EEGLAB following 
the general methods described in PI Tso’s published work. 
 

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Session 1:  Obtain informed consent. Screen potential participants by 
inclusion and exclusion criteria; pregnancy status; clinical and self-
assessments; baseline EEG. 
Session 2 
Clinical assessments, 
Self-assessments, 
tACS (active)-EEG, 
AE assessments 
Session 3 
Clinical assessments, 
Self-assessments, 
tACS (sham)-EEG, 
AE assessments 
Randomize 
Group A 
Group B 
Session 2 
Clinical assessments, 
Self-assessments, 
tACS (sham)-EEG, 
AE assessments 
Session 3 
Clinical Assessments, 
Self-assessments, 
tACS (active)-EEG, 
AE assessments 
30 day follow up: 
AE assessment  
 
  
  
  
 
STUDY SCHEMA 
 
 

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1.0 BACKGROUND AND RATIONALE 
1.1 Disease Background 
Bipolar disorder (BD) is an impairing neuropsychiatric condition with high rates of relapse, morbidity, 
and mortality. Treatment of BD is challenging due to its complex clinical presentations and variable 
response to traditional pharmacologic treatments across individuals. Effective, personalized interventions 
are severely hindered by our lack of mechanistic insight of the disorder. 
1.2 Study Agent(s) Background and Associated Known Toxicities 
Recent groundbreaking work showed that transcranial alternating current stimulation (tACS), a non-
invasive neuromodulation, can be programmed such that its wave patterns mimic natural theta-gamma 
coupling, a critical neural mechanism of cognitive control 4,16. Critically, applying frontal tACS targeting 
individualized peak theta/gamma coupling frequencies is able to enhance theta-gamma coupling and 
improve cognitive control performance among healthy non-psychiatric participants. These findings 
provide support for tACS’s ability to modulate the neural underpinning of cognitive control in humans. 
This study will pursue critical next step towards realizing this potential therapy by demonstrating both 
feasibility (safety and tolerability) and efficacy of personalized tACS in engaging the neural target of 
affective cognitive control-related neural synchrony in BD patients. 
1.3 Rationale 
A growing body of research suggests that deficient cognitive control, the ability to modulate cognitive 
and emotional processes in order to optimize behavior and enhance adaptation with respect to the current 
context, may be a key mechanism contributing to these characteristics of BD. Specifically, behavioral 
studies strongly indicate that cognitive control, expressed as response inhibition, is impaired in BD1 and 
associated with impulsivity and illness outcome.2,3 Therefore, understanding and leveraging the neural 
underpinnings of cognitive control is a promising avenue to developing neurobiologically-informed and 
precise treatments that target the underlying network dysfunction.  
 
We have shown in a series of EEG studies that frontal theta-band (4-8 Hz) neural oscillatory activity and 
phase-amplitude coupling with gamma (30-60 Hz) activity are reduced in bipolar disorder during socio-
emotional processes requiring cognitive control. This provides support that theta-gamma coupling is a 
promising neural target to engage for BD. Recent groundbreaking work showed that transcranial 
alternating current stimulation (tACS), a non-invasive neuromodulation, can be programmed such that its 
wave patterns mimic natural theta-gamma coupling, a critical neural mechanism of cognitive control. 
Critically, applying frontal tACS targeting individualized peak theta/gamma coupling frequencies is able 
to enhance theta-gamma coupling and improve cognitive control performance among healthy non-
psychiatric participants. These findings provide support for tACS’s ability to modulate the neural 
underpinning of cognitive control in humans. This study will pursue critical next step towards realizing 
this potential therapy by demonstrating both feasibility (safety and tolerability) and efficacy of 
personalized tACS in engaging the neural target of affective cognitive control-related neural synchrony 
in BD patients. 
1.4 Objective 
This project will provide a critical proof of concept that personalized tACS is feasible and effective in 
engaging the neural target of theta-gamma coupling in BD patients, and importantly, helping them to 

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regain cognitive control. The ultimate goal of this research is to make this innovative and customizable 
treatment modality widely accessible for individuals living with BD. 
2.0 STUDY DESIGN, AIMS AND OUTCOME MEASURES 
The randomized, double-blind, sham-controlled, cross-over study will involve three sessions. The first 
session will involve a clinical interview, questionnaires, and EEG recording during a computerized task. 
The second and third sessions will involve tACS brain stimulation (or placebo stimulation) during a 
computerized task and EEG recording. Participant’s psychiatric phenotypes and functioning will be 
dimensionally characterized. Affective cognitive control in bipolar disorder will be assessed using the 
Emotion Go-NoGo Task.  
 
Aim #1: Evaluate the feasibility and acceptance of tACS among bipolar patients. Neuromodulation 
studies typically use dropout rate and reported adverse events as measures of acceptability and 
tolerability, respectively10. We will compare the percentage of participants requesting to discontinue the 
session and the severity of side effects reported following the tACS vs. sham procedure using Bayes 
factors (BF). 
 
Intervention:  One-session tACS 
Primary outcome measure 1:  Severity of side effects reported at end of stimulation session. This is 
calculated by summing the severity score of items (0-4) that are rated by the participant as related to 
stimulation (ratings of 3=probable or 4=definite) on the Stimulation Side Effects Questionnaire. 
Primary outcome measure 2:  Withdrawal during or after the stimulation session. 
 
Aim #2: Estimate the preliminary effects of personalized tACS on theta-gamma phase-amplitude 
coupling (PAC) and cognitive control behavior in BD. 
 
Intervention:  One-session tACS 
Primary outcome measure 3:  Accuracy signal detection theory metric sensitivity (d’) derived from 
the behavioral responses to Go and NoGo trials on the cognitive control task. 
Primary outcome measure 4:  Accuracy signal detection theory metric response bias (β) derived 
from the behavioral responses to Go and NoGo trials on the cognitive control task. 
Primary outcome measure 5:  Reaction time (millisecond) of Go trials on the cognitive control task. 
Primary outcome measure 6: Theta-gamma PAC (Kullback-Leibler Modulation Index) during the 
rest EEG blocks interleaved between stimulation blocks. 
 
3.0 SUBJECT ELIGIBILITY 
Subjects must meet all the selection criteria to be enrolled to the study. Study treatment may not begin 
until a subject has been consented and meets the full eligibility criteria. 
3.1 Inclusion Criteria 
Participants will be: (1) Age 18-55 inclusive; (2) Ability and willingness to give informed consent; (3) 
Confirmed diagnosis of BD based on DSM-IV criteria being met from previous enrollment in the 
Prechter Bipolar Longitudinal Study (HUM00000606, PI: McInnis); (4) We will select BD patients 
scoring above published norms (upper 50th percentile) on the NEO-PI impulsivity facet 6 to ensure that 

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the recruited patients exhibit the network dysfunction targeted by the tACS paradigm and therefore have 
the potential to benefit from this neuromodulation technique. (5) On a stable dose of medication for 2 
weeks prior to Sessions 2 & 3. 
3.2 Exclusion Criteria 
Participants will not have: (1) Significant neurological abnormalities, such as seizure disorder, mass 
lesions, etc.; (2) Known Mendelian disorder; (3) Active problematic substance use in the past 30 days (as 
determined by the Substance Use Disorder module of SCID); (4) Evidence of suicidal intentions or 
behaviors in the past month, as judged by affirmative responses to question #4 or #5 on the Columbia 
Suicide Severity Rating Scale (CSSRS) or report of suicidal behaviors in the last 6 months (refer to 
Appendix A for suicide protocol); (5) Pregnant or trying to become pregnant, or currently lactating; (6) 
unremovable hair extensions, braids or weaves; (7) implants or neurostimulators which could interact 
with applied electrical currents; (8) history of serious traumatic brain injury (loss of consciousness > 20 
min) 
4.0 SUBJECT SCREENING, ENROLLMENT, AND RECRUITMENT 
We will recruit 30 individuals with a DSM-IV diagnosis of Bipolar Disorder (I, II, or NOS) from the 
Prechter Longitudinal Bipolar Disorder Study which consists of a cohort of 800+ well-characterized BD 
patients.5  
4.1 Screen Failures 
Those found to be ineligible to participate after the Session 1: Screening & Assessment visit will 
still be compensated a total of $20 for their time. Those who leave the study early will be paid for 
the sessions they completed. 
4.2 Blinding 
Participants, study coordinator and clinical assessor will be blind as to which session the participants 
receive active or sham treatment. The PI and the data analyst will be aware of the intervention 
assignment. 
4.3 Subject Recruitment and Retention 
We will recruit 30 individuals with a DSM-IV diagnosis of Bipolar Disorder (I, II, or NOS) from the 
Prechter Longitudinal Bipolar Disorder Study which consists of a cohort of 800+ well-characterized 
BD patients.5 Participants are expected to match the sex and racial composition of the Longitudinal 
study (50% female, 50% male; 81% white, 12% African-American, 6% Asian, 1% Other). 
Participants who are enrolled in the Prechter Study, and who have been identified by the Prechter 
Study staff as possible participants, will be emailed a description of this study, including contact 
information about how to learn more.  
 
Pre-screening will occur when the study coordinator contacts the potential participant, via phone or 
email to discuss a series of eligibility questions. Patients who appear eligible in the pre-screen will 
be invited for an initial assessment session. Reminder calls, emails and/or texts will be provided to 
subjects before each scheduled session. 
 

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5.0 STUDY ASSESSMENTS AND PROCEDURES  
5.1 Assessments 
Clinician Administered Assessments (~ 60 mins): 
1) Demographic/medical history form 
2) Structured Clinical Interview for DSM-IV (SCID-IV), substance use disorder  only (Module 
E). Note: Subjects endorsing unhealthy substance use in the last 30 days but do not meet full 
criteria for abuse or dependence will be given a urine drug screen. 
3) The Mental Illness Research, Education and Clinical Centers Global Assessment Functioning 
(MIRECC GAF) 
4) Social and Occupational subscales only Young Mania Rating Scale (YMRS) – scale to grade 
the severity of mania symptoms 
5) Hamilton Depression Rating Scale (HAM-D) – scale to grade severity of depression 
6) Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
Self-Rated Assessments (~ 30 mins):  
1) Beck Depression Inventory (BDI) 
2) Altman Self-Rating Mania Scale (ASRM) 
3) Barratt Impulsiveness Scale (BIS) 
4) Behavioral Inhibition System/Behavioral Activation System (BIS/BAS) 
5) Stimulation Side Effects Questionnaire 
6) Penn State Worry Questionnaire (PSWQ) 
5.2 Procedures 
The following procedures will be conducted in-person following the University of Michigan’s Covid safety 
protocols.  
 
Pre-Visit Preparations. Participants who meet criteria after initial phone screening, will be scheduled for 
three in-person sessions at the Rachel Upjohn Building. Participants will be emailed a blank copy of the 
consent form to review prior to their visit. 
 
Session 1: Screening & Assessment (~ 2-3 hours) 
 
1) Informed Consent. Formal consent will be obtained at the beginning of the visit. The participant will 
arrive at the Rachel Upjohn Building at the University of Michigan East Ann Arbor Health Campus. 
A study coordinator or a trained research assistant will greet the participant and take them to a private 
interview room where the study will be explained, the consent form reviewed, and any questions 
answered. Participants will have the option to electronically consent (using SignNow, according to 
IRBMED guidelines) prior to the in person visit through a Zoom meeting with one of the study team 
members.  
Pregnancy Screening. All woman of childbearing age will be asked during their screening whether 
they are pregnant or are trying to become pregnant and will not be enrolled in the study if they 
are. They will be given an option for a urine pregnancy test at the start of each session. Woman with 
a positive pregnancy test will not be permitted in the study. They may decline this option and sign a 
pregnancy attestation form at each session indicating that they do not believe they could be pregnant. 

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Sexually active women of childbearing potential will be required to use a reliable birth control 
method for the duration of this study. 
 
2) Clinician Administered Assessments. This interview process will be conducted to determine a 
participant’s inclusion/exclusion eligibility. If the participant is ineligible to participate in the study, 
the rationale for their exclusion will be explained to them.  
 
3) Urine Drug Screening (UDS). Participants who screened positive for current substance use disorder 
will be administered a UDS. If their UDS indicates the presence of a substance, they will not undergo 
that day’s visit. At the PI’s discretion, the participant may be given the option to abstain from all 
substance use and be rescheduled to provide another urine sample. If they have a clean UDS at that 
time, they will be able to continue with the visit at that time. Those that are not given the option or 
who refuse to do the UDS will be a screen fail. Participants who have no active current substance use 
will not be required to provide a urine sample. 
 
4) Self-Rated Assessments. Participants deemed eligible will complete self-rated assessments and 
computerized tasks through Qualtrics, using an anonymous survey link. No identifiable information 
will be collected within the survey. 
 
5) Baseline EEG. EEG will be recorded using a 64-channel electrode cap using EEG procedures that are 
standard in cognitive ERP and time-frequency analysis research. The cap is an elastic cap that fits 
snugly over the scalp of the participant, holding the electrodes in place. A standard conductive 
electrode gel will be inserted into each electrode using a blunt-needle syringe. The scalp will be 
gently rubbed with a swab to improve electrode impedance (i.e., to lower the electrical resistance). 
Typical application time for an electrode cap lasts around 30 minutes. The electrode for monitoring 
eye movements will be affixed with adhesive collars. The skin will also be cleaned with an alcohol 
swab for this electrode. The cap and electrodes will be disinfected after each use with a disinfectant 
recommended by BrainVision Company (e.g., Cavicide). Other items will be disposed of after each 
use. The experimenter will wipe the residual electrode gel from the participant’s hair and skin after 
the EEG session.  
 
Emotion Go-NoGo Task. Participants will undergo an EEG and perform a cognitive control task 
(Emotion Go-NoGo task; described below).  
 
Flanker Task. After completing the Emotion Go-NoGo task, participants will perform a separate 
cognitive control task (i.e., Flanker task; described below). Accuracy and reaction time will be used 
to index cognitive control behavior as outcome measures. EEG recorded during the Flanker task will 
be used to assess neurological indicators of attention control. Participants will then be 50-50 
randomized to receive either the Sham treatment first or tACS treatment first at Session 2. 
 
7) Randomization. Subjects will be randomized on a 50-50 basis to receive active vs. sham stimulation. 
If participants are randomized to the active group at Session 2, they will go to the sham group at 
Session 3, and vice versa. The participant will not be told which group they were randomized to. 
The randomization schedule will ensure an equal distribution across the group.  Randomization lists 

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will be generated by random condition generator and will be programmed into the computer that 
controls the tACS device by the postdoc fellow or PI. 
 
Sessions 2 and 3: Sham vs. Active tACS Session (~ 2-3 hours) 
These sessions will occur at the University of Michigan Rachel Upjohn Building. Participants will undergo 
two sessions, separated by ~ 1 week.  Procedures will be identical for each session.   
 
1) Pre-Visit Preparations. Research staff will contact the participant to remind them about the study 
visit and to ask if they have had any medication changes since their last visit. If yes, the participant 
will be re-scheduled for an appointment time in which the criteria for a stable dose of at least two 
weeks has been achieved. Additionally, participants will also be asked if they have had any 
recreational drug use since their last study visit. If yes, the participant will have to be re-scheduled 30 
days out. 
 
2) Arrival on scheduled session day. Participants will arrive at the Rachel Upjohn Building where they 
will be greeted by a member of research staff and escorted to the treatment room. Pregnancy urine 
test will be given if participant opted out of signing the Pregnancy Attestation Form. 
 
3) Clinician Administered Assessments. In-person clinical assessments will be completed by a trained 
member of staff. All study clinicians are blinded to the treatment arm. 
 
4) Self-Rated Assessments. Participants will fill out BDI, ASRM, and PSWQ questionnaires. Any 
additional questionnaires not completed at the previous visit may be completed at this time or given 
to the participants to complete at home. 
 
5) EEG and brain stimulation. EEG procedures will be repeated from 
Session 1. CF (cross frequency)-tACS targeting theta-gamma PAC 
will be administered in accordance to Consultant Frohlich’s published 
protocol4, which has successfully enhanced theta-gamma PAC and 
cognitive control in non-psychiatric individuals. Participants will be 
fitted using a montage consisting of 9 electrodes placed over the left 
frontal scalp. 
 
Soterix Medical High-Definition Transcranial Alternating Current Stimulation device (HD-tACS) 
will be used to deliver current to the electrodes to generate tACS resembling theta-gamma PAC4,10,11. 
The impedance of each stimulation electrode will be kept below 10 kΩ. The stimulation waveform 
will consist of a theta component (5 Hz) delivered at 0.96 mA (1.92 mA peak-to-peak) delivered in a 
constant sine wave and a gamma component (50 Hz), 3.5 cycles of a sine wave delivered at 0.64 mA 
(1.28 mA peak-to-peak) superimposed on the theta component and centered on the peak of each 
cycle. For both tACS and sham conditions, the stimulation will slowly ramp up over the course of 12 
s, then the task will begin soon after maximum stimulation output is reached. Stimulation will be 
maintained at a stable level until the task is complete and the stimulation will ramp down over 12 s. 
Actual parameters may be varied slightly, but not enough to affect the risk to the participants. 
 

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Previous literature suggests that participants are sensitive to stimulation until the sensory neurons in 
the skin acclimate to the stimulation. Thus, we will use sham stimulation as an active control 
condition. We will inform our participants that they will sense the stimulation in the skin but will 
acclimate to the stimulation soon after it begins. They will be informed that they will receive two 
version of the stimulation, to facilitate blinding in case the participant does not acclimate to the 
stimulation. For sham, a genuine cross-frequency waveform will be delivered at maximum strength 
for 12 s, followed by a ramp-down. The ramp-up and ramp-down during the sham stimulation is 
designed to mimic the feeling of acclimation that is experienced with verum stimulation due to 
sensory adaptation.  Published data from Consultant Frohlich’s lab indicate that this procedure 
provides sufficient participant blinding to the condition4. 
 
6) Cognitive Control Task (Emotion Go-NoGo Task) 
Participants will engage in an Emotion Go-NoGo task to activate affective cognitive control during 
the baseline EEG as well as the stimulation sessions. In this task, participants view facial images 
exhibiting different emotions (neutral, happy, sad, or angry). For each face (150 ms), they are to press 
a button within 1500 ms if the face expresses the target emotion (Go trials; 80%) and withhold the 
response if the face expresses the distractor emotion (NoGo trials; 20%); the pairing of target and 
distractor emotions vary across blocks. The task includes a total of 640 trials, divided into 8 blocks of 
80 trials each. Half (4) of the blocks include original face images (Easy condition), and the other half 
(4) include visually degraded images (Difficult condition). The two difficulty conditions are 
presented in alternating order (counter-balanced across participants). Accuracy (particularly on NoGo 
trials) and reaction time (on Go trials) will be used to index cognitive control behavior as outcome 
measures. [*Note: the timing and trial parameters of the actual task may be modified slightly 
depending on initial testing results]. 
 
7) Stimulation Side Effects Questionnaire. Participants will complete this questionnaire regarding their 
experience following each stimulation session. They will also be asked to rate how much the 
stimulation improved cognitive performance as well as if they experienced any side effects (e.g., 
headache, neck pain, tingling).  
 
8) Flanker Task. After completing the Emotion Go-NoGo task, brain stimulation, and Stimulation Side 
Effect Questionnaire, participants will perform a separate cognitive control task (i.e., Emotional 
Flanker task). Participants will complete the Emotional Flanker task to evaluate the impact of brain 
stimulation on cognitive control after stimulation has been completed (i.e., offline effects). 
Participants will perform a modified Eriksen flanker task in which gray-scaled unpleasant (e.g., 
injured limbs, barking dog), pleasant (e.g., cute animals, erotic pictures), and neutral stimuli (e.g., 
lamp, spoon) images from the International Affective Picture System (IAPS) will appear on a 
computer display. There will be two parts to this task: (1) Unpleasant vs Neutral and (2) Pleasant vs 
Neutral. Three images will be presented with congruent (e.g., unpleasant - unpleasant - unpleasant) 
and incongruent (e.g., unpleasant -neutral- unpleasant) conditions. Participants will be instructed to 
respond by pressing one of two buttons indicating the valence of the central image (i.e., unpleasant 
versus neutral), while ignoring the adjacent images, and to respond as quickly and accurately as 
possible. The stimuli will remain on the screen for ~400 ms in the initial block, with an interval of 
about ~4000 ms between consecutive stimuli. Following a practice block of 30 trials, each participant 
will complete 10 blocks of 30 trials for a total of 300 trials for each part (Unpleasant vs Neutral and 

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Pleasant vs Neutral), and a grand total of 600 trials. Performance feedback will be provided and the 
stimuli presentation time will be adjusted based on performance after each block (e.g., if performance 
is above 90%, a 40ms shorter presentation time will be used in the next block) to ensure adequate 
number of errors and consistency in performance across participants within each part. Actual 
presentation and interval time may differ slightly in implementation from that described above. 
Estimated to take ~40 minutes. This task is designed to assess error and response monitoring within 
emotional contexts, which has been shown to be different from monitoring in other contexts, such as 
emotionally neutral context using arrows. Accuracy and reaction time will be used to index cognitive 
control behavior as outcome measures. EEG recorded during the Emotional Flanker task will be used 
to assess neurological indicators of attention control. [*Note: the timing and trial parameters of the 
actual task may be modified slightly depending on initial testing results. In order to reduce subject 
burden, experimenters may shorten the task and drop the display of pictures (neutral and valenced), 
using simple arrow cues instead to indicate a right or left button press]. 
 
Follow-up Phone Call (~ 5-10 min) 
Approximately 4 weeks (+/- ~7 days) following the completion of Session 3, research staff will call to 
administer the Stimulation Side Effect Questionnaire as a final safety check and evaluate for any other 
possible side effects. 
 
Stopping Rules  
If a participant reports intolerable discomfort during the tACS procedure, the session will be discontinued. 
Immediately after each stimulation session ends, participants will complete a tACS side effects 
questionnaire. A study team member will review the responses and will immediately consult the PI if a 
participant reports a high (3) to very high (4) rating for any of the side effects rated to be related to the 
stimulation (4=probable or 5=definite).  Subjects may also be withdrawn by the investigator when continued 
participation would present an unacceptable risk (e.g., worsening symptoms, suicidal thoughts, etc.). 
5.3 Participant Compensation 
Participants can earn up to $250 if they complete all available procedures in this study: 
 
Session 1 –  
$ 45.00 
 
 
Session 2 –  
$ 80.00  
 
 
     
 
 
Session 3 –  
$125.00 
 
 
TOTAL 
$250.00 
 
 
  
Participants found to be ineligible after the assessment will be compensated a total of $20 for their 
time. They will be paid either by gift card or check upon completion of the study. Participants who 
leave the study before completing all visits will be paid for time. 
 
 

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5.4 Time and Events Table 
 
 
 
Session 1  
Session 2 
Session 3 
Follow up 
Phone call 
Procedure 
Pre-
Screen 
Screening & 
Assessment 
Week 1 
 
Week 2 
 
Week 6 
 
Phone Interview 
X 
 
 
 
 
Informed consent 
 
X 
 
 
 
Pregnancy Screen 
Attestation 
 
X1 
X1 
X1 
 
Demographics/Med 
History 
 
X 
X 
X 
 
Concomitant Meds 
 
X 
X 
X 
 
MIRECC GAF 
 
X 
 
 
 
SCID-IV (substance use 
module only) 
 
X 
 
 
 
YMRS 
 
X 
X 
X 
 
HAM-D 
 
X 
X 
X 
 
C-SSRS 
 
X 
X 
X 
 
BDI 
 
X 
X 
X 
 
ASRM 
 
X 
X 
X 
 
PSWQ 
 
X 
X 
X 
 
BIS 
 
X 
 
 
 
BIS/BAS Scale 
 
X 
 
 
 
Pregnancy Urine Test 
 
X2 
X2 
X2 
 
Urine Drug Screen 
 
X3 
X3 
X3 
 
Randomization 
 
X 
 
 
 
EEG 
 
X4 
X4 
X4 
 
tACS 
 
 
X4 
X4 
 
Stimulation Side Effects 
Questionnaire 
 
 
X 
X 
X 
Adverse Events 
Assessment 
 
 
 
 
X 
 
X1- Optional if agree to pregnancy test 
 
X2- Required if attestation is not signed 
 
X3- Required if indicated by verbal report 
 
X4- Emotion Go-NoGo Task 
 
6.0 ADVERSE EVENTS 
6.1 Adverse Event Reporting Requirements 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial and is done to 
ensure the safety of subjects enrolled in the studies as well as those who will enroll in future studies 
using similar agents. Data on adverse events will be collected after Sessions 2 and 3 through 30 days 
after study completion. Any serious adverse event that occurs more than 30 days after the last study 

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Session and is considered related to the study procedure must also be reported. Serious Adverse 
Events (SAEs) will continue to be followed until: 
• Resolution or the symptoms or signs that constitute the serious adverse event return to 
baseline. 
• There is satisfactory explanation other than the study procedure for the changes observed; or  
• Death. 
The investigator is responsible for the detection, documentation, grading, and assignment of 
attribution of events meeting the criteria and definition of an AE or SAE. The definitions of AEs and 
SAEs are given below. It is the responsibility of the PI to ensure that all staff involved in the trial is 
familiar with the content of this section. 
 
Any medical condition or laboratory abnormality with an onset date before initial study procedure is 
considered to be pre-existing in nature. Any known pre-existing conditions that are ongoing at time 
of study entry should be considered medical history. 
 
All events meeting the criteria and definition of an AE or SAE, as defined in Section 6.2, occurring 
from the initial study procedure through 30 days following the last Session must be recorded as an 
adverse event in the subject’s source documents and on the clinical research file (CRF) regardless of 
frequency, severity (grade) or assessed relationship to the study procedure.  
 
In addition to new events, any increase in the frequency or severity (i.e., toxicity grade) of a pre-
existing condition that occurs after the subject begins study procedure is also considered an adverse 
event. Review of AE and SAE data will be performed and documented on a routine basis by the study 
team and the PI during weekly study meetings.  
6.2 Definitions 
6.2.1 Adverse Events 
Adverse Event Definition 
An adverse event (AE) is any untoward medical occurrence in a subject participating in an 
investigational study or protocol regardless of causality assessment.  An adverse event can be 
an unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
syndrome or disease associated with or occurring during the use of an investigational product 
whether or not considered related to the investigational product. 
 
6.2.2 Serious Adverse Event 
The study will comply with IRB and FDA reporting requirements and guidelines for SAEs. 
An adverse event is considered “serious” if, in the view of the investigator, it results in any of 
the following outcomes: 
• Death 
If death results from (progression of) the disease, the disease should be reported as event 
(SAE) itself. 
• A life-threatening adverse event 
An adverse even is considered ‘life-threatening’ if, in the view of either the investigator [or 
sponsor], its occurrence places the subject at immediate risk of death. It does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.  

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• Inpatient hospitalization or prolongation of existing hospitalization for > 24 hours. 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect 
• Important medical event 
Any event that may not result in death, be life-threatening, or require hospitalization may be 
considered serious when, based upon appropriate medical judgment, it may jeopardize the 
subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition of “Serious Adverse Event.” Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home; 
convulsions that do not result in inpatient hospitalization or the development of drug 
dependency or drug abuse. 
 
Previously planned (prior to signing the informed consent form) surgeries should not be 
reported as SAEs unless the underlying medical condition has worsened during the course of 
the study. Preplanned hospitalizations or procedures for preexisting conditions that are 
already recorded in the subject’s medical history at the time of study enrollment should not 
be considered SAEs. Hospitalization or prolongation of hospitalization without a 
precipitating clinical AE (for example, for the administration of study therapy or other 
protocol-required procedure) should not be considered SAEs. However, if the preexisting 
condition worsened during the course of the study, it should be reported as an SAE. 
 
6.2.3 Expected Adverse Events 
An adverse event (AE) is considered “expected” in clinical research studies, information on 
expected adverse events is summarized in the protocol and in the consent document.   
 
6.2.4 Unexpected Adverse Event 
An adverse event (AE) is considered “unexpected” if the event is not listed at the specificity 
or severity that has been observed. 
6.3 Adverse Event Characteristics 
6.3.1 Terms and Grading 
The severity or grade of an adverse event may be measured using the following definitions: 
 
Mild:  Noticeable to the subject, but does not interfere with subject’s expected daily 
activities, usually does not require additional therapy or intervention, dose reduction, or 
discontinuation of the study. 
 
Moderate:  Interferes with the subject’s expected daily activities, may require some 
additional therapy or intervention but does not require discontinuation of the study. 
 
Severe: Extremely limits to the subject’s daily activities and may require discontinuation of 
study therapy, and/or additional treatment or intervention to resolve and may be life-
threatening of fatal. 
 

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6.3.2 Attribution of the AE 
The investigator or co-investigator is responsible for assignment of attribution. 
Definite – The AE is clearly related to the study treatment/intervention. 
Probable – The AE is likely related to the study treatment/intervention. 
Possible – The AE may be related to the study treatment/intervention. 
Unlikely – The AE is doubtfully related to the study treatment/intervention. 
Unrelated – The AE is clearly NOT related to the study treatment/intervention. 
6.4 Serious Adverse Event Reporting Guidelines 
The PI must be notified within ONE business day of study team’s knowledge of any event meeting 
the criteria and definition of a serious adverse event, regardless of attribution, occurring during the 
study or within 30 days of the last administration of the study related treatment/intervention. 
 
The investigator must report all events meeting the criteria and definition of a serious adverse event 
as per the IRBMED reporting guidelines.  
 
6.5 Other Reportable Information or Occurrence (ORIO) 
There are types of incidents, experiences, and outcomes that occur during the conduct of human 
subject research that represent unanticipated problems but are not considered adverse events. For 
example, some unanticipated problems involve social or economic harm instead of the physical or 
psychological harm associated with adverse events. In other cases, unanticipated problems place 
subjects or others at increased risk of harm, but no harm occurs. 
 
Unanticipated problem: Per FDA Procedural Guidance for Clinical Investigators, Sponsors, and IRBs 
(January 2009), an unanticipated problem is defined as a serious problem that has implications for the 
conduct of the study (requiring a significant and usually safety-related, change in the protocol (such 
as revising inclusion/exclusion criteria or including a new monitoring requirement), informed consent 
or investigator’s brochure). 
 
Upon becoming aware of any incident, experience, or outcome (not related to an adverse event) that 
may represent an ORIO, the investigator should assess the incident and follow IRBMED’s reporting 
guidelines.  
6.6 Unblinding Procedures 
In the event of any adverse event requiring unblinding, the study staff can be made immediately 
aware of intervention assignment and the PI will be notified. 
 
7.0 STATISTICAL CONSIDERATIONS 
Aim 1 - Acceptability and Tolerability. Neuromodulation studies typically use dropout rate and 
reported adverse events as measures of acceptability and tolerability, respectively.12 We will compare 
the percentage of participants requesting to discontinue the session and the severity of side effects 
reported following the tACS vs. sham procedure using Bayes factors (BF).  
 

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Aim 2 - tACS Effects on Neural Synchrony and Cognitive Control Behavior. EEG data 
preprocessing and spectral analyses will be conducted using custom MATLAB scripts and EEGLAB 
following the general methods described in PI Tso’s published work.7 Briefly, data will be 
downsampled to 500 Hz, filtered (0.1 – 100 Hz), re-referenced to common average, segmented into 
short epochs (for task data, -400 to 1800 ms time-locked to onset of stimuli; for rest data, 2 s epochs), 
applied independent component analysis to reject non-neural artifacts, baseline adjusted, followed by 
automatic artifact rejection of epochs containing voltage exceeding ±100 µV. Data will be mirrored 
on both ends to minimize edge artifacts, applied Morlet wavelet convolution to extract power of 
different frequencies from 2 to 60 Hz. Theta-gamma PAC will be computed using the Kullback-
Leibler Modulation Index (KLMI)8 implemented in the PAC Tools plugin for EEGLAB.9 Neural 
synchrony (theta-gamma PAC) during the rest EEG blocks and cognitive control performance 
(sensitivity d’, response bias β, and reaction time on the Emotion Go-NoGo task) will be analyzed in 
separate repeated-measures ANCOVAs, with stimulation (tACS, sham) as within-subjects factor. 
 
Potential Problems & Alternative Strategies 
Participants Dropout. The study design entails each participant completing all 3 sessions. Our 
experience of conducting multiple-session neuromodulation studies suggests that average dropout 
rate for each subsequent session is 10-15%. We will enroll 30 participants to ensure that at least 20 
participants will complete the study even with an overall dropout of 30%. 
Statistical Power. For the repeated-measures ANOVAs in Aim 2, assuming a conservative within-
subjects correlations of 0.8, a sample size of 20 would provide 80% power at alpha level of .05 to 
detect small-to-medium within-subjects effect sizes of f=0.21. Although N = 20 may not be sufficient 
to detect smaller effects, our findings will still be useful in providing effect size estimates aiding the 
sample size calculations for subsequent clinical trials. Additionally, we will use Bayesian methods 
described in Dr. Tso’s publication15 to estimate the posterior probabilities of beneficial tACS effects. 
Although the sample will be small, we will also analyze for effects of sex, as the expectation is that 
we will have 50:50 distribution of male:female. 
 
8.0 DATA AND SAFETY MONITORING PLAN 
8.1 Overall framework 
Study monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with International 
Conference on Harmonization Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s) 
 
8.2 Roles & responsibilities for regular operations 
PI: The PI will meet with study staff on a weekly basis to monitor the progress of the study. During 
phases when subject recruitment is occurring, the PI will review screenings and scheduling of 
assessments, as well as strategies to improve recruitment yield at weekly meetings with the study 
team.  Issues such as maintaining confidentiality and privacy of participants during screening, 

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assessment and data collection, protocol deviations and adverse events will be reviewed.  For serious 
adverse events, the PI will be notified as soon as the SAE comes to the attention of study staff. 
 
 
 Study coordinator/research assistant: This bachelors level individual will carry out the screening 
and informed consent, and they will provide additional study information, all under the supervision of 
the PI.  The individual will be trained in screening, administering consent and information to the 
participants. Questions about eligibility will be discussed with the PI. This individual will administer 
surveys and neuropsychological tests, monitor the participants during the procedure and administer 
the tACS stimulation.  They will receive training in the administration of tACS to ensure they can 
safely operate the device and are aware of potential side effects. They will conduct any necessary 
follow-up safety reviews. 
 
Clinical Assessor:  Screenings will include thorough assessment of psychiatric health by a masters-
level clinician with experience in administration of psychiatric interviews.  They will ensure the 
absence of any neuropsychiatric conditions in the subjects, as well as health conditions that would be 
a contra-indication to TMS or MRI procedures. 
 
8.3 Frequency and type of other study monitoring: 
Institutional Review Board monitoring: Approval of all procedures, advertisements and materials 
given to subjects will be secured from the University of Michigan IRBMED.  Annual reviews will be 
conducted by IRBMED, including the number of subjects screened, enrolled and withdrawn.  The 
IRB will also review protocol deviations, adverse events (according to the reporting timetable of 
IRBMED) and complaints that arise in connection with the study. 
 
Data monitoring: Data entry will be audited by study staff, who were not involved in primary data 
entry. Patient questionnaire data will be entered largely through electronic data capture, e.g., 
REDCap. Research data will be maintained on password protected computers, behind UM firewalls. 
All enrolled participants will receive participant identifiers, which will be used to code all research 
records for this project.  Paper records with no identifying data beyond the research code are stored in 
locked cabinets in the PI’s office. Copies of executed consent forms will be stored in separate locked 
cabinets. Demographic data will be entered into spreadsheets, and behavioral data will be merged 
into files. Password-protected electronic files separated from the research data will track consents, 
including the link between the research identifier and individual participants. This tracking file will 
be the sole link between participant identifiers and research data. By deleting the field linking 
identifiers with participant names, research records can be effectively anonymized. 
8.4 Management of withdrawals and drop-outs: 
When participants drop out during the assessment, but before enrollment, all data including consent 
form will be destroyed. However, if a participant would agree to be re-contacted for future studies, 
the consent form will be retained. Limited, de-identified data regarding ethnicity, age, gender, and 
diagnosis will be retained through the screening process in order to establish the sampling frame. If a 
participant drops out due to substance use but would otherwise meet the inclusion criteria, all data 
will be retained until the closing of the project, in case the participant becomes eligible and wishes to 
be reconsidered for the study before conclusion of recruitment. When participants drop out after 

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enrollment, data may be destroyed, depending upon the wishes of the participant. However, consent 
forms and the research number will be retained. 
 
9.0 
BENEFITS/RISKS 
9.1 Benefits 
There are no direct benefits from being in this study. However, others may benefit from the 
knowledge gained from this study as it may lead to better interventions in the future. 
9.2 Risks 
9.2.1 Subject Confidentiality  
Measures to protect patient privacy. Study staff will make every effort to limit identifiable 
information on potential subjects during recruitment.  Conversations in which a patient's name must 
be mentioned, e.g. to determine potential eligibility, will occur in private settings of the clinic.  The 
minimum amount of information will be recorded, and staff are alerted to the dangers of printing, 
faxing and emailing sensitive information.  Phone conversations with potential research subjects will 
occur behind closed doors, and staff will ask callers if they are in a location where sensitive 
information can be discussed without danger of revealing confidential information.  Any information 
gathered on subjects who prove ineligible will be destroyed as soon as possible (a list of patients who 
have declined or screened out will be maintained through the recruitment phase to avoid contacting 
these subjects again). 
9.2.2 Known Potential Risks and Minimization of Risks 
(1) Confidentiality risks and Protected Health Information (rare) - Loss of confidentiality around 
sensitive information such as psychiatric status, history of substance abuse, etc.  
Minimization of Risk: 
• Investigators and research staff who are responsible for conduct, management, and oversight 
of the study will be required to fulfill all training requirements for Good Clinical Practice 
(GCP). All investigators and research staff will be required to handle protected health 
information as outlined by the Health Insurance Portability and Accountability Act (HIPAA).  
• Confidentiality of participant records is assured by assigning a research code and identifying 
all computer and paper files only by this code, except for a single tracking file. Paper records 
are kept in locked drawers in a locked room and electronic records are kept on secure server, 
to which only authorized research personnel have access.  
• Screening forms for subjects who do not qualify for the study will be destroyed, except for 
anonymous information (such as age, gender and education).  
• After the completion of data analysis, the record linking subjects to the research codes will be 
destroyed, thereby anonymizing the data. 
(2) Risk of psychological discomfort, stress, or symptom exacerbation (infrequent) - Risks of 
psychological discomfort associated with the questions asked in the clinical interview or on some of 
the questionnaires. 
Minimization of Risk: 
• During the assessment process, subjects are reminded that they do not have to answer 
questions that make them feel uncomfortable. 

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• Participants are also reminded during the study that they may choose to terminate 
participation at any time throughout the study. 
• Staff will check in with the participant frequently to if they are alright. Breaks will be offered 
to reduce any fatigue or stress. 
(3) Risk of symptom worsening, suicidal thoughts, plans, and intentions (rare). 
Minimization of Risk: 
• Clinically trained study staff will be alert for the emergence of new suicidal thoughts 
amongst enrolled subjects during the course of participation.  
• In the event of concerns about suicide risk (revealed during the assessment phase), the PI 
will be promptly notified, and plans will be formulated for additional emergency 
evaluation at the psychiatric emergency room (University of Michigan Psychiatric 
Emergency Services), if appropriate (see Appendix A – MiScanlab Suicide Protocol) 
Risks associated with completing the EEG:  
 
(4) Discomfort or anxiety with EEG (infrequent) - The electrode application procedure involves 
putting gel on your head to help the wires measure brain signals. The gel will seem wet, which some 
people find slightly uncomfortable. There is also a minor risk of discomfort or anxiety/panic from 
being in the confined space for the EEG measurement. 
Minimization of Risk: Participants can check the EEG measurement equipment and room to 
check if they will feel comfortable before agreeing to participate. They are also free to stop 
the study at any time if they become too uncomfortable. 
 
(5) Risk of boredom, fatigue, or discomfort (likely) - It is possible that participants will become 
fatigued, frustrated, or uncomfortable.  
Minimization of Risk: Participants are reminded during the study that they may choose to take 
a break or terminate participation at any time throughout the study. 
 
Risk associated with tACS:  
 
(6) Risk of Injury and Discomfort (mild and temporary) - The side effects of tACS are mild and 
transient; the participant may report mild tingling, burning, or itching under the electrode sites.  
Minimization of risk: 
• To monitor 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.   
If procedure becomes intolerable for the participant, the stimulation will be stopped. They 
may request a break from the procedures and/or may decline to answer any questions that 
make them feel uncomfortable. 
 
 

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10.0 
QUALITY ASSURANCE AND AUDITS 
10.1 Audits and Inspections 
A regulatory authority (e.g. FDA) may wish to conduct an inspection of the study, during its conduct 
or even after its completion. If an inspection has been requested by a regulatory authority, the study 
staff must immediately inform IRB, Medical School Regulatory Affairs, MIAP, etc.  
10.2 Event Windows, Missed Assessments, Missed Sessions and Protocol Deviation Reporting 
Any safety-related assessments (AE Questionnaire, etc.) which are missed will be reported to the IRB 
as a protocol deviation. For the other assessments, missing assessments will not be reported as 
protocol deviations unless they constitute > 10% of the total assessments. The time elapsed between 
the initial assessment and tACS sessions are intended to be approximately 1 week, but scheduling 
logistics may mean this is not possible for all subjects, and may be longer for some (~ 30 days). 
These deviations are expected to be minor and will not be reported, although they will be recorded. 
These allowances should affect neither the scientific integrity nor the safety monitoring provisions of 
the protocol. 
11.0 
REGULATORY 
11.1 Institutional Review Board (IRB) 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to be provided to subjects, must be reviewed and approved by a properly constituted 
IRB. Any amendments to the protocol must be reviewed and approved by the IRB. 
11.2 Subject Information and Consent 
Study team member will explain to each subject the nature of the study, its purpose, the procedures 
involved, the expected duration, the potential risks and benefits involved and any discomfort it may 
entail.  Each subject will be informed that participation in the study is voluntary and that he/she may 
withdraw from the study at any time and that withdrawal of consent will not affect his/her subsequent 
medical treatment or relationship with the treating physician. 
 
This informed consent will be given by means of a standard written statement, written in non-
technical language. The subject should read and consider the statement before signing and dating it 
and should be given a copy (electronic or paper form) of the signed document. No subject can enter 
the study before his/her informed consent has been obtained. The informed consent form is 
considered to be part of the protocol and will be submitted for IRB approval. 
 
 

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12.0 
REFERENCES 
1. Wright L, Lipszyc J, Dupuis A, Thayapararajah SW, Schachar R. Response inhibition and 
psychopathology: a meta-analysis of go/no-go task performance. J Abnorm Psychol. 2014 May;123(2):429-
39.  
2. Swann AC, Lijffijt M, Lane SD, Steinberg JL, Moeller FG. Severity of bipolar disorder is associated with 
impairment of response inhibition. J Affect Disord. 2009 Jul;116(1-2):30-6. 
3. Kwapil TR, Miller MB, Zinser MC, Chapman LJ, Chapman J, Eckblad M. A longitudinal study of high 
scorers on the hypomanic personality scale. J Abnorm Psychol. 2000 May;109(2):222-6.  
4. Riddle J, McFerren A, Frohlich F. Causal role of cross-frequency coupling in distinct components of 
cognitive control. Prog Neurobiol. 2021 Jul;202:102033.  
5. McInnis MG, Assari S, Kamali M, Ryan K, Langenecker SA, Saunders EFH, Versha K, Evans S, O'Shea 
KS, Mower Provost E, Marshall D, Forger D, Deldin P, Zoellner S; Prechter Bipolar Clinical Research 
Collaborative. Cohort Profile: The Heinz C. Prechter Longitudinal Study of Bipolar Disorder. Int J 
Epidemiol. 2018 Feb 1;47(1):28-28n.  
6. Costa, P. T., Jr., & McCrae, R. R. (1985). The NEO Personality Inventory manual. Odessa, FL: 
Psychological Assessment Resources. 
7. Grove TB, Lasagna CA, Martínez-Cancino R, Pamidighantam P, Deldin PJ, Tso IF. (2021). Neural 
oscillatory abnormalities during gaze processing in schizophrenia: Evidence of reduced theta phase 
consistency and inter-regional theta-gamma coupling. Biological Psychiatry: Cognitive Neuroscience and 
Neuroimaging, 6(3): 370-379.  
8. Tort AB, Komorowski R, Eichenbaum H, Kopell N. Measuring phase-amplitude coupling between 
neuronal oscillations of different frequencies. J Neurophysiol. 2010 Aug;104(2):1195-210. 
9. Martínez-Cancino R, Heng J, Delorme A, Kreutz-Delgado K, Sotero RC, Makeig S. Measuring transient 
phase-amplitude coupling using local mutual information. Neuroimage. 2019;185:361-378.  
10. Raichle ME. Two views of brain function. Trends Cogn Sci. 2010 Apr;14(4):180-90.  
11. Polanía R, Nitsche MA, Korman C, Batsikadze G, Paulus W. The importance of timing in segregated 
theta phase-coupling for cognitive performance. Curr Biol. 2012 Jul 24;22(14):1314-8. 
12. Aparício LVM, Guarienti F, Razza LB, Carvalho AF, Fregni F, Brunoni AR. A Systematic Review on 
the Acceptability and Tolerability of Transcranial Direct Current Stimulation Treatment in Neuropsychiatry 
Trials. Brain Stimul. 2016 Sep-Oct;9(5):671-681. 
13. Antal A, Alekseichuk I, Bikson M, Brockmöller J, Brunoni AR, Chen R, Cohen LG, Dowthwaite G, 
Ellrich J, Flöel A, Fregni F, George MS, Hamilton R, Haueisen J, Herrmann CS, Hummel FC, Lefaucheur 
JP, Liebetanz D, Loo CK, McCaig CD, Miniussi C, Miranda PC, Moliadze V, Nitsche MA, Nowak R, 
Padberg F, Pascual-Leone A, Poppendieck W, Priori A, Rossi S, Rossini PM, Rothwell J, Rueger MA, 
Ruffini G, Schellhorn K, Siebner HR, Ugawa Y, Wexler A, Ziemann U, Hallett M, Paulus W. Low intensity 

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transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines. Clin 
Neurophysiol. 2017 Sep;128(9):1774-1809. 
14. Matsumoto H, Ugawa Y. Adverse events of tDCS and tACS: A review. Clin Neurophysiol Pract. 2016 
Dec 21;2:19-25. 
15. Tso IF, Taylor SF, Johnson TD. (2021). Applying hierarchical Bayesian modeling to experimental 
psychopathology data: An introduction and tutorial. Journal of Abnormal Psychology, 130(8): 923–936. 
16. Frohlich, F., Riddle, J. Conducting double-blind placebo-controlled clinical trials of transcranial 
alternating current stimulation (tACS). Transl Psychiatry 11, 284 (2021) 
 
 

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13.0 APPENDIX 
 
Appendix A – MiScanlab Suicide Protocol 
 
 
MiSCAN Lab: Suicide Protocol 
 During normal business hours:  
page first, call second 
Outside normal business hours:  
call first, page second 
 
  To page clinician, go to 
 https://uhmspaging.med.umich.edu/homepaging/PagingSend/search.aspx and submit a clinical page using the appropriate message 
template: 
  
In-Person 
“SUICIDE PROTOCOL for [Tso/Taylor] study. 
Participant in RUB [ROOM #]. Call [PHONE#]. – 
[YOUR NAME]” 
Over-the-Phone* 
“SUICIDE PROTOCOL for [Tso/Taylor] study. 
Participant on phone. Call [PHONE #]. – [YOUR 
NAME]” 
 
 
 
 
 
 
*NOTE FOR POST-COVID REMOTE PHONE SCREENINGS: If you are conducting a phone screen remotely, have the clinician call 
your cell phone (or the number of whatever phone you used to call the participant). Once the clinician is calling you, tell the participant, 
“We want to make sure that you are safe, so I am going to have one of our clinicians on the team ask you a few additional questions by 
having them join our call. Let me place you on brief hold while I add them to the call.” Then place the participant on hold (press ‘hold and 
accept call’ if using an iPhone), answer the clinician’s call, QUICKLY explain the information you collected thus far, and then merge the 
two calls so you are on a three-way call with the participant. Introduce the participant to the clinician and let the clinician take over from 
there. You should stay on the line until they are done.  
 
 
Chain of Command 
1. 
Laura Stchur 
Cell – (586) 604-0025 
2. 
Stephan Taylor 
Pager – 7545 
Cell – (734) 717-5413 
3. 
 Melvin McInnis 
Cell – (734) 355-8803 
4. 
Sarah Sperry 
Pager – 25194  
5. 
 Cynthia Burton 
Pager – 20890 
Cell – (714) 393-2978 
 
 
 
 
 

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Suicide Questionnaire 
 
1. 
Ideation (goal: if and how frequent/serious are the ideas?): 
 
Have you had thoughts about hurting yourself? 
What kinds of thoughts have you had about killing yourself? (note frequency and duration) 
 
 
 
2. Intent (how determined is the person on committing suicide?): 
How do you feel about being suicidal? 
What makes you want to die? 
What do you expect your future to be like? 
 
 
 
3. 
Plan (how well thought out?): 
If you decided to kill yourself, how would you do it? 
 
 
 
3b. Means (can they kill themselves by the above method?): 
e.g. Do you own a gun? 
 
 
 
4. Control (what works to help stop the thought?): 
What has kept you from killing yourself before? 
What helps you control your thoughts about wanting to die? 
 
 
 
5. 
Support 
Do you have anyone who keeps you feeling safe? 
Would you like numbers of a hotline, outpatient treatment center, etc…? 
 
  
 
 
INSTRUCTIONS BELOW ARE FOR TRAINED CLINICIANS ONLY: 
 
High risk participants → send to PES. 
Low-moderate or moderate risk participants → clinician member (NOT study coordinator or undergrad RA) should complete a safety 
plan with the participant.  
 
IF IN-PERSON: Clinician and participant should both sign the safety plan. Clinician should make a copy of the safety plan to give to 
participants and also provide them with the ‘UM emergency reference’ document on the next page. 
 
IF OVER-THE-PHONE:  Clinician and participant should complete a safety plan over the phone. Be sure to obtain an email address from 
participant so the coordinator can email them the ‘UM emergency reference document.