Transcranial Direct Current Stimulation (tDCS) as a Treatment for Acute Fear
Phase: NA
Conditions: Fear
Sponsor: University of California, San Francisco

 
 
Transcranial Direct Current Stimulation (tDCS) as a Treatment for Acute Fear 
 
NCT02410954  
 
Document Date: 11/06/2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Study Application (Version 1.13) 
 
B) Research Support Staff 

Andrews, Katherine B  
 Study Coordinator 
Lee, Andrew  
Technician 
3.3 *Please add a Study Contact: 
  
Andrews, Katherine B  
Krystal, Andrew MD  
The Study Contact(s) will receive all important system notifications along with the Principal 
Investigator. (e.g. The project contact(s) are typically either the Study Coordinator or the Principal 
Investigator themselves). 
3.4 If applicable, please add a Faculty Advisor/Mentor: 
  
3.5 If applicable, please select the Designated Department Approval(s): 
  
Add the name of the individual authorized to approve and sign off on this protocol from your 
Department (e.g. the Department Chair or Dean). 
4.0  
Initial Screening Questions 
Updated June 2017 
4.1  * PROJECT SUMMARY: (REQUIRED) Give a brief overview of this project (250 words or less). Tell us 
what this study is about, who is being studied, and what it aims to achieve. If you have an NIH 
Abstract, paste it here:   Click on the orange question mark to the right for more detailed 
instructions. 
This NIMH-funded project was started at Duke University in 2015 and is being transferred to UCSF 
because the PI moved from Duke to UCSF. Once the study is IRB approved and initiated at UCSF all 
patient-related activities at Duke will cease. Modeling of tDCS electric field distribution for new tDCS 
electrode placements to be tested at UCSF will continue at Duke. We have included below the abstract 
of our grant.  
NIH ABSTRACT: 
This application responds to RFA-MH-15-300 (Exploratory Clinical Trials of Novel Interventions for 
Mental Disorders [R21/R33]) by proposing to translate neuroscience findings into a novel non-
pharmacologic treatment for Acute Fear, a Research Domain Criteria (RDoC) construct common to 
many DSM defined anxiety disorders.  The neuroscience findings which serve as the basis for this effort 
are an extensive preclinical body of work documenting that the region of the brainstem known as the 
locus coeruleus (LC) plays a key role in mediating symptoms of Acute Fear. We capitalize on evidence 
that LC activity can be non-invasively measured with pupillometry and our pilot data indicating that we 
can modulate LC activity with transcranial direct current stimulation (tDCS) applied via electrodes 
attached to the skin/scalp.  Our approach is to develop tDCS as a means of inhibiting LC activity and 
then determine if this diminishes symptoms of Acute Fear. 
Our translational effort will consist of two stages, a 2 year R21 phase where we establish feasibility, 
tolerability, safety, and proof-of-concept (POC) in terms of capacity to engage the neural target, 
followed by a 3 year R33 parallel-group, double blind, controlled trial. In the R21 phase we will employ 
an iterative approach where we use electric field modeling with a realistic head model to identify 
promising treatment electrode placements which we will test across a series of electrical doses in 3 
cohorts of healthy controls to attempt to identify a tDCS treatment electrode configuration with which 

we can identify a dosage in each subject that is: (1) tolerable (5-point Likert ratings of no more than 
mild discomfort); and (2) engages the target neural circuitry by transiently inhibiting LC activity as 
reflected in prevention of the pupil dilation response in the anxiety task or to rare stimuli in the 
auditory oddball task (AOT), tasks which reliably activate LC. If successful we will proceed to a 3 year 
R33 parallel group trial where 60 healthy volunteers are randomized to electrical dose-personalized 
active tDCS vs an active control therapy (tDCS that delivers the same skin current density as the active 
but does not affect LC) here clinical symptoms Acute Fear, the primary outcome, are elicited by 
inhalation of 7.5% CO2. Future development viability will be assumed if there is preliminary evidence 
that engaging the target (inhibiting LC) safely diminishes clinical Acute Fear symptoms. 
Our broad scientific goal is to evaluate if engagement of the target brain circuitry, inhibition of LC, is a 
viable target for treating Acute Fear.  This is of high public health importance as Acute Fear is an 
extremely widespread and debilitating problem and current treatment options are quite limited.  
4.2  * HUD DEVICE: (REQUIRED) Does this application involve a Humanitarian Use Device (HUD): 
No  
Yes, and it includes a research component  
Yes, and it involves clinical care ONLY  
4.3  * TYPE OF RESEARCH: (Click the Help link for definitions and guidance): (REQUIRED)  
Biomedical research  
Social, behavioral, educational, and/or public policy research  
Hybrid - includes aspects of BOTH types of research (check this option if your research is mainly 
social 
/behavioral but also involves specimen collection or blood draws to look at biological measures)  
4.4  * SUBJECT CONTACT: (REQUIRED) Does this study involve ANY contact or interactions with 
participants: 
Yes (including phone, email or web contact)  
No (limited to medical records review, biological specimen analysis, and/or data analysis)  
4.5  * RADIATION EXPOSURE: Does your protocol involve any radiation exposure to patients/subjects 
EITHER from standard care OR for research purposes (e.g., x-rays, CT-scans, DEXA, CT-guided 
biopsy, radiation therapy, or nuclear medicine including PET, MUGA or bone scans): (REQUIRED) 
 
  Yes    
  No 
4.6  * RISK LEVEL: (REQUIRED) What is your estimation of the risk level, including all screening 
procedures and study activities (Help Text updated 9/13): 
Minimal risk  
Greater than minimal risk  
4.7  * REVIEW LEVEL: (REQUIRED) Requested review level (Click on the orange question mark to the 
right for definitions and guidance): 
Full Committee  
Expedited  
Exempt  
4.11  * CLINICAL TRIAL: (REQUIRED)     Is this a clinical trial? According to The World Health 
Organization (WHO) and the International Committee of Medical Journal Editors (ICMJE) a clinical 
trial is:      

 

 

 

 

 

Preliminary Studies 
Procedures 
Statistical Methods 
References 
Later sections include: 
Drugs and Devices 
Sample Size, Eligibility, and Subjects 
Recruitment and Consent 
Risks and Benefits 
Data and Safety Monitoring Plan 
Confidentiality, Privacy and Security 
Financial Considerations 
Qualifications of Personnel 
Other Approval and Registrations 
8.2  HYPOTHESIS: Describe the hypothesis or what the study hopes to prove (Help Text updated 9/13): 
Locus coeruleus (LC) norepinephrine (NE) neuron activity has been convincingly linked to regulation of 
acute fear. This study will address whether pupillometry (measurement of pupil size) will reflect LC NE 
activity elicited by inhalation of 7.5% CO2 (an established method for activating LC and inducing acute 
fear) in humans and if transcranial direct current stimulation (tDCS) can block both the induced pupil 
effects and associated experience of fear. Our hypothesis is that tDCS has promise as a treatment for 
acute fear as evidenced by tDCS administration targeting the LC inhibiting both the pupil dilatory 
response and fear response to 7.5% CO2 inhalation. A 2 year R21 phase will establish feasibility, 
tolerability, safety, and proof-of-concept (POC) in terms of capacity to block the pupil response to 7.5% 
CO2 followed by a 3 year R33 parallel-group, double-blind, randomized, controlled trial which will 
assess the degree to which blocking the pupil response to CO2 inhalation with tDCS prevents the 
development of acute fear in response to CO2 inhalation. 
8.3  AIMS: List the specific aims: 
Specific Aim 1: R21- Establish methods required for R33 controlled trial of 
transcranial direct current stimulation (tDCS) treatment of Acute Fear 
Specific Aim 2: R21- Establish feasibility, tolerability/safety, and Proof of 
Concept (POC) (determine degree to which we can engage the locus 
coeruleus [LC]) of tDCS as an intervention for acute fear.  
Specific Aim 3: R33 – Conduct a parallel group, double-blind, randomized, 
controlled trial of dose-personalized tDCS (current amplitude dose chosen to 
prevent pupil dilation occurring with an auditory oddball task and be well 
tolerated) in 60 healthy subjects given CO2 to elicit fear to assess safety and 
efficacy of tDCS as a treatment for Acute Fear 
  
8.4  DESIGN: Briefly describe the study design (e.g., observational, interventional, randomized, 
placebocontrolled, blinded, cross-over, cross-sectional, longitudinal, pharmacokinetic, etc.):   
Design & Procedures 
1. Subject recruitment: Participants will be recruited in Dr. Krystal’s laboratory at UCSF. We plan to 
enroll a total of 240 subjects healthy volunteers (age range: 21-65 years) in order to complete 100 
for the entire effort (R21 and R33 Phases combined). This corresponds to enrolling 68 subjects in the 
R21 (34/year) and 172 (58/year) during the R33 phase.  This takes into account the expected rate of 
failure to: have a pupillary response to the fear conditioning paradigm (25%) and CO2 challenge 
(50% - relevant for last 10 R21 and all R33 subjects); and to meet other screening criteria (see 
inclusion and exclusion criteria sections). These subjects will be recruited from the local community 
using posted flyers. 

2. R21/R33 Components: R21 Phase: 
First 30 Subjects, following the screening visit, these subjects will undergo 2-3 sessions separated by 1 
week in which a promising electrode configuration (three promising configurations will each be tested 
in a cohort of 10 subjects) will be used with tDCS stimulation at increasing electrical dosage during 
which pupillometry will be carried out to determine the Anxiety Task (a test of responses to electrical 
pulses delivered to the fingers) or Auditory Oddball Test (AOT; a test of responses to rare vs common 
sounds) response.  During pupillometry while undergoing tDCS, ECG, EEG, respiratory rate, or galvanic 
skin conductance measures may be obtained. A maximum of 5 total tDCS dosages and sham will be 
tested.  
Last 10 Subjects. These subjects will take part in a double-blind, controlled, randomized, cross-over 
study over 3 sessions following their screening visit. At session 1 subjects will undergo electrical dose 
titration with the tDCS electrode configuration resulting from the 3 rounds of optimization using the 
same procedure as in the first 30 subjects to determine the lowest well-tolerated dose that suppresses 
the pupil dilation response to the Anxiety Task or Auditory Oddball Test, except that a maximum of 5 
tDCS dosages will be tested at this session. At the second and third sessions (1 week apart) subjects 
will receive doseoptimized tDCS and the control treatment with order randomized along with 7.5% CO2 
(to evoke an LC response) for 20 minutes. The 7.5% CO2 will be delivered pre-mixed as provided by 
Airgas.  7.5% CO2 is commonly and safely used in the field of study.  A mixture of CO2 7.5%/O2 
21%/N 71.5% with be purchased premixed from Airgas and shipped to UCSF. At these sessions, the 
VAS-A and STA-I will be administered 5 minutes prior to and just after the 20 minute session and VAS-
A will also be obtained at 5, 10, 15, and 20 minute points of the CO2 inhalation. tDCS will be 
administered during the last 5 minutes of the 20 minute CO2 inhalation period. Subjects will be 
monitored for an hour post-session for safety and will undergo study physician assessment to 
determine suitability to leave. Following the 2nd treatment session participation will end except that 
subjects will be called the next day to assess for adverse effects and appropriate care will be given if 
any are found. 
R33 Phase: 60 subjects will participate in a double-blind, randomized, controlled, parallel-group trial. 
They will be randomized to either active or control treatment and at the first post-screening visit they 
will undergo electrical dose titration as described above for the treatment they are randomized to. For 
all titrations, during the 5 minutes between tDCS treatments an unblinded member of the study team 
not having contact with the subjects will compute their Anxiety Task or Auditory Oddball Test response 
(these tests will be used to determine optimal dosing in terms of the tDCS level that blocks the pupil 
response in these tests) and convey to the tDCS treatment physician whether to continue or stop 
titration. Subjects randomized to the control treatment will undergo a sham titration where the stop 
level will be randomly selected from the distribution of titration outcomes occurring in the R21 phase. 
Subjects will then return in 1 week and undergo optimal dose tDCS or control treatment for a single 
treatment session as described in the prior paragraph.  Primary outcome will be the VAS-A “fearful” 
rating obtained at the end of tDCS/CO2 inhalation. Anxiety Task or AOT pupil responses will be 
obtained every 10 minutes after the end of the tDCS/CO2 inhalation period to map the duration of 
persistent effects on LC (heart rate and skin conductivity will also be obtained as exploratory 
measures). At the end of this session participation will end except that subjects will be called the next 
day to assess for adverse effects and care given if necessary.  Data from the R21 phase will be used to 
provide justification for the larger R33 study, and prior to initiation of the R33 phase, the study will be 
submitted to the IRB for review/approval.  
8.5  BACKGROUND AND SIGNIFICANCE: Briefly provide the background and significance of this study 
(e.g.  
why is this study needed) (space limit: one half page):  
If this is a first in humans study, please summarize the safety data from the animal 
studies. For pediatric drug or device studies, please identify if this is the first study 
in pediatric populations.   
The National Institutes of Mental Health (NIMH) has recently identified that 
a major limitation to the understanding of neuropsychiatric disorders and 
the development of treatments for these conditions has been the inability to 
identify key dimensions of observable behavior that are central to these 
disorders and linked to underlying neurobiology by measurable biomarkers. 
This proposal is intended to address this problem by establishing that 

measurement of pupil size using pupillometry, which has been established 
to reflect the activity in norepinephrine neurons in the locus coeruleus, is a 
biomarker of the acute fear dimension of observable behavior and that the 
acute fear response can be blocked with transcranial magnetic stimulation 
(tDCS) targeted to inhibit locus coeruleus neurons. This is intended to 
establish that tDCS is promising for serving as a much needed treatment for 
acute fear which is a core feature of neuropsychiatric conditions such as 
anxiety disorders for which improved treatments are needed.  
  
We will first establish feasibility and proof of concept by employing the  
Anxiety Task or Auditory Oddball Test which activate the Locus Coeruleus 
(LC) and assessing whether we can block the activation of LC neurons as 
measured with pupillometry via administering tDCS targeted to inhibit LC 
neuronal activity.  We will then further establish proof of concept by using 
pupillometry to assess whether we are able to inhibit the locus coeruleus 
neuronal response the adminsitration of 7.5% CO2, an established means of 
activating locus coeruleus neurons and provoking fear responses, with tDCS 
targeted to inhibit locus coeruleus activity as measured by pupillometry.  If 
these proof of concept tests are successful, we will then proceed to carrry 
out a clinical trial in healthy controls where we will test whether tDCS 
targeted to inhibiting locus coeruleus neurons blocks the clinical acute fear 
response to 7.5% CO2 administration.  
  
  
8.6  PRELIMINARY STUDIES: Briefly summarize any preliminary studies relevant to your proposed 
research (space limit: one half page): 
    Preclinical Work on Brainstem Circuitry Modulating LC Function. Among the bases for this proposal is 
preclinical work carried out by Co-Investigator Dr. Szabo on the brainstem circuits which modulate 
locus coeruleus (LC) activity. This work supports the proposed effort because it suggested that we 
could target a brainstem circuit with a treatment such as tDCS and modulate LC activity without having 
to target the LC itself which is quite small. His work in rats documented that 21-day but not acute or 2-
day SSRI therapy attenuates LC spontaneous firing activity paralleling the lag in onset of therapeutic 
action of antidepressant drugs in anxiety disorders. A brainstem LC modulatory circuitry was found that 
explains why time is needed to decrease LC activity.  Further, he found that manipulations such as paw 
pinch transition LC NE neurons from a tonic pacemaker to a burst firing pattern, and that anxiogenic 
drugs also enhance tonic firing rates and bursts in LC activity (Szabo et al., 2004).  Dr.Szabo’s work 
supports that interventions which augment and reduce LC activity can induce and attenuate fear and 
anxiety, respectively.  
  
     Vestibular Stimulation with Direct Alternating Current (tACS). Dr. Krystal completed a 
doubleblind, sham-controlled study of tACS vestibular stimulation in healthy volunteers as a 
treatment for insomnia.  This study also speaks to Dr. Krystal’s experience in successfully leading 
double-blind, controlled, transcranial electrical stimulation studies where stimulation is carried out 
targeting a  region adjacent to the brain stem.  
  
    Electric Field Modeling Using a Realistic Head Model. Co-investigators Peterchev and Deng  
have extensive experience creating models of the electric field induced in the brain by various 
transcranial electric stimulation paradigms such as tDCS.  These models include realistic rendering of 
the head anatomy based on an MRI scan, and allow the determination of the electric field strength in 
specific brain structures such as the LC. This work speaks to our capacity to carry out the proposed 
electric field modeling and optimization of tDCS electrode configuration.  
   Study Demonstrating Link of Clinical Fear Symptoms and Resting Pupil Diameter. The team of 
investigators carried out a pilot study identifying mean resting pupil diameter as a biomarker of 
selfreported clinical symptoms of fear/anxiety which supports the use of this measure in the proposed 
study and the team’s ability to successfully obtain that measure. They recruited 19 subjects (11 

medication-free patients with mood and anxiety spectrum disorders and 8 healthy controls. A validated 
anxiety scale with well-established psychometric properties was employed: the Hamilton Anxiety Rating 
Scale (HAM-A).   We found that greater pupil diameter was associated with greater HAM-A (r=0.56; p< 
0.02) and PAS (r=0.53; p< 0.02) scores (See Figure 2).  Although these measures do not directly 
reflect Acute Fear, it can be assumed that those with significantly elevated levels of fear in the prior 
week are more likely to experience fear in the laboratory.  However, this analysis underestimates the 
strength of the relationship of mean resting pupil diameter and acute fear that will be seen in the 
proposed study where all subjects will be induced to have fear during testing in the laboratory and we 
will attempt to mitigate the fear and LC activation with tDCS. Based on these findings we propose to 
employ mean resting pupil diameter as a biomarker of target engagement (LC activation level) 
occurring in association with the induction of Acute Fear symptoms induced by 7.5% CO2 in the 
proposed R21 and R33 studies.  
     Pilot study of administering tDCS to modulate LC activity in healthy controls. The team of 
investigators carried out a pilot study in which we tested 2 two-electrode tDCS electrode configurations 
that had potential to affect the region of the LC based on the rough general principal that the LC should 
lie between the two treatment electrodes.  We employed measurement of pupil diameter in the 
auditory oddball test (AOT) to determine our capacity to modulate LC activity in terms of whether we 
could affect the degree of separation between the pupil diameter response to rare vs common tones. It 
was understood that with this gross electrode configuration approach we were as likely to enhance as 
inhibit LC activity, though we assumed that doing either was proof-of-concept that we could modulate 
LC activity with tDCS. We administered the highest well tolerated tDCS stimulus electrical dosage for 
each subject which varied from 2–4 mA for the 5 people studied.  
It is important to note that the 4 mA maximum dosage is within recommended safety limits.  We 
evaluated tDCS with: 1) the electrodes placed over the ears (external auditory meatus) and; 2) one 
electrode at the inion (notch on the back of the head at the top of the neck) and the other just under 
the chin. Pupillometry was carried out during the auditory oddball tasks (AOT) where two tones are 
played one more frequently than the other and the rare tones are well-established to lead to a neural 
response approximately 300 msec after the rare tones are played.  We found that treatment was well-
tolerated in general. We were able to find at least one electrode configuration and polarity (orientation 
of anode and cathode) associated with a tolerable stimulus intensity for all subjects that had a 
statistically significant effect on the pupillary AOT response. In 4/5 subjects there was an electrode 
configuration where the LC pupil dilation response to the rare stimuli was significantly suppressed by 
tDCS compared with both immediate pre and immediate post-stimulation testing (see Figure 3 for 
example). In 1 subject the response to the rare tones was enhanced by stimulation. In two of the 
subjects the direction of effect (suppression or enhancement) differed for the electrode configurations 
and polarities tested.  These findings suggest that we can modulate LC function with tDCS with a 
substantial effect size, though the findings further indicate that electric field modeling will be needed to 
determine optimal treatment electrode placement given that effects appear to vary from person-to-
person and that it is not possible to predict effects in a simple way, such that without modeling and 
iteration, we may be as likely to augment as inhibit LC activity, at least in some individuals. The 
findings also indicate that the effect size of inhibition is large enough to be statistically significant at the 
p< 0.05 level in a single trial in an individual. These findings serve as a key basis for the proposed 
effort, support the need for work to determine optimal electrode placement before trials of tDCS for 
acute fear could be carried out, and support the use of the AOT as a target engagement measure.   
8.7  * TREATMENT PROTOCOL: Is this a treatment study, i.e. does this study intend to provide treatment 
to individuals with a medical or psychological condition: (REQUIRED)  
 
  Yes    
  No 
8.8  * COMMON RESEARCH ACTIVITIES: Types of research activities that will be carried out. Check all 
that apply and describe in more detail in the 'Procedures / Methods' section: (REQUIRED) 
Interviews, questionnaires, surveys 
Educational or cognitive tests 
Focus groups 
Observation 
Non-invasive imaging or testing (MRI, EEG, pulse oximetry, etc.) 
Administration of contrast agent 
Imaging procedures or treatment procedures that involve radiation (x-rays, CT scans, CT-guided 
biopsies, DEXA scans, MUGA or PET scan) 
Biopsy conducted solely for research purposes 

Use of placebo 
Sham surgical procedure 
Collection of data from wearable tech such as Fitbit, Apple Watch, Garmin, motion actigraphs, etc.) 
Fitness tests or other exertion activities 
Use of mobile health apps or other apps 
Social media-based research activities 
None of the above 
8.9  * PROCEDURES / METHODS: (REQUIRED) 
For clinical research, list all study procedures, tests and treatments 
required for this study, including when and how often they will be 
performed. If there are no clinical procedures, describe the research 
activities. 
  
If some of the activities would occur even if the person were not in the 
study, as in the case of treatment or tests performed for diagnostic 
purposes, clearly differentiate between those activities that will be done 
solely for research purposes and those that are happening as part of 
routine care. 
  
Examples may include: 
additional scans outside standard clinical diagnosis or monitoring 
additional biopsies to collect tissue for research extra clinic visits 
extra lab tests not required for clinical care 
If you have a procedure table, attach it to the submission with your other 
study documents. 
1. 
Pupillometry Procedure: We will employ a Tobii Pro eye tracking system to measure pupil 
response. Pupil diameter will be recorded continuously from the each eye at a sampling rate of 60 Hz 
via a sensor bar attached to a computer monitor. We will capture pupil size at baseline, in response to 
the Anxiety Task or Auditory Oddball Test (AOT), pain-induced conditioned fear test, and administration 
of 7.5% CO2.  Data will be segmented into epochs from 0 to 12 s relative to the acquisition onset of 
each stimuli or experimental condition. An average pupil diameter measure will then be calculated for 
the corresponding volume by taking the mean across the remaining non-artifactual samples in that 
epoch. During tDCS the pupil diameter will be averaged over 1 minute periods while subjects are 
staring at a dark screen in a dark room. For 7.5% CO2 response the pupil diameter will be averaged 
over 1 minute periods while subjects are staring at a dark screen in a dark room. This will be computed 
at baseline, and at 5, 10, 15, and 20 minutes after the start of CO2 inhalation and 5 minutes and 30 
minutes post-inhalation. During pupillometry while undergoing tDCS, ECG, EEG, respiratory rate, or 
galvanic skin conductance measures may be obtained. 
2. 
Transcranial Direct Current Stimulation (tDCS): tDCS involves non-invasive transcranial 
electrical stimulation using direct current with a sustained intensity of a few milliamperes and duration 
of up to tens of minutes.  Administered in this way tDCS is a safe procedure (See Bickson et al., 2016 
attached). Evidence from relevant animal models indicates that brain injury by such Direct Current 
Stimulation occurs at predicted brain current densities (6.3–13 A/m) that are over an order of 
magnitude above those produced by tDCS such as we will administer it (Bickson et al., 2016). To date, 
the use of conventional tDCS protocols in human trials (40 min, 4 milliamperes, 7.2 Coulombs) has not 
produced any reports of a Serious Adverse Effect or irreversible injury across over 33, 200 sessions and 
1000 subjects with repeated sessions and including a wide variety of subjects, including persons from 
potentially vulnerable populations (Bickson et al., 2016).  tDCS will be administered with a multichannel 
direct current stimulation device (NeuroConn DC stimulator MC-4, neuroCare). This device can be 
programmed so that the operator doesn’t know the combination of electrodes being used for 
stimulation, and, thereby allow double-blinding. The active tDCS electrode configuration to be used will 
be determined with the 3 round iterative procedure described above; based on electric field modeling 
and personalized electrical dose titration to find the lowest dose that is well-tolerated and engages the 

target in terms of inhibiting the Anxiety Task or AOT pupillary response and pain-induced conditioned 
fear response. Electrical dosage will be personalized for each subject by titrating dosage (gradually 
increasing) until the dosage is found that is both well-tolerated (no more than mild discomfort on a 5-
point Likert scale) and suppresses the pain-induced conditioned fear response. If the 5-point Likert 
tolerability rating is greater than “mild discomfort” or if maximum amperage is reached without effect 
on the conditioned fear response then subject participation will terminate. 
3. 
Anxiety Task: Using the eye-tracking system to track pupil changes, the subject may undergo 
the anxiety task which involves two different epochs: high tone and low tone. Before the anxiety task 
begins, the level of “annoying buzz” will be determined for the subject by the research team, based on 
the verbal responses from the subject. First, a low level “buzz” (set at 5V) will be presented through 
stimulation generated to the index and middle fingers of the subject, using the BIOPAC STM-200 
Stimulator (duration of less than 0.5 seconds) by the researchers. The subject will be asked to report 
on a scale of 0 (not at all annoying) to 10 (extremely annoying), how the stimulus feels. The 
presentation of the “buzz” will increase in increments of 5-10V (with a maximum of 100V) until the 
subject reports a level 7 for highly annoying. The purpose of this “annoying buzz” is to be highly 
annoying, but not to provoke pain. Once this level is set, the anxiety task is initiated during which the 
subject will be seated in a dark room and instructed to focus on crosshairs displayed on a computer 
monitor. The anxiety task consists of two block types: (1) high tone and (2) low tone. Two tones of 
different frequencies (high and low) are played for 5 seconds at a time throughout a trial. Each trial 
lasts 12 minutes and consists of each tone (high and low) played 20 times (totaling to 40 tones at 5 
seconds each). Stimulation will be delivered 50% of the time in association with either the high or low 
tone in a given trial (subject receives stimulation 10 times per trial). At each study visit (up to 3 visits, 
scheduled one week apart) for subjects 1-30, the subject will complete 4-6 trials during which tDCS will 
be administered at gradually increasing electrical doses during 50% of the trials. The other 50% of the 
trials will be administered without tDCS or with sham tDCS to establish the subject's baseline pupil 
response to the anxiety task. Subjects will be given a 5 minute break between each trial. 
4. 
Visual Analogue Scale for Anxiety (VAS-A). The VAS-A is the primary measure of clinical 
symptoms of Acute Fear in both the R21 and R33. It has been used extensively as an indicator of acute 
fear symptoms. It is included because it provides a reliable indicator of rapid changes of affective state. 
VAS-A consists of 11 items for 11 different symptoms (anxious, alert, fearful, relaxed, happy, feel like 
leaving, paralyzed, tense, nervous, irritable and worried) where for each item a mark is made on a 100 
mm line scaled from 0 (not at all) to 100 (the most ever) to indicate symptom severity. Some of the 11 
items from the VAS-A may be used during the anxiety task before, during, or after to measure changes 
in levels of subject anxiety from baseline to post-task administration. 
5. 
Generalized Anxiety Disorder-7 (GAD-7). The 7 item questionnaire may be administered at 
screening visits to identify anxiety state and trait correlations with pupil physiology. 
  
6. 
Beck Anxiety Inventory (BAI). This questionnaire may be administered at screening visits to 
identift anxiety state and trait correlations with pupil physiology. 
7. 
Auditory Oddball Test (AOT): Pupil changes may also be monitored using the eye tracking 
system to two pitches of tones. Some will be high pitched tones and some will be lower pitched tones. 
One of these will occur less frequently than the other. Multiple studies have confirmed that there is a 
neural response from the LC to the less common tones occurring approximately 300 msec after the less 
common tones accompanied by a pupil dilation response. 
8. 
Administration of 7.5% CO2: Inhalation of 7.5% CO2 for 20 min will be carried out and is 
being employed because it elicits a well-documented fear response in healthy controls with good test-
retest reliability/safety and there is evidence that it works via activation of LC. Also, repeated 
inhalations do not increase the risks of experiencing anxiety or having panic attacks. Subjects will be 
instructed to avoid alcohol for 36 h and caffeine for 12 h prior to testing and to eat a light lunch at least 
one hour prior to testing. A urine pregnancy test will be administered to women of childbearing 
potential on both days of gas exposure with a negative result needed in order to continue in study 
participation. Gas will be delivered via a nasal–oral face mask (Hans Rudolph, Kansas) connected via 
tubing to a 100 L reservoir bag filled with 7.5% CO2/21% O2/71.5% N2.  Subjects will receive air 
through the mask in the 10 min prior to CO2 administration during which baseline measures will be 
obtained. In order to minimize risks of CO2 during each 20-min inhalation period, ECG monitoring and 
recording will occur continuously using a 12-lead ECG (Mortara Instruments) and breathing will be 
carefully monitored and recorded using pneumotachograph /integrator and data acquisition systems 
(Hans Rudolph). Breath-by-breath changes in %CO2 will be monitored continuously and recorded using 
a CO2 sensor connected to a data acquisition system (Hans Rudolph, SmartLab unit). EEG or galvanic 
skin conductance measures may also be obtained. Two members of the study team including 1 study 
physician will remain with the participant during inhalations as a safety measure. During gas 
administration and for 1 hour afterwards, subjects will undergo continuous monitoring of vital signs.  

Participants will be able to terminate the inhalations at any point and will remain in the testing room 
until a study physician clears the subject to leave. 
9. 
Galvanic Skin Conductance: Skin conductance responses can change during various levels of 
arousal monitored using a technique called galvanic skin conductance. Conductance values are obtained 
by placing two sticky patches, which are electrodes, on the palms and passing a tiny electrical charge 
between the two electrodes which is painless. Conductance may be measured during the anxiety task 
or CO2 administration. 
10. 
Electrocardiogram (ECG/EKG): Heart rate can change during various levels of arousal as 
measured by a 12-lead ECG system (Mortara Instruments). ECG may be measured during the anxiety 
task or CO2 administration. 
11. 
Electric Field Modeling: Electric field simulation will include segmenting the structural MRI 
scan from a single subject into white matter, cortical matter, cerebrospinal fluid, skull, scalp, eyes, fat, 
muscle and air using Simpleware ScanIP. The volumes defining head tissues and the attached 
electrodes will be meshed into finite elements using the Simpleware module. The electric field will be 
computed using COMSOL simulation software. The electric field will be calculated in the LC and other 
brain regions thought to be relevant to our tDCS effort including prefrontal cortex, limbic system 
structures, and brain stem, which will be segmented using Brain Parser, and manually checked per 
published guidelines. For multielectrode targeting optimization we will first construct a head model with 
a multi-electrode grid. We solve for the component field solutions by sequentially activating individual 
electrodes relative to a reference. We then define a desired field distribution, which takes relatively 
large values near the target (LC), and zero value everywhere else in the brain. 
8.11  INSTRUMENTS: List all questionnaires, surveys, interview, or focus group guides that will be used 
for this study: 
1. Mini-International Neuropsychiatric Interview (MINI). The MINI is a short structured 
diagnostic interview for DSM-IV and ICD-10 psychiatric disorders.  It will be used to screen 
potential subjects for neuropsychiatric disorders and has acceptable reliability and reliability 
when used for this purpose.  
2. Treatment Tolerability Ratings. In order to determine the tolerability of particular tDCS 
electrode placement and electrical stimulus intensities, subjects will rate their discomfort 
immediately after each tDCS stimulus on a 5-point Likert scale that has been widely used to 
assess the tolerability of procedures including colonoscopy, nasogastric tube insertion, burn 
dressing application, and orthodontic procedures. The anchors are: 0=”No Discomfort”, 
1=”Minimal Discomfort”, 2=”Mild Discomfort”, 3=”Moderate Discomfort”, and 4=”Severe 
Discomfort”.   We employ a cutoff of no more 2 as an indicator of acceptable tolerability.  
3. Visual Analogue Scale for Anxiety (VAS-A). The VAS-A is the primary measure of clinical 
symptoms of Acute Fear in both the R21 and R33. It has been used extensively as an indicator of 
acute fear symptoms. It is included because it provides a reliable indicator of rapid changes of 
affective state and is sensitive to the fear-inducing effects of 7.5% CO2 in healthy volunteers. 
VASA consists of 11 items for 11 different symptoms (anxious, alert, fearful, relaxed, happy, feel 
like leaving, paralyzed, tense, nervous, irritable and worried) where for each item a mark is  
made on a 100 mm line scaled from 0 (not at all) to 100 (the most ever) to indicate symptom 
severity. The “Fearful” item will be used as the single primary endpoint due to its being 
consistently significantly increased in prior studies of CO2 administration to healthy controls and 
evidence that anxiolytics can prevent 7.5% CO2 mediated increases in this measure.  The other 
10 VAS-A items will be secondary outcomes.  For each CO2 administration ratings will be carried 
out at baseline (5 min prior to inhalation), and at 5, 10, 15, and 20 minutes into the inhalation 
and 15 minutes after inhalation ends. The peak effect will be obtained immediately after the end 
of the inhalation when the subjects will be asked to retrospectively rate the greatest intensity of 
effects experienced.  A 26% increase in peak effect over baseline on the “fearful” item will be 
utilized as criteria for responding to CO2 challenge as recommended based on prior work which 
suggests that approximately 50% of subjects will meet this criterion.   The VAS-A “fearful” rating 
at 20 minutes from the start of CO2 administration will serve as the primary outcome measure 
with the rating of peak effect being a key secondary outcome. The VAS-A may also be used 
during the anxiety task before, during, or after to measure changes in levels of subject anxiety 
from baseline to post-task administration. 
4. State Trait Anxiety Inventory (STAI). The 20 item STAI will be included as a secondary 
clinical symptoms measure of state anxiety occurring with CO2 administration.  This was 
included because it has well-established psychometric properties and reflects changes in anxiety 
level with CO2 administration in healthy controls and anxiolytic medication attenuated the CO2 
response with this measure.   It consists of 20 items listing feelings and subjects rate their 

current state with respect to those feelings from 1 (not at all) to 4 (very much so).  It will be 
administered just before and just after CO2 administration. 
5. Generalized Anxiety Disorder-7 (GAD-7). The 7 item questionnaire may be administered at 
screening visits to identify anxiety state and trait correlations with pupil physiology. 
6. Beck Anxiety Inventory (BAI). This questionnaire may be administered at screening visits to 
identift anxiety state and trait correlations with pupil physiology. 
7. Adverse Effects (AE) Assessment.  The Systematic Assessment for Treatment Emergent 
Events (SAFTEE) will be used to monitor AEs. It is reliable and valid and used by Dr. Krystal in 
prior studies. 
  
Attach any unpublished instruments in the 'Other Study Documents' 
section of the Initial Review Submission Packet form after completing the 
study application. Published instruments should NOT be attached. 
8.12  * BIOSPECIMEN COLLECTION: Are you drawing any blood or collecting other biosamples (e.g. 
tissue, buccal swabs, urine, saliva, hair, etc.): (REQUIRED) 
 
  Yes    
  No 
8.25  STATISTICAL METHODS: Briefly summarize the methods and types of analyses that will be 
performed: 
All dependent measures will be tested for distribution normality and meeting homogeneity of variance 
requirements for parametric statistics.  Data transformations will be conducted where indicated.  
1. Primary Hypotheses.  
  
R21. Testing R21 hypotheses equates to testing if the “Go-No-Go” criteria for proceeding to the R33 are 
met.   
1) 
Hypothesis 2a: We can identify an electrode configuration for active tDCS that is well-
tolerated (5point Likert scale rating mild discomfort) and significantly suppress the Anxiety Task or 
Auditory Oddball  
Task (AOT) pupil dilation response in 8/10 subjects in the 3rd round of treatment optimization. The  
Anxiety Task or AOT response will be determined using a repeated measures analysis of variance * 
(RMANOVA) with condition (common vs rare) as the independent measure and pupil diameter as the 
dependent repeated measure.   If there is a statistically significant difference between the two 
conditions during treatment it will be assumed that suppression did not occur.   
2) 
Hypothesis 1b: In 10 controls in a cross-over study, 7.5% CO2 inhalation significantly 
increases the VAS-A “fearful” rating compared to baseline rating. This will be tested with a 
RMANOVA where condition (7.5% CO2 vs air) is the independent variable and VAS-A “fearful” rating 
is the repeated dependent measure.    
3) 
Hypothesis 2a, 1b, 1a: In a cross-over study, active dose-personalized tDCS significantly 
suppresses the LC pupil response to 7.5% CO2.  This will be tested by carrying out a RMANOVA 
where treatment (active tDCS vs control) is the independent variable and mean resting pupil 
diameter is the repeated dependent measure.  This will also establish that 7.5% CO2 elicits an LC 
response as measured by mean pupil diameter (Hypothesis 1b) and whether subjects can guess 
whether they received active tDCS or the control to assess the viability of the control treatment 
(Hypothesis 1a).  
4) 
Hypothesis 2b: Active tDCS will be safe in terms of there being no adverse effects of more 
than mild severity and rated to be possibly, probably, or definitely related to treatment.  
  
R33 Testing R33 hypotheses assesses if the criteria for proceeding to further development are met.  
1) Hypothesis 3a:  Dose-personalized tDCS decreases VAS-A “fearful” rating compared to sham in a 
parallel-group, randomized, double-blind study.  This will be determined by computing the effect size 
in terms of Cohen’s D for the tDCS vs control treatment effect on the VAS-A “fearful” rating at the 
expected peak CO2 effect (20 minutes after start of CO2).  
2) Hypothesis 3b:  tDCS is safe as indicated by the absence of adverse effects of more than mild 
severity rated to be possibly, probably, or definitely related to treatment.   
  
Secondary/Exploratory Analyses.  Examples of Exploratory/Secondary analyses of interest include: 1) 
Testing if there are significant differences between active tDCS and the control therapy on the 
pupillary response to CO2 in the R33 study; 2) Evaluating tDCS vs control treatment effect sizes for 

other VAS-A items and the STAI in the R33 study; 3) mapping the time-course of effects on LC post-
tDCS  
8.26  REFERENCES: List only the 5-10 most relevant references (a separate bibliography can be attached 
for reference purposes if this study involves novel approaches, agents, or an emerging technology 
that the IRB may not be familiar with): 
Bailey JE, Argyropoulos SV, Kendrick AH, Nutt DJ. Behavioral and cardiovascular effects of  
7.5% CO2 in human volunteers. Depress Anxiety. 2005;21(1):18-25. PMID: 15782425 
  
Bikson M, Grossman P, Thomas C et al., Safety of Transcranial Direct Current Stimulation: 
Evidence Based Update 2016.  Brain Stimul. 2016 [Epub ahead of print]. 
  
  
Bailey JE, Kendrick A, Diaper A, Potokar JP, Nutt DJ. A validation of the 7.5% CO2 model of 
GAD using paroxetine and lorazepam in healthy volunteers. J Psychopharmacol. 2007 Jan;21 
(1):42-9. 
  
  
Koss M. Pupillary dilation as an index of central nervous system_2-adrenoceptor activiation. J  
Pharmacol  Methods 1986;15:1–19.  
  
Lepine J. The epidemiology of anxiety disorders: prevalence and societal costs. The Journal of  
Clinical Psychiatry 2002;63 Suppl 14: 4–8. 
  
Murphy PR, O'Connell RG, O'Sullivan M, Robertson IH, Balsters JH. Pupil activity covaries with 
BOLD activity in human locus coeruleus. Hum Brain Mapp. 2014 Feb 7.  
  
Nitsche, M. A., Cohen, L. G., Wassermann, E. M., et al. Transcranial direct current stimulation:  
State of the art 2008. Brain Stimul (2008) 1(3):206-23. 
  
Poma SZ, Milleri S, Squassante L, Nucci G, Bani M, Perin  GI, Merlo-Pich E. Characterization of 
a 7% carbon dioxide (CO2) inhalation paradigm to evoke anxiety symptoms in healthy subjects.  
J Psychopharmacol. 2005 Sep;19(5):494-503. PMID: 16166187  
  
Prenoveau JM, Forsyth JP, Kelly MM, Barrios V.  Repeated exposure to 20% CO2 challenge and 
risk for developing panic attacks: a controlled 6 and 12 month follow-up in a non-clinical sample.  
J Anxiety Disord. 2006;20:1158-67.   
  
Redmond DE Jr, Huang YH. Current concepts. II. New evidence for a locus 
coeruleusnorepinephrine connection with anxiety. Life Sci. 1979 Dec 24;25(26):2149-62. PMID: 
120478 
  
Schmitz, A., Grillon, C. Assessing Fear and Anxiety in Humans Using the Threat of Predictable and 
Unpredictable Aversive Events (the NPU-threat test). Nature Protocols. 2012 Feb 23;7(3):52732.  
  
Shannon RV. A model of safe levels for electrical stimulation.  IEEE Trans Biomed Eng. 1992;39 
(4);424-6. 
  
Verburg K, Pols H, de Leeuw M, Griez E (1998) Reliability of the 35% carbon 
dioxide panic provocation challenge. Psych Res 78: 207-214 
  
9.0 Drugs and Devices 
9.1  * DRUGS AND/OR BIOLOGICS: Are you STUDYING any drugs and/or biologics that are either 
approved or unapproved: (REQUIRED) 

 
  Yes    
  No 
Note: This question is frequently answered incorrectly. If any drugs or 
biologics, approved or unapproved, are being administered under this 
protocol, you should check 'Yes' unless you are absolutely sure that NONE 
of the drugs are part of the research protocol. Tip: Ask the PI or the sponsor 
if you are not sure how to answer this question. 
9.3  * MEDICAL DEVICES: Are you STUDYING any medical devices, in vitro diagnostics, or assays that 
are either approved or unapproved:(REQUIRED)  
 
 Yes    
 No 
9.4    * NSR: Are you requesting a Non-Significant Risk (NSR) determination for an investigational 
device:  
(REQUIRED)         Note: an NSR determination is different from an Investigational Device 
Exemption  
(IDE). Check the Help link for more guidance on what types of devices can qualify for an NSR 
determination.    
 
 Yes    
 No 
* Explain why the use of the device in this study poses a non-significant risk: 
(REQUIRED) 
Transcranial Direct Current Stimulation (tDCS) TDCS involves non-invasive 
transcranial electrical stimulation using direct current with a sustained intensity of a 
few milliamperes and duration of up to tens of minutes.  Administered in this way 
tDCS is a safe procecdure (See Bickson et al., 2016 attached). Evidence from relevant 
animal models indicates that brain injury by such Direct Current Stimulation occurs 
at predicted brain current densities (6.3–13 A/m) that are over an order of magnitude 
above those produced by tDCS such as we will administer it (Bickson et al., 2016). 
To date, the use of conventional tDCS protocols in human trials (≤40 min, ≤4 
milliamperes, ≤7.2 Coulombs) has not produced any reports of a Serious Adverse 
Effect or irreversible injury across over 33,200 sessions and 1000 subjects with 
repeated sessions and including a wide variety of subjects, including persons from 
potentially vulnerable populations (Bickson et al., 2016).    The US Food and Drug 
Administration (FDA) considers trials of tDCS as nonsignificantrisk, which means tDCS is without 
reasonable expectation of any Serious Adverse Effect (as de ned here) (Bickson et al., 2016).  As of the 
publishing of the Bickson et al., article, the FDA “MedWatch” database search returns no reports for 
“tDCS” or “transcranial Direct Current Stimulation.”  
Attach any documentation you have from the manufacturer and/or FDA to 
support this determination. 
9.5  LIST THE DEVICES: List the medical devices or in vitro diagnostics to be studied or used. In the 
device details screen you will be asked questions such as:    
Whether the device is FDA approved or investigational 
Medicare device category 
If the device will be provided at no cost 
If an IDE is necessary, the IDE number, and who holds the IDE 
Risk category of the device 
FDA status of the device 
    Please see the UCSF IRB website for more details about the use of devices in research, including 
the Investigator Checklist for Significant Risk, Non-Significant Risk, and/or IDE Exempt Device 
Studies          Verification of IDE numbers: If the sponsor’s protocol does not list the IDE number, you 

must submit documentation from the sponsor or FDA identifying the IDE number for this study. 
Attach this documentation in the Other Study Documents section of the Initial Review Submission 
Packet.           If you have any correspondence from the FDA or sponsor regarding 
this device, please attach it to the application.         
Is this a new  
 
View  
Is the Device FDA  
device or a new  
 
Device Name 
IDE Number 
 
Details 
Approved 
use of an already  
approved device 
NeuroConn DC Stimulator MC- 
No  Yes  
 4  
 
Manufacturer/Supplier of Device 
Rogue Resolutions  
 
Medicare Category 
A 
B 
 
Where will the Devices Be Stored 
Langley Porter Psychiatric Institute  
Will Devices be supplied at no Cost Yes  
 
Is this a HUD (HDE) 
No  
 
HDE Number 
  
 
Is the Device FDA Approved 
No  
Is this a new device or a new use  
Yes  
of an already approved device 
 
Is an IDE necessary 
No   
 
IDE Number 
  
 
Who holds the IDE 
N/A   
 
IDE Details 
  
In the opinion of the sponsor,  
select the level of risk associated  
No Significant Risk  
with this device 
9.6  * Is this an expanded access or compassionate use protocol, meaning the primary purpose is to 
diagnose, monitor or treat a patient's condition, rather than the collection of safety and efficacy 
data of the experimental agent: (REQUIRED)  
 
  Yes    
  No 
10.0 Sample Size and Eligibility Criteria 
10.1  ENROLLMENT TARGET: How many people will you enroll:  
 If there are multiple participant groups, indicate how many people will be in each 
group: 
Participants will be recruited in Dr. Krystal’s laboratory at UCSF. We plan to 
enroll a total of 240 subjects healthy volunteers (age range: 21-65 years) in 
order to complete 100 for the entire effort (R21 and R33 Phases combined). This  
corresponds to enrolling 68 subjects in the R21 (34/year) and 172 (58/year) 
during the R33 phase.  This takes into account the expected rate of failure to: 
have a pupillary response to the Auditory Oddball Test (25%) and CO2 challenge  

(50% - relevant for last 10 R21 and all R33 subjects); and to meet other 
screening criteria (see inclusion and exclusion criteria sections).   These subjects 
will be recruited from the local community using posted flyers. 
10.3  SAMPLE SIZE JUSTIFICATION: Explain how and why the number of people was chosen. For multi-
site studies, this is referring to the number that will be enrolled across all sites: 
Given the nature of the R21/R33, we have few analyses for which consideration of power is  
relevant.  These include the determination of whether there is a statistically significant difference in 
pupil response to the Anxiety Task or the rare and common stimuli in Auditory Oddball Task (AOT) and 
determination of whether in the R21 cross-over study active tDCS has a significantly greater effect on 
the pupil response to CO2 than sham. For the Auditory Oddball Task (AOT), in our pilot work where we 
were able to demonstrate differences between rare and common stimuli and the suppressing effects of 
tDCS (See Preliminary Studies). N=10 subjects in our R21 pilot cross-over study will be sufficient based 
on our pilot work (C.3.5). We estimate that the size of the effect of a dose-personalized, electrode 
configuration optimized tDCS vs control therapy will be at least as large as the effect size we observed 
in our preliminary work with a pilot electrode configuration where we found that in 4/5 subjects we 
could demonstrate a statistically significant suppression of the AOT pupil response compared with no 
stimulation which serves as a pilot proxy for the control therapy.   
10.4  * PARTICIPANT AGE RANGE: Eligible age ranges: (REQUIRED) 

 

Exclusion Criteria. 1) Current or past Axis I DSM-IV disorder based on the MINI; 
2) Current or past history of substance abuse or dependence (excluding 
nicotine) based on history or positive urine toxicology; 3) Current unstable 
medical condition; 4) Any current neurological condition or medical condition 
that is known to affect pupillary function, mood/anxiety, or neurologic function 
generally; 5) Pregnancy based on Urine Pregnancy Test; 6) Women who are 
breast feeding; 7) Use of medications known to affect CNS function within 5 
half-lives screening; 8) Use of magnet controlled or programmed devices such 
as pacemakers, programmable ventriculoperitoneal shunts, or vagal nerve 
stimulators.  
10.9    * RESEARCH CONDUCTED ON PATIENT CARE WARDS: Do any study activities take place on 
patient care units at UCSF medical facilities: (REQUIRED)    
 
  Yes    
  No 
11.0 Recruitment and Consent 
11.1  * RECRUITMENT METHODS: What kinds of methods will be used to identify potential participants 
for recruitment (check all that apply): (REQUIRED) 
Medical records review 
Recruitment registry 
Re-contact of participants from the investigators' previous studies 
Referrals from colleagues (attach the 'Dear Colleague' letter or other recruitment materials you will 
provide to colleagues) 
Referrals from the community / word of mouth 
Advertisements (flyers, brochures, radio or t.v. ads, posting on clinical research sites or social 
media, presentation of the study at community events/media, etc.) 
Online recruiting tool such as TrialSpark 
CTSI Recruitment Services unit 
Other method (describe below) 
Attach your recruitment materials (e.g., flyers, ads, recruitment letter 
templates, email text, etc.) in the Other Study Documents section of the 
Initial Review Submission Packet Form. 
11.3  DETERMINATION OF ELIGIBILITY: How, when, and by whom will eligibility for recruitment be 
determined: 
Flyers are placed around the UCSF campus and on the clinicaltrials.gov providing basic study information 
and eligibility criteria. Potential subjects will contact the study coordinator who will conduct a brief phone 
screen to determine initial eligibility criteria prior to scheduling the in-person screening visit. If the 
subject meets pre-screening criteria, an in-person screening visit will be scheduled at which time the 
subject will undergo screening procedures in Dr. Krystal's laboratory conducted by a study clinician. 
Normal healthy control subjects will be recruited and, following signing of informed consent, screened in 
the laboratory for whether they meet inclusion/exclusion criteria by Dr. Krystal or other study clinician 
and a study coordinator trained by and working under the supervision of Dr. Krystal.  Assessments carried 
out during this visit will include a medical, psychiatric, and medication history, physical examination, 
urine drug screen, pregnancy test, and MINI.  Those meeting entry criteria will then undergo the Anxiety 
Task or Auditory Oddball Task (AOT) administered by Dr. Krystal or the study coordinator.  Those with a 
statistically significantly greater pupil diameter response to the Anxiety Task or the cues for the rare vs 
common stimuli in the AOT will continue in the study and be scheduled for return visits.   
  

Flyers will be placed around the UCSF campus and in non-investigator faculty offices. 
11.4  * INITIATION OF CONTACT: Who initiates contact (check all that apply): (REQUIRED) 
Investigators/study team 
UCSF recruitment unit (e.g. CTSI Consultation Services) 
Potential participant 
Other (explain below) 
11.5  * HOW IS CONTACT INITIATED: (check all that apply): (REQUIRED) 
In person 
Phone 
Letter / email 
Website or app 
Other (explain below) 
Attach the telephone recruitment script in the Other Study Documents 
section of the Initial Review Submission Packet Form. If potential 
participants will initiate contact, attach the telephone screening script that 
will be used to provide more information about the study and determine if 
callers are eligible to participate. 
11.6  RECRUITMENT PLAN: Based on the checkboxes you chose above, please provide a narrative 
describing your recruitment plan. We want to know: 
Who is conducting the search for potential participants, and how? 
How are potential subjects being approached for recruitment? By whom, and when? 
If there will be more than one participant group (e.g. patients, healthy controls, caregivers, 
family members, providers, etc.), provide details about the recruitment plans for each group. 
(Recommended length - 100-250 words) 
Normal healthy control subjects will be recruited from the local community using posted flyers or 
referred by word of mouth, this study is also listed on the clinicaltrials.gov website. Individuals 
responding to the flyers, word of mouth or posting on clinicaltrials.gov website will contact the study 
coordinator and undergo a brief phone screen (phone script attached). The coordinator will schedule 
the subject for the inperson screening visit if they meet basic eligibility criteria. 
  
  
  
11.7  * CONSENT METHODS: How will permission to participate (i.e., informed consent) be obtained 
from each potential participant. If there will be multiple groups and different plans for consenting 
each, check all that apply. See the orange Help bubble to the right for more detailed guidance.   
Participants will (check all that apply): (REQUIRED)  
Sign a consent form at the end of the consent discussion (signed consent) 
Provide online 'eConsent' using DocuSign or another E-Signature system 
Click through a link in a survey or email after reading about the study and then complete the study 
online (electronic consent) 
Be told about the study and be given a handout/information sheet and be asked if they agree to 
participate (verbal consent) 
Complete the study activities and turn in materials, as in the case of a completed survey that is 
placed in a drop box or mailed to the study team (implied consent) 
Not be able to provide consent and will have a family member consent for them, as in the case of a 
critically ill or unconscious patient (surrogate consent) 

Not be able to provide consent (emergency waiver of consent - allowed for minimal risk research or 
greater than minimal risk research with an approved community consultation plan) 
Not know about the study, as in the case of chart reviews or observations of public behavior (waiver 
of consent) 
Other method (describe below) 
Attach your consent form, information sheet, or electronic consent text in 
the Informed Consent Documents section of the Initial Review Submission 
Packet Form. 
11.8  * CONSENT PROCESS: Describe the process for obtaining informed consent, including details such 
as who will have the consent discussion and when participants will be asked to sign the consent 
form in relation to finding out about the study: (REQUIRED)         We encourage researchers to 
review our guidance on obtaining and documenting informed consent.    
If there are multiple groups being consented differently, provide details about the consent 
process for each group. 
If you are relying on verbal or implied consent, provide details about how that will happen. 
For studies using online recruitment and consent or consent via mail, provide details here. 
Written Informed Consent will be obtained from each subject prior to 
enrollment into the study.   The process of informed consent will be carried 
out so as to ensure that potential subjects are properly informed as to the 
purpose of the study and the potential risks and benefits that are known, or 
that can be reasonably predicted or expected.  All potential subjects will first 
have the study described to them verbally.  This will then be followed by 
giving those subjects who remain interested in participating a copy of the 
informed consent document to review.   This will then be followed by an 
opportunity to ask questions and express concerns.  The Investigator will 
retain the original copy of the Informed Consent Form signed by the patient, 
a duplicate will be provided to the patient.  Only the consent form approved 
by the IRB will be used. Potential subjects who do not have the capacity to 
give legally effective consent will not be included in this study.   
* It is important that the people obtaining consent are qualified to do so. Briefly 
describe the training and experience these individuals have in obtaining informed 
consent: (REQUIRED) 
The study coordinator, Blakely Andrews, will obtain informed consent. Blakely Andrews has been 
involved in research for over 10 years and has over 4 years of experience obtaining informed consent. 
The PI may also obtain consent and he has 25 years of experience consenting subjects in clinical 
research studies. 
11.9  * CONSENT COMPREHENSION: Indicate how the study team will assess and enhance the subjects' 
understanding of study procedures, risks, and benefits prior to signing the consent form (check all 
that apply): (REQUIRED)         Tip: Review the Consent Comprehension - Learning Notes in the 
Help bubble at the right for specific questions that can be asked to assess comprehension, 
consider using the UCSF Decision-Making Capacity Assesment Tool, and review our guidance on 
obtaining written or verbal informed consent for more detail on how to conduct the assessment.  
The study team will engage the potential participant in a dialogue, using open-ended questions 
about the nature of the study or the experimental treatment, the risks and benefits of participating, 
and the voluntary nature of participation 
Potential participants will be asked or shown a series of questions to assess their understanding of 
the  

study purpose, procedures, risks and benefits, as well as the voluntary nature of participation 
(especially appropriate when the consent process happens online or through a mobile health app) 
Other method (describe below): 
Provide details of the other approaches that will be used, if using another method 
to assess comprehension: 
11.13  TIME: What is the estimated time commitment for participants (per visit and in total): 
Estimates for the R21 portion of the effort are included here: 
  
For enrolled subjects 1-30, there are up to three total visits each scheduled 1 week apart. Screening 
procedures will take place at the first visit and will be combined with study procedures if the subject 
passes screening. The first visit will take 2 hours and the remaining 2 study visits will take 1.5 hours 
each for a total study committment time of 5 hours. 
  
For the last 10 enrolled subjects, there are four total visits scheduled 1 week apart: Screening + 3 
study visits. Screening will take between 1-1.5 hrs and the remaining 3 study visits will take 2-2.5 hrs 
each for a total study committment time of 7-9 hours. 
IMPORTANT TIP: Ensure this information is consistent with the 
information provided in the consent form. 
12.0 Risks and Benefits 
12.1  RESEARCH-RELATED RISKS: Check if your study involves any of these specific research-related 
risks to participants that may need to be disclosed in the consent form: 
For interventional studies, risk that the regimen may be more harmful or less effective than other 
available interventions 
Risks associated with radiation exposure for imaging studies specifically for research purposes 
Risks associated with the administration of contrast agent for imaging studies 
Risks associated with withholding of treatment or discontinuation of current treatment (e.g., 
washout period is required by the study protocol) 
For randomized, placebo-controlled trials, possible temporary or permanent health consequences 
from the deprivation of effective therapies during the placebo administration period 
For studies involving a sham surgical procedure, the risk that participants may experience increased 
morbidity without the possibility of benefit 
Risks associated with modification or extension of a surgical procedure primarily for research 
purposes  
(e.g. risks associated with prolonging anesthesia, time in the operating room, etc.) 
Risk of pain or physical discomfort caused by the research intervention 
Possible personal discomfort due to sensitive topics (stress, embarassment, trauma) 
12.2  RISKS: Describe any anticipated risks and discomforts not listed above: 
There are no more than minimal medical or psychological risks associated with this research. 
tDCS. Commonly observed adverse effects of tDCS are that skin irritation may occur at the site of the 
tDCS electrodes. tDCS may also cause minor adverse effects such as headache. 
Pupillometry. Pupillometry is a minimal risk procedure and entail wearing eye glasses and potential 
discomfort of wearing the eyeglasses can occur with this procedure. Every effort will be made to 
maintain confidentiality, however this cannot be guaranteed.   
Anxiety Task. Discomfort may be felt when determining the level of the "buzz" stimulus. We will start 
with a low level of "buzz" and step up gradually until the patient reports a level 7 for "annoying". The 
stimulus is meant to be "highly annoying" but not painful. At any time the patient reports pain, we will 

decrease the "buzz" stimuli to the patient's level of comfort, as they self-report "annoying" but not 
"painful" level. The patient may stop at any time or have the stimulus reduced at any time. The number 
of stimulations delivered will be limited to 10 per 12 minute trial (stimulation associated with either the 
high or low tone). Parts of the task may become boring or repetitive. Efforts will be made to limit the 
number of trials administered per visit to minimize subject boredom and discomfort, while ensuring that 
adequate amounts of data are being collected. 
Inhalation of 7.5% CO2. The primary adverse effect of 7.5% CO2 inhalation is the induction of Acute 
Fear which is also the reason that it is being carried out in this study. The fear is generally well-
tolerated and resolves within roughly 10 minutes of the end of inhalation. A small percentage of 
subjects report increased sweating, tremor, tension, and tight muscles during or shortly after inhalation 
which is generally well tolerated. A gradual rise in blood pressure and pulse with a final systolic blood 
pressure rise of approximately 18 points, diastolic blood pressure rise of approximately 3 points, and 
heart rate elevation of approximately 8 points occurs with CO2 gas as compared to when subjects 
received “air” inhalation. In rare circumstances severe anxiety could be elicited. There is no evidence 
that repeated inhalations increases the risks of severe anxiety in response to inhalation testing or in the 
year following the inhalations. Several studies have evaluated the effects of repeated inhalations with 
7.5% CO2 and higher percentages of CO2 and not found evidence that there is an increase in fear 
elicited or an increase in adverse effects with repeated exposures (Poma et al., 2005; Verburg et al., 
1998). In addition, a group of healthy non-anxious subjects undergoing repeated exposure to 20% CO2 
inhalation (N=155) were followed for up to a year and compared to a group of healthy non-anxious 
control subjects who breathed room air (N=56) and there was no evidence that the exposures to 20% 
CO2 increased the risk for anxiety /panic during the year of follow-up (Prenoveau et al., 2006).   
ECG. Skin irritation from the ECG electrode pads or pain when removing the pads is a possible risk. 
12.3   
MINIMIZING RISKS: Describe the steps you have taken to minimize the risks/discomforts to 
subjects. Examples include: 
designing the study to make use of procedures involving less risk when appropriate 
minimizing study procedures by taking advantage of clinical procedures conducted on the 
study participants 
mitigating risks by planning special monitoring or conducting supportive interventions for 
the study having a plan for evaluation and possible referral of subjects who report suicidal 
ideation 
This investigation has been designed to minimize the risks and discomfort incurred by study 
participants. Efforts will be made to reduce inconvenience to participants by scheduling 
assessment and experimental sessions at times that are most convenient to them. There will 
be no inclusion of vulnerable populations in this project (e.g., no children; mentally impaired 
persons; prisoners). To protect women of reproductive potential from risk, pregnant women, 
women who are breast feeding, or those who plan to become pregnant during the study will be 
excluded from study enrollment. For women of childbearing potential, a urine pregnancy test 
will be conducted, and must be negative before their entry into this study. If sexually active, 
women must agree to use appropriate contraceptive measures for the duration of the study. 
Medically acceptable contraceptives include: (1) surgical sterilization, (2) approved hormonal 
contraceptives  
(such as birth control pills, Depo-Provera, or Lupron Depot) in combination with a barrier 
method,  
(3) barrier methods (such as a condom or diaphragm) used with a spermicide, or (4) an 
intrauterine device (IUD). Women participants will be instructed to inform their study doctor 
immediately if they become pregnant during the study at which point participation in the study 
will end. The study doctor will then track the pregnancy and report the outcome to the  
Institutional Review Board (IRB). Adverse events will be monitored at each experimental 
session and standard procedures will be followed whenever an adverse event is recorded. In 
the event that a participant finds the screening interviews and questionnaires disturbing, the PI 
will be available to speak with the participant. The Study Coordinators will be trained by the 
site PI to handle personal material with confidentiality and sensitivity. 
  
tDCS.  Multiple steps will be taken to decrease the risks of tDCS.  This includes using an 
electrical dose titration procedure with ongoing adverse event assessment and subject self-
rating of discomfort which will guide whether dose increases occur in order to minimize 
discomfort and risk.   This will also allow us to meet a goal of administering a dosage that is 
the minimum electrical dosage that engages our target to minimize risk.  Also, because the 

risks of tDCS which we propose to administer are not well characterized we plan to administer 
treatment for relatively brief periods (up to 10 minute stimulation sessions) and not administer 
treatments that have an impact on our target neural circuitry as indicated by pupillometry 
more frequently than weekly. Further, we may monitor ECG and breathing throughout and 
after all tDCS treatments to further minimize risks. Subjects will also be instructed to indicate if 
they have pain or discomfort and treatment will be stopped immediately if requested by a 
subject.  Also, electrode sites will be checked for any skin abrasions prior to each treatment, as 
the presence of these increases the risk of skin burns. Treatment is not given if there are skin 
abrasions at the electrode sites. We will also carefully monitor subjects for adverse events after 
every stimulation with the SAFTEE tool and specifically ask them about the presence of the 
following side effects: itchiness, dizziness, lightheadedness, blurred vision, or headache. If any 
of these are answered positively, the duration of the symptom/s will be monitored and if it 
does not dissipate within an hour, which is typical of of the symptom/s will be monitored and if 
it does not dissipate within an hour, which is typical of tDCS, the participant will be assessed 
by a medical practitioner and appropriate care provided. 
  
 Pupillometry.  In order to minimize risks of pupillometry, sessions will be kept as short as 
possible and there will be a study physician with all subjects during the procedure.  Subjects 
will be assessed for adverse events and if they are detected, appropriate care will be made 
available.  
  
 7.5% CO2 Administration. In order to minimize risks of CO2 during each 20-min inhalation 
period, ECG monitoring and recording will occur continuously using a 12-lead ECG (Mortara 
Instruments) and breathing will be carefully monitored and recorded using pneumotachograph 
/integrator and data acquisition systems (Hans Rudolph). Skin conductance measures and 
breathby-breath changes in %CO2 will be monitored continuously and recorded using a CO2 
sensor connected to a data acquisition system (Hans Rudolph, SmartLab unit). Further, two 
members of the study team including 1 study physician will remain with the participant 
constantly during inhalations as a safety measure. Participants will be able to terminate the 
inhalations at any point and will remain in the testing room until a study physician determines 
that it is appropriate for them to leave based on an examination.  If adverse events are 
detected, appropriate care will be made available.  
  
Anxiety Task. Efforts will be made to limit the number of trials administered per visit to 
minimize subject boredom and discomfort, while ensuring that adequate amounts of data are 
being collected. The subjects will be allowed rest periods between trials to minimize fatigue, 
they may also elect to terminate testing at any time. Comfort level for the irritating stimulus is 
determined prior to testing and set for each individual at their own comfort level. Before the 
anxiety task begins, the level of “annoying buzz” will be determined for the subject based on 
their verbal responses. First, a low level “buzz” (set at 5V) will be presented through 
stimulation generated to the ring and pinky fingers of the subject, using the BIOPAC STM-200 
Stimulator (duration of less than 0.5 seconds) by the researchers. The subject will be asked to 
report on a scale of 0 (not at all annoying) to 10 (extremely annoying), how the stimulus feels. 
The presentation of the “buzz” will increase in increments of 5-10V (with a maximum of 100V) 
until the subject reports a level 7 for annoying. The purpose of this “annoying buzz” is to be 
highly annoying, but not to provoke pain. When the subject states the stimulus feels at a level 
“7” for highly annoying, the “buzz” settings will be set at this voltage. 
Protection of Confidentiality will be accomplished by assigning each participant a distinct 
research code number and using this code number rather than the person’s name on all 
documents and electronic data acquired from that individual. Data acquired from all 
participants will be kept in locked files at the study site and only this project’s staff will have 
access to these files. When data are analyzed the data sets will include only participants’ 
research code numbers as identifiers. No names or other unique identifiers will be included in 
any of the data sets used in the planned analyses of this project. 
12.4  RESOURCES: Describe the resources in place to conduct this study in a way that assures protection 
of the rights and welfare of participants:   These resources typically include appropriately trained 
and qualified personnel (in terms availability, number, expertise and experience), funding, space, 
equipment, and time to devote to study activities.   Depending on the nature of the research 
study, investigators should consider the proximity or availability of critical resources that may be 
essential to the safety and welfare of participants, such as 
the proximity of an emergency facility for care of participant injury 
availability of psychological support after participation resources for 
participant communication, such as language translation services 

  Resources in place to conduct this study in a way that assures the protection of the rights and welfare 
of participants include:  
1) all personnel involved in the study, which include the PI, Study Coordinators and Study Clinciians will 
all be appropriately trained and qualified.  The PI has extensive experience as a PI of clinical 
research studies including studies involving tDCS and other brain stimulation modalities.  He also has 
extensive experience training Study Physicians and Project Coordinators who have safely and 
effectively completed research projects; 
2) Adequate funding from NIMH is available for completion of the study 
3) Sufficient space for the successful completion of the study is available for carrying out the study at 
Langley Porter Psychiatric Institute 
4) The necessary equipment is available for successful completion of the study 
5) The PI, Study Coordinator, and Study Clinicians have the time available to successfully complete this 
study 
  
12.5  * BENEFITS: (REQUIRED) Note: These are the benefits that the IRB will consider during their 
review.  
They are not necessarily appropriate to include in the consent form. 
Possible immediate and/or direct benefits to participants and society at large 
(check all that apply): 
Positive health outcome (e.g. improvement of condition, relief of pain, increased mobility, etc.) 
Closer follow-up than standard care may lead to improved outcomes or patient engagement 
Health and lifestyle changes may occur as a result of participation 
Knowledge may be gained about their health and health conditions 
Feeling of contribution to knowledge in the health or social sciences field 
The research presents a reasonable opportunity to further the understanding, prevention, or 
alleviation of a serious problem affecting the health or welfare of children 
Other benefit (describe below) 
None 
12.6  RISK TO BENEFIT RATIO: Explain why the risks to subjects are reasonable in relation to 
anticipated benefits, if any, to the participant or society: 
  Acute fear occurs with many of the anxiety disorders when affected patients are exposed (including 
imagining or remembering) to fear evocative stimuli, such as to the object of their phobia, a trauma 
reminder etc.  Although epidemiologic data do not exist specifically for Acute Fear, it can be assumed 
that it is an extremely widespread problem as anxiety-related disorders are the most prevalent class 
of psychiatric conditions, affecting approximately 18% of adults. Despite the existence of non-
medication therapies and pharmacotherapy for addressing this problem many individuals fail to 
respond to treatment.  Further, no treatments exist that have been developed specifically to address 
Acute  
Fear.  Accomplishing the aims of this proposal will advance our understanding of the mechanisms of 
Acute Fear and represents a step towards developing a treatment specifically for this common condition 
which has the potential to improve the lives of many individuals who suffer from this type of difficulty.   
These benefits to society outweigh the risks of the study outlined in the previous sections and taking 
into account the steps being taken to minimize those risks.  
  
13.0  
Data and Safety Monitoring Plan 
13.2  * DATA AND SAFETY MONITORING PLAN: (REQUIRED) 
All greater than minimal risk studies are required to provide a plan. Lack 
of an adequate plan is one of the most common reasons why IRB approval 
is delayed. 
  

Instructions: 
Describe the plan for monitoring data quality and participant safety. Key areas that 
should be included in the plan are: 
An explanation of the plan to monitor data collection, study progress, and 
safety 
A description of who will perform the monitoring and at what frequency (e.g., 
the PI only, a contract research organization, a Data and Safety Monitoring  
Board or Data Monitoring Committee, etc.) 
The type of data and events that will be reviewed (e.g., adverse events, 
breaches of confidentiality, unanticipated problems involving risk to 
participants or others, unblinded efficacy data, etc.) 
Procedures and timeline for communicating monitoring results to the UCSF  
IRB, the study sponsor, and other appropriate entities 
Assurance that the research team will adhere to the UCSF IRB reporting 
requirements 
As appropriate: 
A plan for conducting and reporting interim analysis 
Clearly defined stopping rules 
Clearly defined rules for withdrawing participants from study interventions 
   Because of the novel nature of the proposed work and that the adverse effects profile of the form of 
tDCS we propose to study is not well-documented, we have set up a Data and Safety Monitoring Board 
(DSMB) for both the R21 and R33 phases of the proposed effort.  The individuals who serve on the 
DSMB were chosen in conjunction with NIH Program staff and have extensive experience conducting 
clinical trials and are highly familiar with the proposed methodology.  The DSMB will convene every 6 
months to review ongoing study procedures, discuss AEs and other safety issues, and to evaluate 
ongoing methods for maintaining data integrity and confidentiality.  They will be provided with a 
summary of all AEs, outcome data, progress data and subject ratings of treatment tolerability prior to 
each meeting.  They will play a critical role in working with the PI and NIH Program to assess whether 
the “Go-No-Go” criteria are met for proceeding to the R33 phase.  If a decision is made to proceed, 
they will then monitor the R33 study. Should the DSMB members develop any 
concerns on the basis of information provided to them by the PI, they may request to examine hard or 
electronic copies of the participants’ research records or other information.  In transferring information 
to the DSMB participants’ identities will be protected by transferring only data that are de-identified 
(hard copies) and/or encrypted (electronic data). In considering the frequency of meetings, we have 
tried to strike a proper balance between maintaining participant safety and the integrity of the study, 
and the consequent time and workload. Traditionally, DSMBs convene once a year. However, given the 
novel nature of this trial and that the risks of the form of tDCS we are administering are not well 
documented it was felt that every 6 month meetings were appropriate. After each meeting the DSMB 
will compile the information gained from the monitoring activities and subsequently prepare a report 
summarizing findings.   Also included in the report is their recommendation to continue or discontinue 
the study.   This report is completed and delivered to the NIH and the PI. If the DSMB concludes that 
the study should be terminated, this opinion will be conveyed to the UCSF business officials as well in 
the case of this latter type of recommendation.  Subsequently the PIs, appropriate business officials at 
UCSF, and NIH Program will likely discuss the matter further before a final decision regarding study 
termination is made.  
  
Local Monitoring of Subjects, Rules for Withdrawing Participants from Study Interventions, and Safety Stopping Rule: All 
subjects who undergo tDCS treatments will be carefully monitored locally by one of the study physicians.  A study physician will 
be in the room with all subjects when any study procedures are carried out.   There will be close monitoring of the tolerability of 
each of the tDCS electrode configurations studied.  In order to determine the tolerability of particular tDCS electrode placement 
and electrical stimulus intensities, subjects will rate their discomfort immediately after each tDCS stimulus on a 5-point Likert 
scale that has been widely used to assess the tolerability of procedures including colonscopy, nasogastric tube insertion, burn 
dressing application, and orthodontic procedures. The anchors are: 0=”No Discomfort”, 1=”Minimal Discomfort”, 2=”Mild 
Discomfort”, 3=” Moderate Discomfort”, and 4=”Severe Discomfort”.   We employ a cutoff of no more 2 as an indicator of 
acceptable tolerability.  We will employ the following stopping rule for each tDCS configuration test: "If any tDCS electrode 
configuration is rated at 3 or higher by 3 subjects, all testing with that electrode configuration will cease."   In addition, if there is 
an SAE consisting of the development of new neuropsychiatric symptoms, the study will be halted until the cause of the symptoms 
is ruled not to be due to the study and, if such an event is determined to be related to the study, the study will not be restarted until 
modifications to the study methods are made that reduce the risk of such an event recurring based on a review and approval by the 
DSMB.    Any subject who rates tolerability as 3 or greater for any electrode configuration will be withdrawn from further 
participation.  Subjects will be informed that, at any time, they may request to the study physician that study procedures stop and 
this will occur.  This includes that they will specifically be told that they should indicate if they would like tDCS stimulation to 

stop during stimulation and it will cease and that they should indicate if they would like to stop CO2 inhalation during the CO2 
inhalation procedure and that procedure will immediately be terminated.   
  
Plan for Conducting and Reporting Interim Analysis and Stopping Rule 
The study structure is such that there will be 4 cohorts of subjects each consisting of 10 subjects.  Each of the first 3 cohorts will be 
stimulated with a different tDCS electrode configuration to determine if we can find one which is tolerable and inhibits locus 
coeruleus activity (as indicated by inhibition of a pupil dilatory response).   After each cohort we will carry out an interim analysis 
to determine if this was the case (80% had tolerability ratings of 2 or less and there was statistically significant inhibition of the 
pupillary response to the anxiety task or auditory oddball task).  Each of these interim analyses will be reported to the DSMB.   If 
after the 3 cohorts are completed and if none of the 3 tDCS configurations tested meet the success criteria, then the study will 
cease.  If one of the tDCS configurations meets the success criteria then an additional 10 subjects will be run using the successful 
tDCS configuration and using 7.5% CO2 instead of the anxiety task or auditory oddball test to elicit a pupillary response.  
  
13.3  * DATA AND SAFETY MONITORING BOARD (DSMB): Will a Data and Safety Monitoring Board 
(DSMB) be established: (REQUIRED) 
Yes  
No  
13.4  DSMB DETAILS: Provide details from the DSMB's charter, including meeting frequency, and 
affiliations and qualifications of members:   If the DSMB has not yet been established, submit 
these details to us as they become available. 
The DSMB will convene every 6 months to review ongoing study procedures, discuss AEs and other 
safety issues, and to evaluate ongoing methods for maintaining data integrity and confidentiality.  They 
will be provided with a summary of all AEs, outcome data, progress data and subject ratings of 
treatment tolerability prior to each meeting.   In transferring information to the DSMB participants’ 
identities will be protected by transferring only data that are de-identified (hard copies) and/or 
encrypted (electronic data).  After each meeting the DSMB will compile the information gained from the 
monitoring activities and subsequently prepare a report summarizing findings.   Also included in the 
report is their recommendation to continue or discontinue the study.  This report is completed and 
delivered to the NIH and PI. If the DSMB concludes that the study should be terminated, this opinion 
will be conveyed to the UCSF business officials as well. In the case of this latter type of 
recommendation.  Subsequently the PIs, appropriate business officials at UCSF, and NIH Program will 
likely discuss the matter further before a final decision regarding study termination is made.   The 
members of the DSMB are: William McDonald MD (Chairman), Professor of Psychiatry, Emory University 
who has extensive experience in carrying out research studies involving BrainStimulation therapies; 
William Coryell, MD, Professor of Psychiatry University of Iowa who has extensive experience in 
carrying out studies employing pupillometry in assessing psychiatric disorders; and Doug Case, Ph.D., 
Professor of Biostatistics at Wake Forest University who has extensive experience in Biostatistics.  
14.0 Confidentiality, Privacy, and Data Security 
14.1  PROTECTING PRIVACY: Indicate how subject privacy will be protected: 
Conduct conversations about the research in a private room 
Ask the subject how they wish to be communicated with – what phone numbers can be called, can 
messages be left, can they receive mail about the study at home, etc. 
Take special measures to ensure that data collected about sensitive issues do not get added to 
their medical records or shared with others without the subject’s permission Other methods 
(describe below) 
14.2  SENSITIVE DATA: Do any of the instruments ask about illegal or stigmatized behavior: 
 
 Yes    
 No 
IMPORTANT NOTE: Indicate in the consent form what kinds of sensitive 
information will be collected. 
14.3  CONSEQUENCES OF A LOSS OF PRIVACY OR CONFIDENTIALITY: Could a breach of privacy or 
confidentiality  result in any significant consequences to participants, such as criminal or civil 

liability, loss of state or federal benefits, or be damaging to the participant's financial standing, 
employability, or reputation: 
 
  Yes    
  No 
14.4  EXTRA CONFIDENTIALITY MEASURES: Explain any extra steps that will be taken to assure 
confidentiality and protect identifiable information from improper use and disclosure, if any: 
14.5  * REPORTABILITY: Do you anticipate that this study may collect information that State or Federal 
law requires to be reported to other officials, such as elder abuse, child abuse, or threat to self or 
others: (REQUIRED) 
 
  Yes    
  No 

 

 

15.1  * PAYMENT: Will subjects be paid for participation, reimbursed for time or expenses, or receive 
any other kind of compensation: (REQUIRED) 
 
 Yes    
 No 
15.2  PAYMENT METHODS: Subjects payment or compensation method (check all that apply): 
Payments will be (check all that apply): 
Cash 
Check 
Gift card 
Debit card 
UCSF Research Subject Payment Card 
Reimbursement for parking and other expenses 
Other: 
15.3  PAYMENT SCHEDULE: Describe the schedule and amounts of payments, including the total subjects 
can receive for completing the study:  
If there are multiple visits over time, explain how payments will be prorated for partial 
completion 
If deviating from recommendations in Subject Payment Guidelines, include specific 
justification below 
Participants will be provided monetary compensation to cover the time and effort they will invest 
completing the various study procedures. All but the last 10 subjects will receive up to $150 for 
completing the study which involves a screening session plus two visits.  The last 10 subjects will 
receive $200 for completing the study, which involves a screening session plus three visits ($50 per 
visit) where tDCS will take place.  
15.4  COSTS TO SUBJECTS: Will subjects or their insurance be charged for any study activities: 
 
  Yes    
  No 
16.0 Qualifications of Key Study Personnel 
16.1             NOTE: This information is required and your application will be 
considered incomplete without it. If this study involves invasive or risky 
procedures, or procedures requiring special training or certification, please 
identify who will be conducting these procedures and provide details about 
their qualifications and training. Also identify each person who will be 
involved in the consent process. Click the orange question mark for more 
information and examples.    Under qualifications, please include:    
Academic Title 
Institutional Affiliation (UCSF, SFGH, VAMC, etc.) 
Department 
Certifications 
             November, 2015 - NEW Definition of Key Study Personnel and  
CITI Training Requirements:       
  UCSF Key Study Personnel include the Principal Investigator, other 
investigators and research personnel who are directly involved in conducting 
research with study participants or who are directly involved in using study 

participants’ identifiable private information during the course of the research. 
Key Personnel also include faculty mentors/advisors who provide direct 
oversight to Postdoctoral Fellows, Residents and Clinical Fellows serving as PI 
on the IRB application.         The IRB requires that all Key Study Personnel 
complete Human Subjects Protection Training through CITI prior to approval of 
a new study, or a modification in which KSP are being added. More information 
on the CITI training requirement can be found on our website.             
Description of Study 
Responsibilities - Briefly 
describe what will each person 
be doing on the study. If there  
Qualifications, Licensure, and  
 
KSP Name 
are procedures requiring special  
Training 
expertise or certification, 
identify who will be carrying 
these out. Also identify who 
will be obtaining informed 
consent. 
Dr. Krystal, Andrew MD 
Dr. Krystal will be responsible  
for overseeing all aspects of 
the proposed study. This 
includes training all personnel 
who will be involved in the 
study. Dr. Krystal will train 
and oversee the Project 
Coordinator who will along 
with Dr. Krystal will be 
obtaining informed consent. 
Ray and Dagmar Dolby  
Distinguished Professor of  
Psychiatry 
Executive Vice Chairman of  
Psychiatry for Langley Porter  
Psychiatric Institute 
(Research) 
Department of Psychiatry 
UCSF 
Board Certified in Psychiatry,  
Sleep Medicine, EEG and 
Clinical Neurophysiology  
He has more than 25 years of 
experience being the PI of 
clinical research studies.  
Andrews, Katherine B 
K. Blakely Andrews is the study Blakely Andrews has 
coordinator and responsible for completed her study 
oversight, protocol 
BA and has served as a 
management, screening research 
/eligibility study coordinator for over determination, obtaining 
three 
consent, 
years with experience in and data collection.
 
performing 
informed consent and 
carrying out study 
procedures. Training in 
informed consent specifically 
for this 
study and in study procedures  
will 

be performed prior to study 
initiation. 
Dr. Seritan, Andreea L MD, MD 
Dr. Seritan may be present  
Dr. Seritan is a licensed 
during study visits serving as  
psychiatrist. a study 
clinician. 
Marton, Tobias F, MD/PhD 
Dr. Marton may be present  
Dr. Marton is a licensed  
during study visits serving as  
psychiatrist and possesses a a 
study clinician. PhD in Neuroscience. 
Dr. Scangos, Katherine MDPhD 
Dr. Scangos may be present  
during study visits to observe 
or assist with clinical 
evaluations. 
Dr. Scangos is a licensed physician. 
Dr. Lee, Andrew MD PhD 
Andrew (Moses) Lee may be  
present during study visits to 
run the tasks or assist with 
setup on subjects. He may 
also conduct data analysis. 
Dr. Lee is a resident in 
the  
Psychiatry department 
at UCSF. 
17.0 Other Approvals and Registrations 
17.1  * ADMINISTRATION OF RECOMBINANT DNA: Does this study involve administration of vaccines 
produced using recombinant DNA technologies to human subjects (Help Link added Aug '15): 
(REQUIRED) 
 
  Yes    
  No 
17.2  * HUMAN GENE TRANSFER: Does this study involve human gene transfer (NOTE: Requires NIH  
Recombinant DNA Advisory Committee (RAC) review prior to IRB approval): (REQUIRED)  
 
  Yes    
  No 
17.4  OTHER APPROVALS: Indicate if this study involves other regulated materials and requires 
approval and/or authorization from the following regulatory committees: 
Institutional Biological Safety Committee (IBC) 
Specify BUA #: 
Institutional Animal Care and Use Committee (IACUC) 
Specify IACUC #: 
Controlled Substances 
18.0 End of Study Application 
18.1  End of Study Application Form 
           To continue working on the Study 
Application: Click on the section you need to edit in the left-hand menu. Remember to save 
through the entire Study Application after making changes.         If you are done working on 
the Study Application:          
Important: Before proceeding, please go back to Section 4.0 
Initial Screening Questions and Save and Continue through the form to make sure all the 
relevant sections and questions have been included. If you've changed any answers since 

you started, the branching may have changed. Your application will be incomplete and it will 
have to be returned for corrections.          Once you are sure the form is complete, click  
Save and Continue. If this is a new study, you will automatically enter the Initial Review 
Submission Packet form, where you can attach consent forms or other study documents.  
Review the Initial Review Submission Checklist for a list of required attachments.            
Answer all questions and attach all required documents to speed up your approval.         
                             
The UCSF IRB wants your feedback about this new form. Please click 
the link to take a brief survey about the new application form.