Effect of tDCS Timing on Safety Memory in PTSD
Phase: NA
Conditions: PTSD
Sponsor: Butler Hospital

COVER PAGE – STUDY PROTOCOL 
 
Title: Effect of tDCS Timing on Safety Memory in PTSD 
NCT number: NCT04152772 
Document date: 12/07/2023 

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Local IRB # 1901-002            IRBNet # 1346426 
BUTLER HOSPITAL 
INSTITUTIONAL REVIEW BOARD 
PROTOCOL 
1.) Project 
 
Title of Project: ____Effect of tDCS timing on safety memory in PTSD__________________________________________ 
Principal Investigator (PI):   
Mascha van ‘t Wout-Frank, PhD 
 
 
 
______ 
Other Investigator(s):   
 
 Noah Philip, MD; Nicole McLaughlin___________________________________  
Revision History: 
Version Number 
Version Date 
Summary of Revisions 
1.0 
11/03/2018 
First version 
2.0 
05/31/2019 
1.Will enroll participants who have completed testing day 1 at the Providence 
VA Medical Center (PVAMC) to complete study visits 2-5. 
2.Added a fear renewal phase to experimental procedures on study visit 5. 
3.Update recruitment language after Butler Hospital marketing . 
4.Addition of REDCap for the randomization of participants, and collection 
and storage of data. 
3.0 
10/25/2019 
1.Update/broaden recruitment locations to include public areas in the 
greater Providence community as well as the Providence VA Medical Center  
(PVAMC).  
2.Update language of recruitment materials to be distributed at the PVAMC.  
3.Update the tDCS safety screening form to include screening for scalp 
conditions or damaged skin on the head, as well as obtain info on use of 
hormonal contraceptives and clarify questions related to neurological 
conditions. 
4.0 
03/02/2020 
1.Removed references to study protocol occurring at the Providence VA 
Medical Center (PVAMC) or PVAMC recruited participant’s having a different 
study procedure.  
2.Removed time constraint between Visits 1 and 3. 
3.Removed flyer text from protocol appendix. 
4.Updated recruitment materials to be distributed at the PVAMC and VA 
associated locations; changes include a new photo, new language, moving 
the disclaimer location, and making the project title more prominent. 
5.0 
03/16/2020 
1.Including the option to conduct baseline procedures remotely via 
phone/HIPAA compliant video conferencing. 
2.Will allow for verbal consent for the use of e-mail to be obtained. 
3.Will allow for participants to electronically provide consent. 
4.Will allow for participants to electronically sign CNE paperwork. 
5.Will allow research staff to send REDCap survey links to participants via 
email. 
6.Updated the data storage options for PHI. 
6.0 
03/20/2020 
Will allow researchers to collect additional information needed for 
participant safety during remote baselines. 
7.0 
07/08/2020 
1.Added language to allow for flexibility of MRI scan on Day 2.  
2.Added COVID-19 Specific Precautions.  
3.Updated protocol language to account for flexibility in study location 
(Brown MRF and Butler Hospital.)  
4.Updated electrode placements to reflect current transcranial direct current 
montage (tDCS).  
5.Updated protocol to make Day 2 and Day 5 MRI supplemental rather than 
required for completion of study protocol.  
6.Updated compensation to account for the optionality of the Day 2 and Day 
5 MRI scans.  

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7.Updated protocol to include potential risks of discomfort associated with 
participants being asked to wear a face mask. 
8.Updated tDCS safety measures to account for tDCS procedures occurring at 
Butler Hospital.   
9.Updated monitoring options during tDCS administration to continuously 
observe participants.  
10.Updated online advertisement text to reflect new flexibility with Day 2 
and Day 5 MRI. 
8.0 
08/25/2020 
1.Updated recruitment methods and PHI Waiver to allow research staff to 
perform targeted recruiting via review of Butler Hospital medical records 
related to Partial Hospital Programs. 
2.Submission of outreach handout to provide to potentially eligible 
participants. 
3.Addition of a sub-study to allow data collection on the online, panel-based 
platform called Prolific in response to ongoing SARS-CoV-2 pandemic. This 
sub-study will involve the administration of questionnaires pertaining to 
symptoms of posttraumatic stress disorder, anxiety, and depression as well 
as experimental tasks assessing contextual processing.  
4.Updated protocol to reflect current data storage locations. 
9.0 
09/08/2020 
Updated recruitment language for online advertisement text to allow for two 
options for describing compensation. 
10.0 
05/12/2021 
Minor increase in participant remuneration for taking part in the study. 
11.0 
05/28/2021 
1.Updated language to account for visits not occurring in the real or 
simulation scanner.  
2.Updated transcranial direct current stimulation language to match current 
procedures.  
3.Updated consent procedure language to remove qualifier that the consent 
process will be administered in person, allowing for remote consenting.  
4.Will allow for study staff, not just primary investigator, to debrief 
participants. 
12.0 
10/05/2021 
Allow for text messaging. 
13.0 
07/07/2022 
Human subject participant population to be increased from a sample of 90 
participants to a sample of 150 participants who complete all study 
procedures. The original protocol allows for 108 participants to be collected 
to account for a 20% attrition rate. Therefore, to accommodate that rate, 180 
participants will be recruited for a sample of 150 who complete the study 
tasks to be included in the final analyses. 
14.0 
11/15/2022 
1.Clarify use of scripts and services for the online study, i.e., the use of 
Pavlovia to run experiments programmed in PsychoPy online, and the use of 
Qualtrics (Brown-license) for data collection. Psychopy collects a date-of-
completion time stamp, which is considered a HIPAA identifier.  
2. Limit age (in years) of online study participants to 89 to avoid data 
collection of age being a HIPAA identifier. 
3.Update the Online Study Consent to reflect the possibility of collecting 
identifiable data. 
4.Correct the CNE Research Application to reflect previously obtained 
approval for the total number of participants, i.e., we updated the “summary 
portion” of the application (which still read 90 participants) and the 
“Anticipated number of records” (which still read 150) to reflect approved 
number of 150 participants for the main study and 500 participants for the 
online study as is correctly stated in the “Proposed number of subjects to be 
enrolled at this site”.  
5.Update CNE Research Sponsor from Dr. Garnaat to Dr. McLaughlin. 
15.0 
12/15/2022 
Changes made to the protocol following full board review for continuing 
review. 

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16.0 
12/07/2023 
Changes made to Aim 4 Sub-Study 
 
 
 
                              
2.) Description of Study 
A.  Specific Aims   
Aim1: Determine the temporal effects of tDCS in relation to extinction processes on extinction retention. 
Prediction: Anodal tDCS targeting VMPFC immediately following extinction learning will improve 
extinction retention 24 hours later, compared to tDCS during extinction learning and sham stimulation. 
Approach: Using a standardized Pavlovian fear conditioning paradigm, 150 participants with a diagnosis 
of PTSD will be randomized to receive either 1) anodal tDCS targeting the VMPFC during extinction 
learning, 2) similar tDCS immediately after extinction learning, or 3) sham stimulation. Extinction 
learning and subsequent extinction retention will be quantified by psychophysiological arousal, i.e. skin 
conductance responses. 
 
Aim 2: Define temporal tDCS effects on VMPFC activity and psychophysiology during extinction retention. 
Prediction: Compared to sham and tDCS during extinction, anodal tDCS after extinction will result in 
greater VMPFC activation during retention and correlate with associated psychophysiology. Approach: 
Participants will undergo fMRI during extinction retention. Imaging analyses will be used to compare 
groups based on VMPFC activity during extinction retention and its relationship to skin conductance 
responses. 
 
Exploratory Aim 3: Evaluate whether VMPFC connectivity predicts extinction retention after tDCS. 
Prediction: VMPFC to amygdala and hippocampus resting state connectivity will predict extinction 
retention success, most prominently for participants who received active tDCS after extinction learning. 
Approach: Participants will undergo resting state functional connectivity MRI prior to fear conditioning 
procedures. Imaging analyses will be used to compare groups based on VMPFC to amygdala and 
hippocampus functional connectivity. 
 
Aim 4 – Sub-study (online): Evaluate the impact of posttraumatic stress symptoms on contextual 
processing. The objective of this sub-study (“Learning and Memory in Virtual Rooms”) is to test 
performance differences between configural and elemental contextual processing in individuals across 
the PTSD spectrum using an online, panel-based platform, e.g., Prolific (https://www.prolific.co/). 
Context plays a vital role in safety learning; whereas fear generalizes easily across contexts, learning that 
situations no longer need to be feared and are in fact “safe” is context-bound with limited generalization 
(Bouton & Bolles, 1979). Deficits in contextual processing are well-recognized in PTSD (Garfinkel et al., 
2014; Liberzon et al., 2016). As such, difficulties in the recall of safety memories might not be a safety 
learning or memory problem, but a contextual processing problem instead. Recent research proposes that 
PTSD may be related to deficits in configural processing specifically, while other context-based 
association learning, such as elemental processing, may be spared (Stout et al., 2018). Collected data from 
the study will be used for further task development to design an informed research approach that allows 
the integration of non-invasive brain stimulation techniques. Protocol details for this sub-study are 
described below (starting on page 15); this sub-study has a separate consent form. 
 
B.  Background  
Posttraumatic stress disorder (PTSD) is a common psychiatric disorder that occurs after exposure to a 
traumatic event, and is characterized by arousal symptoms, re-experiencing, avoidance, negative 
cognitions, and mood. PTSD is associated with significant psychiatric and medical comorbidity and health 
care utilization (1)(2)(3), and poor quality of life (4). Up to 7% of the U.S. population experiences PTSD 
over their lifetime (5) and PTSD occurs in up to 70% in specific samples of military Veterans (1, 6-7). Yet, 
even the most effective treatment options are often followed by relapse. Therefore, there is a pressing 
need to identify novel and more effective PTSD treatment options.  

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At its core, PTSD reflects a maladaptive fear response (8, 9), in which patients repeatedly and 
erroneously continue to respond to situations or events that – consciously or not – remind them of the 
trauma as “dangerous”. Exposure-based psychotherapy aims to help patients learn that the hazardous 
experience (i.e., the cause of their PTSD) is no longer present or threatening in their current environment 
(10, 11). The extinction of conditioned fear, also called “extinction learning,” is a laboratory analogue for 
exposure therapy and investigates how the brain forms new safety-based memories (12). Studies in 
humans and rodents confirm that extinction does not involve erasing or overwriting the original fear 
memories; instead extinction involves new learning (13-17). Thus, the goal of extinction is to form new 
safety memories that can be recalled to inhibit fear responses associated with the original trauma. The 
ability to recall new safety memories after extinction is termed “extinction retention”. Abnormalities in 
extinction retention, and to a lesser extent in extinction learning, are extensively associated with PTSD 
(18-21). This corroborates observations that many patients do not adequately benefit from exposure 
treatment (22-24) and the majority experience symptomatic relapse in the months or years after 
treatment (25-27). 
Neuroimaging studies broadly implicate aberrations in prefrontal-limbic neural circuitry associated 
with PTSD. In both human and translational animal studies of PTSD, the most commonly replicated 
finding is VMPFC hypoactivity (or its homologue in rodents) alongside hyperactivity in the amygdala, 
dorsal anterior cingulate cortex and insula as well as hippocampal abnormalities (9, 12, 28-31). VMPFC 
activation during extinction learning predicts extinction success, and is associated with reduction of 
amygdala-driven fear expression (29, 32, 33). Compared to non-PTSD control groups, individuals with 
PTSD show reduced VMPFC activation during fear extinction (19, 34-36). The VMPFC further plays a 
critical role in memory consolidation after extinction acquisition (37, 38). Memory consolidation refers to 
a set of neural processes that stabilize labile memories after they are acquired (39), and includes a 
synaptic consolidation phase that occurs in minutes to hours after learning (40, 41). The role of the 
VMPFC in extinction consolidation is supported by rodent studies where VMPFC blockade of calcium-
dependent molecular cascades or proteins – critical mechanisms required for neurons to change synaptic 
connections in response to changing environments (i.e. plasticity)– immediately following extinction 
learning (i.e. during synaptic consolidation) impairs later extinction retention (42-44). The hypothesized 
role of the VMPFC in extinction consolidation is particularly relevant given that PTSD is primarily 
associated with extinction retention deficits, suggesting inadequate consolidation of extinction learning 
(e.g. 18, 19, 20).  
Taken together, the evidence suggests that finding new ways to increase VMPFC activity – in the 
framework of extinction – is a promising approach to develop new PTSD treatments. Translational rodent 
studies support this notion (45, 46). The purpose of the proposed research is to determine whether the 
timing of transcranial direct current stimulation (tDCS) – a non-invasive brain stimulation technique – 
targeting the VMPFC affects extinction retention. tDCS alters cortical excitability via subthreshold 
modulation of neuronal resting membrane potentials using a weak constant electrical current (47, 48). 
Simplistically said, positive current flow (i.e., anodal stimulation) increases the likelihood of neuronal 
depolarization, while negative current (i.e., cathodal stimulation) may reduce this likelihood. Hence, tDCS 
is a truly modulatory technique that does not generate action potentials on its own but works in tandem 
with ongoing intrinsic neural activation. As such, tDCS biases the brain for subsequent responses to 
external stimuli to facilitate learning and memory processes (49), including synaptic consolidation.  
Prior studies indicate that 1-2mA tDCS can impact fear memory processes (50)(51) and threat 
vigilance (52) in healthy controls. Yet, clinically more relevant would be to use tDCS in order to improve 
fear extinction learning and/or consolidation, with the goal to augment extinction retention. Previous 
work in our lab, indicates this is possible. However, the effects of tDCS appear to depend on the timing of 
stimulation in relation to extinction learning; whereas tDCS targeting the VMPFC during fear extinction 
improves subsequent extinction in healthy controls (53), similar tDCS applied during synaptic 
consolidation may boost extinction memory 24 hours later in Veterans with PTSD (54). These 
observations on the importance of timing are consistent with the above-mentioned VMPFC-mediated 
extinction consolidation deficits in PTSD and set the stage for the current study, as it suggests that the 

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time immediately following extinction learning, i.e. the window of synaptic consolidation, might be a 
particularly relevant time period for intervention to improve extinction retention in PTSD.  
In this study we will use a well-validated Pavlovian learning paradigm to serve as an analogue to 
exposure-based treatment, which will allow for performing the critical laboratory testing prior to clinical 
efficacy studies. Prior research demonstrates that this Pavlovian learning paradigm correlates with 
exposure treatment outcomes and is a useful proxy for the processes underlying exposure (55, 56). The 
use of Pavlovian extinction – as opposed to exposure therapy – allows a controlled learning environment 
in order to directly test the effects of tDCS timing on safety memory generation and retention. 
Determining the optimal, i.e. most effective, stimulation timing in order to affect psychological processes 
underlying exposure-based treatment is of utmost importance to evaluate the potential clinical value of 
tDCS-augmented treatment for PTSD. The findings of the proposed research will 1) provide critical 
knowledge on the effects of tDCS timing to augment extinction retention, and 2) enable hypothesis driven 
future studies for the implementation of non-invasive brain stimulation for PTSD treatment. The ultimate 
goal of this line of research is to develop tDCS as an assistive device-based treatment in adjunct to existing 
exposure-based psychotherapeutic interventions for PTSD. 
 
C.  Experimental Method 
C1.  Brief Description of Subjects 
Participants (N=150) will be between 18-70 years with a diagnosis of PTSD. Participants will be of any 
racial or ethnic group and of either sex. Participants with PTSD across trauma types (i.e. combat-related, 
sexual assault, accidents, etc.) will be recruited from Butler Hospital and the larger Providence metro 
area, including the Providence VA Medical Center (PVAMC). Although we will recruit participants across 
trauma types, trauma type and time since trauma will be recorded as potential variables that might affect 
tDCS effectivity in relation to fear extinction and recall. We anticipate including 180 participants in order 
to collect a sample of 150 participants who complete all study procedures.  
 
C2.  Study Design 
This study will use a between-subject design, with 150 adult participants randomized to one of three 
group conditions (n=50 each), namely 1) receiving active tDCS during extinction learning; sham during 
extinction consolidation, 2) receiving sham during extinction learning; active tDCS during extinction 
consolidation, 3) receiving sham during extinction learning; sham during extinction consolidation. 
Recruitment of 50 participants per group incorporates a conservatively high 15-20% estimate of 
participants who may not condition while ensuring a sufficient sample size for data analyses.  
 
This study will take place over 4 to 5 visits to Butler Hospital and the MRI Research Facility (MRF) at 
Brown University. It is possible for baseline procedures to be conducted remotely via phone/HIPAA 
compliant video conferencing. During these visits, participants will complete informed consent, screening 
measures, a semi-structured clinical interview, self-report questionnaires, a fear conditioning, extinction, 
and recall paradigm, and tDCS. Visits will vary in length between 1 to 3 hours.  
 
Any ongoing treatment participants receive will be allowed to continue unchanged throughout the 
duration of the study, and should be stable for at least 6 weeks prior to start date. Participants will be 
asked to keep these unchanged during the study period. Treatment changes will be allowed if medically 
necessary. 
 
The stimuli and experimental protocol to be used in the present study have been used extensively in 
previous studies examining extinction recall in human populations (19, 57-59). Furthermore, this design 
has been shown to reliably induce neural and behavioral responses associated with extinction memory 
(45). In our laboratory, this task has been well-tolerated in individuals with PTSD (53, 54).   
 
 
 

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C3.  Specific Procedures or Treatments 
Procedures:  
COVID-19 Specific Precautions: Research staff will act in accordance with COVID-19 safety guidelines set 
by the Brown MRF and Butler Hospital. 
 
Prescreening. Interested individuals will be provided a brief description of the study and prescreened via 
brief telephone interviews. This prescreening interview will inquire about basic demographic information 
(e.g. name, age, sex), inclusion and exclusion criteria, and whether they have ever been a patient at Butler 
Hospital. Inclusion and exclusion criteria may be verified by inspection of the medical record as part of 
the prescreening process for individuals who have expressed interest in participating (see PHI Waiver 
below). Those meeting entry criteria will be invited to participate and an appointment date/time will be 
arranged; additionally, verbal consent for the use of e-mail will be obtained. 
 
Visit Day 1: Screening.  May occur remotely over the phone/via HIPAA compliant video conferencing or 
in-person at Butler Hospital. At the time of appointment, individuals will be presented with the Informed 
Consent Form and given a verbal explanation of the study procedures, risks and benefits, as well as given 
the opportunity to ask additional questions. For participants who electronically provide consent, the 
consent will be reviewed again at the time of the first in-person visit.  After signing the Informed Consent 
Form, participants will undergo further screening consisting of collection of demographic and clinical 
information (e.g., age, gender, racial/ethnic group, handedness, years of education, use of medication and 
current treatments, colorblindness, menstrual cycle or use of hormonal contraceptives if female) and 
further assessment of tDCS/MRI contraindications, see Appendix. For remote baselines, additional 
information such as the participant’s current location and the privacy and safety of said location will be 
obtained. This is to assist the research team in case suicidal intent is endorsed and study clinician 
intervention or emergency services are required.   
 
Participants will also complete: 
- 
A semi-structured clinical interview with a trained evaluator to assess psychiatric diagnoses and 
inclusion/exclusion criteria, which will include either the Structured Clinical Interview for DSM-5 
(SCID-5) (60) or the Mini International Neuropsychiatric Interview (61), 
- 
the Clinician Administered PTSD Scale (CAPS) (62) which is a 30-item structured interview to 
assess the 20 DSM-5 PTSD symptoms, questions target the onset and duration of symptoms, 
subjective distress, impact of symptoms on social and occupational functioning. The CAPS is 
considered the gold standard in PTSD assessment, 
- 
Inventory of Depressive Symptoms, Self-Report (IDS-SR) (63) is a 30 item self-report 
questionnaire on depression severity with a Cronbach's α ranged around 0.80-0.93. 
- 
the PTSD Checklist (PCL-5) (64), which is a 20-item self-report measure that assesses severity of 
the 20 DSM-5 symptoms of PTSD, 
- 
the Pittsburgh Sleep Quality Index (PSQI) (65) to assess quality of sleep. This scale includes 19 
individual items to generate seven “component” scores: subjective sleep quality, sleep latency, 
sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and 
daytime dysfunction, 
- 
the Positive and Negative Affect Schedule (PANAS) (66) is a 20-item questionnaire to evaluate 
general affective status and mood. Ten questions inquire about negative mood states, and the 
other 10 questions cover positive mood states, 
- 
the State-Trait Anxiety Scale (STAI) (67) to evaluate self-report symptoms of anxiety outside of 
PTSD symptoms. The STAI contains 20 items for assessing trait anxiety and 20 for state anxiety. 
State anxiety items include: “I am tense; I am worried” and “I feel calm; I feel secure.” Trait anxiety 
items include: “I worry too much over something that really doesn’t matter” and “I am content; I 
am a steady person.” All items are rated on a 4-point scale (e.g., from “Almost Never” to “Almost 
Always”). Higher scores indicate greater anxiety. Internal consistency coefficients for the scale 
have ranged from .86 to .95; test-retest reliability coefficients have ranged from .65 to .75 

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Individuals deemed eligible for the study will be randomized to 1) receiving active tDCS during extinction 
learning; sham during extinction consolidation, 2) receiving sham during extinction learning; active tDCS 
during extinction consolidation, 3) receiving sham during extinction learning; sham during extinction 
consolidation.  
 
Visit Day 2: MRI. Participants may be asked to complete an MRI screening form and a resting state 
functional MRI scan, described below under MRI in further detail. Expected duration of Visit Day 2 is 1 
hour.  
 
Visit Day 3: Habituation and Fear Conditioning. On visit 3, participants will be asked to complete 
habituation and fear conditioning phases of the fear conditioning, extinction, and recall paradigm (18, 19, 
45, 53, 54, 57). This task involves the computerized presentation of photographs of two different rooms, 
one serving as the fear acquisition context (CX+; picture of an office) and one as the fear extinction 
context (CX-; picture of a bookcase) in which two conditioned stimuli (CS+; red and blue light) and one 
never-to-be conditioned stimulus (CS-; yellow light) will be presented. One CS+ will be extinguished 
during extinction (CS+E) and the other will not (CS+U). See Figure above at right.  Experimental scripts 
will run in E-Prime, and for all trials during each of four task phases - habituation, conditioning, extinction 
learning and extinction retention - the CX (+/-) will be presented for 9s: 3s alone, followed by 6s in 
combination with the CS (+/-) with a 15s average inter-trial interval (12-18s). During each of the four 
task phases two electrodes will be placed over the second digits of the index and middle fingers of the 
dominant hand, which may or may not deliver an annoying, but non-harmful electrical shock acting as 
unpleasant, unconditioned stimulus (US). Before each task phase, except habituation, participants will be 
instructed that they “may or may not be shocked,” and to “pay attention to any patterns you observe 
between the image that you see and whether or not it is followed by a shock,” Participants will also be 
instructed that “if you observe a pattern, it will hold throughout the session and the rest of the 
experiment.” Participants will not be explicitly informed of the CS/US contingency. 
 
Prior to starting habituation, participants will individually select electric shock intensity to be ‘‘highly 
annoying but not painful” as the US, following previously used procedures in our lab (53, 54). During 
habituation participants will be told that the purpose of this phase is to familiarize them with all possible 
pictures in the experiment, and that no shock would be delivered. Participants will see all stimuli (i.e. to-
be CS+E, CS+U, CS-) once in both contexts (CX+ and CX-). After habituation participants will undergo fear 
conditioning. A total of 32 trials: eight CS+E, eight CS+U, and 16 CS- trials will be presented across two 
blocks in the CX+ only. Both CS+ trials will be paired with US at a 60% reinforcement rate. The US will 
occur immediately after CS+ offset. After fear conditioning, participants will complete contingency ratings 
and the PANAS to assess general affect. Habituation and fear conditioning will either occur at Butler 
Hospital or in the simulation scanner at the MRF. This visit will last approximately one hour. 
 
Visit Day 4: Extinction of Conditioned Fear. Visit 4 will need to occur 24 hours after visit 3, with an 
allowable deviation of 4 hours. Extinction learning will either occur at Butler Hospital or in the simulation 
scanner at the MRF. Participants will be reminded of the instructions and receive either 1) active tDCS 
during extinction learning, or 2) active tDCS immediately following extinction learning, or 3) sham 
stimulation according to the randomization schedule. Regardless of randomization group, all participants 
will be asked to repeat completion of Day 1 tDCS safety screening and tDCS equipment will be placed on 
the scalp before beginning the task. During the extinction phase a total of 12 trials: six CS+E and six CS- 
trials will be presented solely in the CX- and no shocks will be delivered. Median split will determine the 
latter three CS+E trials as ‘late extinction’ trials. After extinction and tDCS procedures, participants will 
complete contingency ratings and the PANAS to assess general affect. This visit will last approximately 
one hour. 
 
Day 5: Extinction Retention and Fear Renewal. Visit 5 will need to occur 24 hours after visit 4, with an 
allowable deviation of 4 hours. The extinction retention and renewal phases serve as the test phase and 

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will either be administered at Butler Hospital or in the real MRI scanner at the Brown MRF. Prior to 
starting extinction retention, participants will be reminded of the instructions. A total of 32 trials: eight 
CS+E, eight CS+U, and 16 CS- trials within the CX- only will be presented and no shocks will be delivered. 
Early recall retention will be based on the first four CS+E and first four CS+U trials. After extinction 
retention, participants will complete contingency ratings and undergo a fear renewal phase. During fear 
renewal participants will see the same content as during fear conditioning, but no finger shocks will be 
delivered. After fear renewal participants will complete contingency ratings and the PANAS to assess 
general affect. This visit will last approximately one hour. 
 
Skin Conductance. Skin conductance will be recorded for 2 minutes prior to each fear conditioning, 
extinction and recall phase to establish a physiologic baseline, and continuously throughout each phase. 
Baseline skin conductance level will be used as a covariate in analysis. To assess skin conductance, two 
MRI-compatible electrodes will be placed on the thenar eminence of the non-dominant hand, as we will 
be assessing skin conductance in both the simulator and real scanner depending on task phase as 
described above. Skin conductance reactivity (SCR) will be quantified by the phasic response that occurs 
after the presentation onset of each CS+/- stimulus following previous guidelines (57) and our prior work 
(53, 54). The first trial during fear conditioning will be removed from analyses to avoid the influence of an 
orienting response on the data. Because of the effects of nicotine and caffeine on SCR we will ask people 
not to consume nicotine or caffeine two hours prior to the start of the study. 
  
Transcranial direct current stimulation. Device: Continuous direct current stimulation will be delivered by 
a CE-certified tDCS device (NeuroConn).  
tDCS Electrode Montage: We will use a conventional 1 (anode) x 1 (cathode) midline bipolar-non balanced 
electrode montage (68) with the anode placed approximately over FP1 of the 10-20 EEG coordinate 
system and the cathode over P10.  
Rationale: To determine the ideal electrode montage, participants will undergo a structural MRI scan 
(with acquisition settings optimized for modeling inputs) on Day 2 to inform finite element modeling 
(69). Initial electrical field modeling of the proposed montage was obtained using tDCS Explore by Soterix 
Medical (v.4.0, New York, NY). This modeling will be confirmed based on individual neuroanatomy MRI 
scans obtained on Day 1 using SimNIBS software (v2.0, DMCR, Germany) and electrode montage will be 
adjusted as necessary in collaboration with the Neuroimaging and Neuromodulation Core. Electrodes will 
be placed at FP1 and P10 and might be adjusted (by Drs. van ’t Wout-Frank and Philip) based on the latter 
individualized modeling to target VMPFC region. Using this approach, we anticipate at least 0.25-0.35 
V/m will reach the VMPFC. Prior tDCS research has demonstrated that tDCS effects in this order of 
magnitude have effects on brain functioning (70).  
Dose Parameters: Active tDCS will consist of approximately 15 minutes 2 mA intensity through 3x3 cm (9 
cm2) or 5x5 cm (25 cm2) electrodes, resulting in a maximum 2.22 A/m2 current density, with an 
additional 30s ramp up/down at the beginning and end of stimulation, respectively. Active tDCS will be 
applied either during extinction learning or immediately after extinction learning. This duration is 
selected based on task duration and allows an additional 2 minutes of tDCS prior to the start of extinction 
learning. Sham stimulation will be applied for the remainder, namely after or during extinction learning 
respectively. Sham stimulation parameters – 1 mA for 30s, with a ramp up/down over 30 sec each – are 
selected to mimic the scalp sensation of active tDCS without prolonged intense stimulation.  
Rationale: 2 mA intensity was chosen based on research showing that more intense stimulation protocols 
may result in stronger effects on the brain (71) and cognition (72). 
 
Transcranial direct current stimulation Procedures: Two conductive rubber electrodes will be inserted 
into reusable sponge pockets saturated with 0.9% normal saline and securely attached to the 
participant’s scalp using a rubber headband prior to beginning the task on Day 4. To reduce the likelihood 
of side effects, the skin under the stimulation sites will be lightly cleaned with alcohol and inspected for 
lesions or abnormalities. Participants will be instructed to notify the experimenter of any discomfort. To 
ensure tDCS tolerability and condition the skin, all participants will receive brief stimulation (1 mA for 30 

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seconds, with a ramp up/down over 30 seconds each) prior to beginning the task. Impedance, indicating 
electrode contact quality, will be monitored and recorded throughout tDCS administration. tDCS (or 
sham) will start 2 minutes prior to extinction learning and will continue throughout the extinction 
learning phase. For participants randomized to tDCS after extinction learning, tDCS will start immediately 
after completion of the last extinction trial. We will evaluate tDCS tolerability and adequacy of blinding 
following task procedures on Day 4. Double-blinding of sessions (active vs. sham) will be achieved 
through the use of participant-specific blinding codes preset in the tDCS device. Dr. Philip (mentor) will 
generate and oversee unblinded codes. Side effects related to tDCS will be recorded using a tDCS side 
effects questionnaire, including but not limited to queries about skin discomfort, headache and dizziness 
based on Brunoni et al. (73), see Appendix. 
 
MRI Procedures and Data Acquisition. MRI data may be collected on Day 2 and/or Day 5 of the protocol. 
The decision to have participants complete a Day 2 and/or Day 5 scan will be made at the discretion of 
the PI. Scans will be obtained using a research-dedicated 3T Siemens Prisma MRI scanner housed at the 
Brown University MRI Facility. During the MRI(s), participants will lay in a supine position inside the 
magnet bore with head resting inside a Siemens 64 channel head coil. To minimize motion artifact, foam 
wedges will be used to stabilize the participant’s head and a large cushion will be placed under the knees. 
Potential Day 2 scans will consist of a structural scan, followed by a resting state functional connectivity 
scan, and Diffusion Tensor Imaging. Potential Day 5 scans will consist of a structural scan, followed by a 
resting state functional connectivity scan, and fMRI during extinction recall and fear renewal phases. The 
simulation scanner is located in a room next to the active MRI scanner. For both the real and simulation 
scanner, visual stimuli during experimental task phases will be back projected onto a screen and viewed 
through a mirror attached to the head coil. Dr. Philip (mentor) will provide oversight for MRI data 
acquisition. If procedures take place at Butler Hospital, i.e. no Day 5 MRI scan, visual stimuli during all 
experimental task phases will be displayed on a computer screen in front of the participant. 
 
All MRI images will be obtained during a 45-55 minute scan session. The first 15 minutes will be used to 
familiarize the participant with imaging procedures, re-assess for pregnancy if indicated, and move the 
participant into the magnet bore. This will be followed by acquisition of high-resolution anatomic images 
and functional multiband echoplanar (MB-EPI) images. Freesurfer-preferred multiecho MPRAGE protocol 
will capture anatomic images (e.g., FOV: 256 mm, 176 sagittal slices, slice thickness 1 mm, phase encoding 
anterior-posterior; TR 20ms, TE 1.85+n2.0 ms (where n = 0,..,7)). Twelve minutes of resting state data 
will be obtained while participants view a light fixation cross against a black background (TR = 1 ms, TE = 
30 ms, FOV = 192mm, 2mm isotropic, multiband factor=4). 
 
C4.  Data Analysis  
The PI(s) will be responsible for and supervise data collection and data management. Data will be stored 
in password-protected excel files. Data analysis will be conducted using SPSS. Data will be analyzed 
through linear models including (M)ANOVA, repeated measures analyses and linear mixed model 
procedures to deal with correlational and order effects. This will be followed by appropriate post-hoc 
analyses comparing specific conditions (e.g. tDCS vs sham stimulation and CS+E, CS-U, CS-). In order to 
maintain anonymity in SPSS files participants will be only listed with their unique identification code. 
Data backup of these files and hard copies of data capture forms will be kept in locked files to which only 
authorized study personnel will have access. Descriptive data will be provided for all participants (e.g., 
mean age, sex, education, etc.). Clinical rating scales will be scored as they are in clinical use. 
 
This study will use Care New England’s instance of REDCap for electronic consenting, obtaining 
signatures for relevant CNE paperwork, the randomization of participants, and collection and storage of 
data. The study will not collect or store any actual data within REDCap until the project has been moved 
into REDCap’s production environment. 
REDCap is a secure, web-based application developed by Vanderbilt University for building and managing 
surveys and databases. It is primarily designed to support online or offline data capture for research 

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studies, quality improvement, and operations. REDCap provides easy data manipulation (with audit trails 
for reporting, monitoring and querying patient records), real-time data entry validation, and an 
automated export mechanism to common statistical packages. When data is downloaded, PHI will be 
removed and only an assigned code number will remain for analysis. Surveys, the informed consent, CNE 
paperwork, etc. may be sent to participants via REDCap. They will receive an e-mail from a study email 
address containing a link, which will securely connect them directly to the REDCap system. A copy of the 
informed consent form will be sent to the participant via email following their e-consent. With regards to 
email communication, all emails will be sent via a secure, encrypted system.  
 
Care New England’s instance of REDCap is hosted within the Care New England data center in Warwick, 
RI. This REDCap instance is role-based and is fully integrated with CNE’s Active Directory structure. It 
enjoys 24/7/365 enterprise-level support and security inherit to CNE’s HIPAA-compliant data center. 
Network transmissions (data entry, survey submission, and web browsing) to and from REDCap are 
protected via TLS 1.2 encryption.  REDCap’s data is stored on encrypted servers within CNE’s data center.  
 
The REDCap Consortium is composed of thousands of active institutional partners in over one hundred 
countries who utilize and support REDCap. REDCap was developed specifically around HIPAA-Security 
guidelines, and more information about the consortium and system security can be found at 
http://www.projectredcap.org/. 
 
D.  Material Inducements 
Compensation will be offered for the study-related procedures administered in this study. For 
participants recruited through Butler Hospital, and who complete all four study visits under the Butler 
protocol, participants will receive $50 for Visit Day 1 and $40 for Visit Days 3-5, respectively, totaling to 
$170 for all four testing days. In addition, participants will receive an additional $50 for each MRI they are 
asked to complete (Day 2 MRI and/or Day 5 MRI). This would then total to $220 for completion of one 
scan or $270 for completion of two scans. Study payment will occur at the end of each visit. If participants 
are deemed ineligible after screening on Visit Day 1 they will receive $50. If participants withdraw from 
the study before completion - either because they terminate consent or the study team decides that study 
continuation might be unsafe - they will receive compensation up until what was completed, at minimum 
$50 (study visit 1 only), plus $10 for each full half hour they participated (study visits 2-5).  
 
Compensation will be in the form of checks or gift cards. If participants opt for compensation through 
checks we will need to collect additional sensitive data (e.g. bank account number and participant home 
address). 
 
E.   Training of Research Personnel 
All research personnel will be trained to properly administer the study protocol by the PI. tDCS will only 
be applied under supervision of the PI, who is trained in its administration. All research staff will have 
completed research ethics training; including data management and procedures for maintaining data 
confidentiality and safety before being allowed to work on the project. 
 
3)  Human Subjects 
A.  Subject Population  
Participants will be 150 individuals with a diagnosis of PTSD and will be of any race, ethnic group or sex. 
Only participants who are able to give fully informed voluntary written consent will be accepted. 
Participants who enter will be free to withdraw from the study at any time without penalty or 
compensation for their time. They will be at minimum 18 years old and maximum 70 years old.  
 
Inclusion criteria are as follows:  
(1) Primary diagnosis of PTSD, assessed by the Structured Clinical Interview of DSM-5 (SCID);  
(2) aged 18-70;  

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(3) ability to speak, read, write, and understand English sufficiently well to complete study procedures 
and provide informed consent;  
(4) Stable psychiatric medication use or treatment for at least 6 weeks.  
 
Exclusion criteria are as follows:  
(1) Lifetime history of psychotic or bipolar disorder;  
(2) Current moderate or severe substance use disorder; if mild, not under the influence at time of study 
participation;  
(3) Acute suicidal or homicidal ideation as detected on screening instruments or in the investigator 
team’s opinion, is likely to attempt suicide within 6 months;  
(4) current (or past) significant neurological disorder, injury, or other intracranial pathology including 
severe traumatic brain injury or lifetime history of a) seizure disorder b) primary or secondary CNS 
tumors c) stroke or d) cerebral aneurysm;  
(5) lifetime history of moderate or, current unstable medical conditions;  
(6) Any problems that would interfere with study participation, including MRI- or tDCS-related 
contraindications (e.g., implanted metallic devices/substances, metallic tattoos, pregnancy, 
claustrophobia, holes in the skull, skin abnormalities under stimulation sites), or indication of 
colorblindness, or presence of any other condition or circumstance that, in the opinion of the investigator 
team, has the potential to prevent study completion and/or inability to schedule visit days within allotted 
time, and/or to have a confounding effect on outcome assessments. 
 
B.  Recruitment and Consent Procedures  
Recruitment will primarily take place through the posting of advertisements onsite at Butler Hospital, 
online (e.g., Craigslist, Butler Hospital website, etc.), and in the larger Providence community including, 
but not limited to, local coffee shops and the Providence VA Medical Center*. Potential participants from 
Butler Hospital clinics/partial hospital programs (e.g., Partial Hospital Programs/Women’s Partial 
Program) may be identified from review of medical records. These potential participants will be 
contacted using an outreach handout to determine whether or not they consent to being contacted for 
more information. Individuals who inquire about participation will be contacted by study staff, provided 
with a brief verbal description of the study, and invited to participate if they appear eligible based on pre-
screening.  At the time of the first study visit, potential participants will again be provided with a 
description of the study and if they remain interested, study staff will obtain written informed consent 
either in-person or via REDCap. The consent process will be administered by a member the study team 
who has received training in the protection of human research participants. Participants will be given the 
opportunity to ask any questions they may have, and they will receive a copy of the informed consent 
document including contact information, should any questions or concerns arise at a later time. If the 
participant has electronically signed the consent form, research staff will review the consent again at the 
first in-person visit prior to beginning other study procedures. For individuals who do not have a medical 
record at Butler Hospital, one will be created at time of enrollment into the study, after having signed the 
appropriate Butler Hospital informed consent form. Participants will be made aware of this procedure at 
time of pre-screening as well as through the informed consent form.   
 
*The following text is mandatory for advertising on the Providence VA Medical Center campus: “This 
announcement is for informational purposes only. This study: is not affiliated with or conducted by the 
PVAMC, has not been reviewed by the VA’s Institutional Review Board, and is not endorsed by the VA. The 
VA is not responsible for any costs incurred by a Veteran participating in this study.” This disclaimer will 
only be added to the recruitment materials that will be distributed at PVAMC, see examples attached. 
 
C.  Potential Risks  
Potential risks to all subjects include: 
(1) Coercion. Subjects may feel coerced to participate. 

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(2) Breach of Confidentiality or loss of privacy. In the course of this study we will collect sensitive 
information which, if released, may cause shame, embarrassment, or distress.  
(3) Distress due to assessment procedures. Asking participants about their thoughts, feelings, behaviors, 
and symptoms during the interviews and completion of rating scales might increase distress or result in 
discomfort. Participants may experience physical discomfort when asked to wear a face mask or may feel 
uncomfortable at their inability to see the facial expressions of research staff wearing face masks.  
(4) Risk related to fear conditioning, extinction and recall paradigm. The electric shocks that participants 
will receive during the extinction recall task may be uncomfortable, but they should not be painful or 
dangerous. Level of shock is personally determined by the participant to an intensity that is “very 
annoying but not painful.” Participants are free to stop the experiment at any time, should any portion 
prove too uncomfortable. There is also a risk of distress associated with testing, especially from receiving 
shocks. 
(5) Risks related to tDCS. Although tDCS is considered a low risk technique that is well tolerated and 
carries minimal to no side effects, there is some inherent risk with the application of electrical current. 
Stimulation is frequently accompanied by an itchy or prickly sensation on the skull under the electrodes. 
The most common side effects include mild local sensations at the electrode sites, including tingling or 
itching, and moderate fatigue, headache, and temporary redness of the skin under the electrodes (74, 75). 
Skin irritations can occur and, in a small number of case reports, local skin burns where the electrodes are 
attached have been reported. In addition, we are aware of reports of a small percentage of patients 
developing temporary hypomania during the course of a daily tDCS protocol for depression targeting the 
dorsolateral prefrontal cortex. It is unclear whether this is a risk for tDCS with the electrode montage 
used in this study, targeting a different brain region and occurring only in a single session. In research 
experience totaling 567 tDCS sessions, Poreisz and colleagues reported that no participants requested 
tDCS be stopped or required any medical intervention during or after stimulation (75).  
(6) Risk related to MRI. The bore of an MRI scanner, whether it is the actual scanner or the simulation 
scanner, is narrow, which can cause a claustrophobic reaction in some participants. For the real scanner 
there is the additional small risk that participants will experience heating during the scan from exposure 
to radio frequency (RF) coils. Furthermore, there are risks associated with MRI scanning associated with 
metal implants in close proximity to the magnet. Finally, there is the risk of discovery of unknown 
potential health problems. During the MRI procedures, it is possible that signs of a previously unknown 
health problem may be discovered (e.g., images that contain possible lesions, tumors, cerebrovascular 
problems) that may cause distress. 
(7) Risks related to e-mail communication. There are risks associated with sending health information via 
e-mail.  There is always a risk that the message could be intercepted or sent to the wrong e-mail address. 
E-mail messages from research staff may contain health information that identifies the participant. 
Information sent by e-mail could allow others to identify the participant along with their medical health 
conditions and psychiatric diagnosis (if applicable).  Only the research team will have access to e-mail 
communications.  We will only communicate by e-mail to send the participant information listed in the 
consent form.  We will not send e-mail messages that contain urgent information or results of medical 
tests or diagnostic procedures. We will not send messages that direct the participant to get medical care. 
(8) Risks related to text messaging. There is always a risk that a text message could be intercepted or sent 
to the wrong number. Only the research team will have access to text message communications. We will 
only communicate by text message to send the participant information listed in the consent form. We will 
not send text messages that contain urgent information or results of medical tests or diagnostic 
procedures. We will not send messages that direct the participant to get medical care.  
 
D.  Protection of the Subject  
D1. Measures to Minimize Potential Risks 
Participants can take breaks when needed during their participation. Participants will be told they may 
stop participating in the study at any time should.  They will be informed that they may refuse to answer 
any questions during the study.     
 

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(1) To minimize risk of Coercion, standard procedures will be followed in obtaining written informed 
consent. The voluntary nature of participation will be emphasized. Risks and benefits of participation will 
be explained, along with the rights of the participant, including the right to withdraw from the study at 
any time. Additionally, participants will be informed that should they choose to withdraw from the study, 
this will in no way affect care they receive at Butler Hospital or their right to participate in future research 
studies. Electronically signed consents will be reviewed with research staff prior to beginning in person 
study procedures. 
(2) To minimize risk of breach of confidentiality or loss of privacy, procedures outline below under “D2.  
Measures to Ensure Confidentiality” will be followed. 
(3) To minimize the risk of distress arising from assessment procedures (interview and questionnaires), 
only study staff that has been adequately trained in the assessment battery will complete all assessments. 
Individuals will also be advised that they may choose not to answer any question that they find upsetting. 
(4) Management of risks associated with the fear conditioning, extinction and recall task. The aversive 
stimuli in the fear conditioning, extinction and recall task (annoying shocks) are presented using standard 
laboratory equipment, which have been extensively used in human studies and have been well tolerated. 
We will closely monitor participants for untoward reactions or distress and modify or terminate the tasks 
as needed to minimize any distress they experience. Participants may choose to stop the task at any point. 
Also, all participants will be debriefed by study staff after completing the study, at which time they will be 
encouraged to ask questions and discuss any discomfort that they felt at any time during the study.  
(5) Management of risks due to tDCS. All participants will be carefully screened prior to tDCS for 
contraindications to tDCS (see exclusion criteria, e.g. as the risks of tDCS in pregnant women are 
unknown, pregnant and breastfeeding women are excluded from participation). Participants will have the 
option of discontinuing the study at any time and will be explicitly instructed to inform the tDCS 
administrator/PI immediately if they experience any discomfort. All tDCS will be administered, according 
to tDCS device instructions, by a trained member of the research staff, under the supervision of the PI.  
 
Regarding tDCS device instructions, the use of an electrically isolated power source (i.e., battery-powered 
DC stimulation device) protects against delivery of more intense currents than intended. These devices 
also feature a continuous visual indication of electrode contact quality during all phases, a clear indication 
of the actual current supplied at time of stimulation, and the ability to deliver sham stimulation for single 
and double-blind studies. Prior to active or sham tDCS, participants will be primed for stimulation by 
applying a 1 mA stimulation for 30 sec, with a ramp up/down over 30 sec each. Impedance of tDCS will be 
recorded and monitored throughout the session to be below 25 kΩ (which is well below the pre-
determined factory device maximum of 55 kΩ). The proposed stimulation is within the typical range of 
intensity (1-2mA) and duration (up to 20 min) for tDCS administration. No serious adverse side effects 
have been reported in previous studies within our lab with the proposed stimulation settings. Prolonged 
passage of direct current across metallic electrodes (where electrons from the stimulator are converted to 
ions carried through the body) can produce undesired electrochemical products such as pH changes. 
Electrodes will be embedded into a specifically designed sponge pad moistened with normal, 0.9% saline 
which will act to physically separate, and thus buffer, the skin from electrochemical changes and maintain 
even current density over time. 
 
Given our proposed stimulation parameters, the proposed tDCS protocol is considered conventional in 
that it meets current, duration and charge safety limits. In tDCS safety testing, subjects were exposed to 
current densities of up to 2.56 mA/cm2, and durations of up to 22 minutes. No burns or significant 
discomfort occurred. In addition, electrodes will not be placed over skin lesions, such as vascular moles 
and angiomas that might have greater conductance than the surrounding skin, and the skin under the 
electrodes will not be abraded prior to stimulation. The safety of conventional tDCS has been recently 
published in a review by Bikson et al. (74). In the numerous tDCS studies performed in recent years, tDCS 
was associated most commonly with a mild tingling sensation (70.6% of 567 tDCS sessions in 102 
subjects), moderate fatigue (35.3%), and a light itching sensation under the stimulation electrodes 
(30.4%). Headache (11.8%), nausea (2.9%) and insomnia (0.98%) were also reported, but fairly 

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infrequently (75). However, the most serious adverse effect of tDCS consists of the formation of small 
circular skin burns under the electrodes (76-78). These studies have demonstrated that the risk for skin 
burns increases when the skin under the electrodes is vigorously abraded before stimulation (Loo et al., 
2011) or tDCS is applied without an adequate skin buffer during multiple, consecutive tDCS sessions. 
Subsequent tDCS practices in which the skin was not abraded before stimulation and the use of sodium 
chloride solution or gel, together with replacement of deteriorated tDCS supplies (e.g. sponge pads or 
electrodes) have not resulted in skin burns. Hence, in this study we will 1) not abrade any skin before 
tDCS application, 2) always use normal saline to moisten the tDCS sponges in which electrodes are 
embedded, and 3) carefully inspect the electrodes and electrode holders for damage or wearing. In 
addition, given the reported case studies of hypomania in a course of daily tDCS application, we exclude 
participants with a history of bipolar disorder.  
 
Other precautions will consist of instructing participants to inform the experimenters of any (increasing) 
discomfort during testing (as such discomfort may be an indication that skin burns could form with 
continued stimulation), inspection of stimulation sites as needed and immediate discontinuing 
stimulation if discomfort occurs. Instantaneously making or breaking of the stimulating circuit results in 
AC current transients that cause neuronal firing (47). This is noticeable as brief retinal phosphenes with 
electrodes near the eyes. Therefore, participants will be told in advance that if the tDCS stimulator needs 
to be turned off suddenly out of safety precautions, they may experience a one-time sensation of a brief 
light flicker (similar to a broken fluorescent light) due to the sudden offset of the device.  
 
 
To assess for presence and tolerability of adverse events, we will use the tDCS Adverse Effects 
Questionnaire, developed by Brunoni and colleagues (73). For tDCS procedures occurring at the Brown 
MRF, the principal investigator will be present in the room for the first five participants and onsite for 
future participants. For tDCS procedures occurring at Butler Hospital, physician with advanced training in 
Neuromodulation techniques will be immediately available for management of emerging events. Dr. 
Philip, in the role as study physician/mentor, will also be available to supervise or consult on tDCS 
administration and will be available to consult on handling of any emergent events. If there is any doubt 
about the mental or physical status of an individual after testing, the supervising physician will be called 
to evaluate the participant and make a recommendation for follow-up care if that is required.  
 
Prior to administering tDCS in this protocol, all staff involved in administration of tDCS will be required to 
undergo training and demonstrate competence in the safe delivery of tDCS. There are multiple 
components of training in order to be able to administer tDCS, including initial didactic training to 
introduce concepts critical to tDCS, direct observation of tDCS procedures, practice of the various steps of 
setting up/administering tDCS on non-patient volunteers, including role-plays of scenarios of when the 
covering physician should be consulted to further address adverse events related to the study protocol, 
and demonstration of competency in all aspects of relevant subject assessment and in administration of 
the entire tDCS procedure under direct observation of a qualified tDCS administrator. 
 
tDCS will be administered by the tDCS Operator (Dr. van ‘t Wout-Frank or the research assistant (TBD)). 
The tDCS Operator is trained in the use of tDCS devices and has knowledge of safety considerations and 
precautions associated with tDCS. Responsibilities include of the tDCS Operator include:  
A) Positioning or assessment of positioning of the tDCS device on the participant prior to initiating 
stimulation. 
B) Operation of or monitoring of the hardware associated with the tDCS device. 
C) Administration of tDCS, or monitoring thereof. 
D) Brief assessment of relevant mental status and general clinical condition before and after tDCS. 
E) Monitoring of the participant during the tDCS session. The tDCS Operator will either remain in the 
testing room, use direct in-between room video feed, or between-room windows, to allow continuous 
observation of the participant’s physical status for the potential occurrence of adverse events throughout 
the entire tDCS session.  

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F) Making routine adjustments to the placement of the device as required and consistent with product 
labeling (e.g., to ensure contact between participant’s head and electrode) during the tDCS session. 
G) Determination of circumstances under which tDCS should be interrupted or terminated (e.g., 
participants expresses increasing comfortableness under the electrodes; observation of participants for 
signs of skin burns, discomfort or other stress; participant wants to discontinue study procedures). 
H) Taking action in accordance with established regulations in case of adverse events, e.g. contacting 
Neuromodulation Facility Attending Physician, reporting adverse events to PI (who will take appropriate 
action, as required).  
 
(6) Minimization of risks associated with MRI: The nature of the scanner environment – real or simulation 
– will be explained to all participants during the consent process (i.e., you will lay on a table that slides 
into a narrow cylinder, you will be asked to lie still, the machine makes very loud noises, you will be 
provided ear protection). Participants will be informed that they may stop the study at any time by 
informing study staff via intercom, or squeezing a safety bulb placed near their hand. To minimize the risk 
of claustrophobic reactions, participants will be screened for claustrophobia. Additionally, participants 
will be informed that if any heating they experience becomes uncomfortable, they should inform study 
staff and they may discontinue participation at any time without penalty. To reduce the possible physical 
risks associated with MRI, participants will be thoroughly screened by study personnel and the Brown 
MRI Research Facility staff prior to entering the magnetic field for the presence of any metallic objects, 
implants, or other safety risks, and they will have all possible risks explained to them verbally and in 
writing. In the event that MRI scans lead to the discovery of a previously unknown potential health 
problem, study staff will notify these participants as soon as possible, and appropriate recommendations 
will be made for further investigation by qualified medical personnel. Although the scan is not diagnostic 
in nature, and the study personnel and MRI technician are not qualified to make diagnoses based on 
imagery data, any findings warranting possible further attention will be shared with the participant and 
the participant will be instructed to follow-up with qualified medical personnel. 
 
D2. Measures to Ensure Confidentiality 
Every effort to maintain participant confidentiality will be made. All research personnel will be trained in 
the responsible conduct of research and the Principal Investigator will be responsible for ensuring that 
adequate training has been completed. All study forms and data will be identified only by code numbers, 
and will be stored in locked file cabinets or on secure research servers. Identifying information (contact 
information, name, consent documents) will be separated from the research data and be stored 
separately in a different locked file cabinet. All computerized data will be stored on a secure research 
server (COBREresearch server) in password-protected files, separated from identifiers. Hard copies of 
data capture forms, e.g. descriptive data and tDCS safety screening, will be kept in locked file cabinets in 
the Annex 3rd Floor Research Lab space at Butler Hospital to which only authorized study personnel will 
have access. No personal participant information will be presented in any publication or presentations 
resulting from this research.  
 
Please note: the tDCS device does not generate any data besides a display notification of contact quality of 
the electrodes. This contact quality notification is recorded for analysis on de-identified hardcopy data 
capture forms. 
 
D3. Data Safety Monitoring Plan 
In order to meet the NIH policy for Data and Safety Monitoring, we have created a system for oversight of 
the project. Oversight and internal monitoring of the participants’ safety will be conducted by Dr. van ‘t 
Wout-Frank in collaboration with Dr. Philip (mentor). Dr. van ‘t Wout-Frank has extensive experience 
conducting non-invasive neuromodulation, especially transcranial direct current stimulation, in both 
healthy volunteers as well as individuals diagnosed with posttraumatic stress disorder. All participants 
will be carefully screened prior to study entry. tDCS will be administered by a tDCS-trained research team 
member. Other participant safeguards with respect to study procedures are described in Protection of 

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Human Subjects (e.g.: use of electrically isolated power source, close observation for signs of skin burns, 
discomfort, or other stress, explicit instruction that participants can discontinue the study at any time, 
etc). A member of the research team will be on-site during all study sessions, and in the event of any 
adverse event, Dr. van ‘t Wout-Frank and/or the study physician (e.g. Dr. Philip, MD) will assess the 
subject and facilitate subsequent treatment or referral. In the event of any subject becoming unstable or 
demonstrating worsening of clinical symptoms, the principal investigator and/or their designee will stop 
study procedures and contact Dr. van ‘t Wout-Frank for assessment and to facilitate treatment or referral. 
In case for need of emergency medical assistance, the principal investigator and/or their designee will 
contact 911 and/or Brown University EMS response team depending on severity. All research staff 
performing tDCS as well as MRI facility staff members at the Brown University MRI Research Facility are 
trained in basic first aid, CPR, and tDCS and/or MRI safety and evacuation protocols. All members of the 
research team will have 24-hour access to investigators or study physician for management of any clinical 
emergency that may arise.  
 
To ensure the integrity of the data the PI will review all the data for errors or inaccuracy within one 
week after it is obtained. All data will be entered into a research database as it is collected, and the 
research assistant(s) and postdoctoral research associate will meet with the PI weekly or as appropriate 
to review ongoing subject data. The PI and mentor(s) will meet weekly to discuss the project, at which 
time they will review progress with regard to enrollment, any adverse events, and 
attrition/noncompliance, review data quality, recruitment, and study retention, and examine other 
factors that may affect outcome. Circumstances surrounding any identified adverse events, incidents of 
subject dissatisfaction, or subject noncompliance or withdrawal of consent will be tracked regularly and 
discussed to determine any changes in participant risk. 
 
Following standard practice, serious and unexpected adverse events will be reported to the IRB of record 
within the designated guidelines. For example, a serious adverse event will be reported by fax or e-mail 
within 1 business day, followed by a written report within 5 days. They will be reported verbally to NIH 
within 24 hours and in a written report within 72 hours to both NIH and the Data Safety and Monitoring 
Board (DSMB; see below). The written report will indicate whether the serious adverse event was 
attributed to the study. A summary of adverse and serious adverse events will be reported in the yearly 
progress report to NIH. The project Standard Operation Procedure binder will provide detailed operating 
procedures including the definitions of SAE’s and AE’s and reporting requirements. If a pattern or 
potential pattern of unexpected adverse events emerges during the course of the study, the PI and 
mentor(s) will discuss this pattern with physicians with expertise in brain stimulation in this population 
as part of the DSMB described below. 
 
The DSMB will be comprised of mental health providers and physicians who have many years of clinical 
and/or clinical research experience and are well versed in the protection of confidentiality. The DSMB 
will meet twice per year to evaluate progress, and review data quality, recruitment, study retention, 
adverse events, and other factors that may affect outcome. These data will be provided by the PIs to the 
Board. A brief report will be generated for the study record and forwarded to the Institutional Review 
Board as necessary. The Investigators and DSMB will be available to meet outside of the regularly 
scheduled meetings, as needed, if concerns regarding a particular participant or any problems arise. If 
necessary, they will make appropriate recommendations for changes in the protocol. The Data and Safety 
Monitoring Board will review all adverse events and serious or unexpected adverse events and provide 
recommendations. Participants will only be identified by number during review of study progress by the 
DSMB. In the event that confidentiality must be breached (e.g., suicidal/homicidal ideation or attempt), 
only the PI would be informed of identifying information in order to report to the DSMB, appropriate 
authorities or health care providers. In the event that a conflict of interest within the DSMB is identified, 
the DSMB will disclose the matter to the involved institutions and NIH. The PI will consider the 
recommendation and make a decision and document the action to the involved institutions and NIH. We 

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will inform NIH of any significant action taken as a result of the Data and Safety Monitoring Board’s 
findings. 
 
E.  Potential Benefits  
There are no direct benefits to participants for participating in the study. Indirectly, participants will be 
helping to further scientific knowledge with the ultimate goal to improve mental health therapy. 
 
F.  Risk-Benefit Ratio  
It is our opinion that the benefits of furthering our knowledge of the effects of tDCS timing on fear 
extinction learning and memory can provide greater insight in the ultimate potential use of tDCS as a 
clinical treatment option for PTSD and related disorders. Therefore we believe that the benefit of this 
study outweighs the potential risks that may occur as a result of participating in this study. 
 
Aim 4 – SUB-STUDY (online): “Learning and Memory In Virtual Rooms”; Contextual processing 
along the PTSD spectrum 
In order to address Aim 4 and evaluate the impact of posttraumatic stress symptoms on contextual 
processing, we include the following online-only sub-study.  
 
Following a within-subjects study design, up to 500 adult participants, between 18 and 89 years, will be 
asked to complete experimental tasks that assesses configural and elemental contextual learning and 
memory. The 89-year age cut-off is used to avoid data collection of age being a HIPAA identifier. For 
example, participants will see different images of virtual rooms that include arrangements of common 
household furniture (e.g., couch, table, rug, plant). Over time participants will learn that certain objects 
(e.g., plant) or furniture configurations (e.g., white couch on left plus plant in foreground) are associated 
with the presence of a “bomb” in specific rooms by showing them an image of an explosion on the next 
screen.  After learning, contingency ratings will be obtained by asking participants whether they think a 
bomb is present in various virtual rooms and how certain they are on a sliding scale. 
 
Participants will also be asked to state their age (in years), sex assigned at birth (male/female), and 
complete questionnaires assessing the presence of symptoms related to PTSD (e.g., PTSD Checklist for 
DSM-5 (PCL-5)), depression (e.g., Patient Health Questionnaire depression scale (PHQ-8)), and anxiety 
(e.g., Generalized Anxiety Disorder 7-item scale (GAD-7)). Additionally, random attention checks using 
“catch” items will be included throughout the experiment. An example of such an item is “Please select 
‘yellow’ out of the following options: a) yellow, b) blue, c) red, d) green.” 
 
It should be noted that we will not be able to review answers to questions in real-time. As such, we are 
not able to detect participants who might be at (higher) risk for self-harm. For that reason, we will list the 
phone number and URL for SAMHSA’s National Helpline – 1-800-662-HELP (4357) and 
https://www.samhsa.gov/find-help/national-helpline – at the bottom of each page when participants are 
completing the above-listed questionnaires as well as at the end of the study on a thank you-page. 
SAMHSA is “a free, confidential, 24/7, 365-day-a-year treatment referral and information service (in 
English and Spanish) for individuals and families facing mental and/or substance use disorders.” Given 
that we will limit our recruitment to individuals residing in the USA only, providing SAMSHA’s contact 
information will be appropriate. Additionally, because we will not directly interact with online 
participants and collect only the minimum amount of data to answer our research question, we will not 
know whether online participants might be pregnant or are justice-involved. However, based on the 
above outlined online study procedures we do not anticipate the protection of these vulnerable subjects is 
affected (e.g., study coercion is low if there is no interaction with the study team; materials and methods 
do not pose an additional risk for pregnant individuals).  
 
Prolific (https://www.prolific.co/researchers) will be used to recruit online participants. Prolific is a 
panel-based platform on which individuals can create an account to participate in online research.  

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Prolific’s privacy policy meets the standards of the European, General Data Protection Regulation law 
(GDPR), and personally identifiable information from participants cannot and will not be collected 
through Prolific. More specifically, although Prolific will collect IP addresses, it is not possible for 
researchers to gain access to such or any personally identifiable data. Instead, participants have a Prolific 
ID that we will collect to provide reimbursement for study participation at a rate of $8-$16/hour (exact 
rate will depend on the complexity and length of individual tasks as well as Prolific’s suggested rate) for a 
study duration of 60-90 minutes. Reimbursement occurs after the approval of study completion 
submissions by the research team. Although it is possible to reject submissions within 21 days of 
completion and forgo reimbursement to a participant, this is only allowed for pre-specified valid reasons 
(and Prolific may overturn rejections in certain occasions). In case of issues with participation, Prolific IDs 
can be used to contact participants through Prolific’s email feature to protect the personal email 
addresses of both researchers and participants.  
 
To run the experimental contextual learning and memory task as well as administer the questionnaires, 
Prolific will link to ‘Pavlovia’ and Brown University’s instance of Qualtrics. Pavlovia is a place to run, 
share, and explore experiments online and which can run the ‘PsychoPy’ script of our experimental task, 
see also https://pavlovia.org/docs/home/ethics. Like Prolific, Pavlovia is GDPR compliant their server 
logs, which contain IP addresses, will not be shared with and cannot be accessed by the research team 
and will not be linked to participant data. The PsychoPy experimental script will automatically log the 
completion date of the experiment. Aside from this completion date no other personal identifiers will be 
collected. Questionnaire responses captured through Qualtrics will be collected in a fully anonymized 
manner, see https://ithelp.brown.edu/kb/articles/use-qualtrics-for-human-subjects-research-
anonymize-responses. 
 
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52. 
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Palm, U., Keeser, D., Schiller, C., Fintescu, Z., Reisinger, E., Padberg, F., & Nitsche, M. (2008). Skin lesions 
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5) CRITERIA FOR WAIVER OF AUTHORIZATION FOR USE OF PROTECTED HEALTH INFORMATION (PHI) 
5A. Does the requested use of PHI involve more than minimal risk to privacy? 
☐ YES [if " YES," project is not eligible for PHI Waiver]   ☒ NO [if "NO," address 1-3 below] 
 
1. Plan to Protect Patient Identifiers from Improper Use and Disclosure: 
Potential risks due to loss of confidentiality will be minimized by having all information collected and 
handled by staff trained to deal appropriately with personal information. All research personnel will 
receive training in the protection of human research participants. All information will be treated as 
confidential information and be kept in locked filed cabinets on-site. Computer data files will be 
available only to study personnel.  
 
2. Plan to Destroy Identifiers or Justification for Retaining Identifiers: 
After identification of potential participants and in the case (s)he does not want to participate, 
identifying information will be safely discarded per Butler Hospital procedures. When the person is 
interested in participating, identifiers will be retained so that they may be used for data analysis in 
this protocol and future investigations.  
 
3. Assurances that the PHI will not be Re-used or Disclosed: 
Information collected will only be used for purposes described below and will be treated as 
confidential. PHI collected as part of the study protocol will be shared only with collaborators and 
shared in de-identified form only. PHI gained from medical record searches will be specifically used to 
identify interested patient participants for the above-mentioned study. Potential participants will only 
be identified for the above-mentioned study. 

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5B. Could the research be practicably conducted without a waiver? YES    ☒ NO 
5C. Could the research be practicably conducted without access to and use of the PHI?   ☐ YES    ☒ NO 
5D. PHI is only needed for activities preparatory to research☐YES    ☒NO 
6) DESCRIPTION OF PHI TO BE COLLECTED UNDER WAIVER  
To identify potential participants, we may need to review the medical records of patients at Butler 
Hospital either after potential participants reached out to us because they are interested in participating 
or because they take part in Butler Hospital clinics (e.g. Partial Hospital Programs/Women’s Partial 
Program). This will involve their name, admitting information, treating clinician, and diagnosis. All PHI 
will be kept confidential within research team and clinic staff. Potential participants who are identified 
from reviewing the medical records of Butler Hospital clinics (e.g. Partial Hospital Programs/Women’s 
Partial Program) will be given an outreach handout asking if they would be interested in 
participating/consent to being contacted. Medical records of participants who inquire about the study 
may be reviewed in order to confirm inclusion/exclusion criteria, and. PHI to be obtained includes patient 
demographic information (age, gender), contact information (name, phone number), treatment provider, 
and medical and treatment history. 
7) ADVERTISEMENTS 
ONLINE ADVERTISEMENT TEXT: 
PROJECT RISE in PTSD 
Research Investigating Stimulation for Extinction in PTSD 
 
We are looking for people who are diagnosed by a clinician with posttraumatic stress disorder and who 
are interested in being part of a research study in which we look at the effects of a very low level of 
electrical current on the scalp (called tDCS) on emotional learning and memory. This study will involve 
four or five study visits. On the first visit we will do a screening and we might ask you to get a brain scan 
on a second visit. On visits three, four and five you will do a computer task that tests emotional learning 
and memory. During one of those days you may or may not also receive the very low level of electrical 
current through two electrodes attached to your head and may or may not also get a brain scan.  
You may qualify if you: 
• 
Are between 18-70 years-old  
• 
Speak and read English fluently  
• 
Have no history of closed-head injury or neurological disease 
• 
Have no implanted electronic hardware, such as metal implants, pacemakers or medication 
pumps or metal in the head 
• 
Have no current or history of psychosis or bipolar depression 
• 
Have no holes in the skull made by trauma or surgery 
• 
Have no history of epilepsy or seizures 
• 
Are not pregnant 
Number of visits: 4 or 5 
Duration of visits: Visit 1 about 3 hours, visits 2-5 about 1 hour each visit.  
[Participants will earn compensation for research participation.] or [Participants can earn up to $170-
$270. 
If interested in learning more, please contact: 
 
[Insert RA name] 
Phone: [Insert study phone number] 
 
8) INFORMED CONSENT FORM (ICF), ASSENT OF MINOR & PARENTAL PERMISSION FORM 
 
See attached