Neurofeedback of Amygdala Activity for Post-traumatic Stress Disorder (PTSD)
Phase: NA
Conditions: Post-Traumatic Stress Disorder
Sponsor: Yale University

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HRP-503B – BIOMEDICAL RESEARCH PROTOCOL 
(2017-1)
Protocol Title: Neurofeedback of amygdala activity for PTSD
Principal Investigator: Ilan Harpaz-Rotem
Version Date: 11/08/2022
(If applicable) ClinicalTrials.gov Registration #: NCT03574974
INSTRUCTIONS
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1.
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If a section or question does not apply to your research study, type “Not Applicable” underneath.
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SECTION I: RESEARCH PLAN
1. Statement of Purpose: State the scientific aim(s) of the study, or the hypotheses to be tested. 
The primary purpose of this study is to investigate the efficacy of biofeedback (or neurofeedback; “NF”) of 
real-time functional magnetic resonance imaging (rt-fMRI) data for reducing symptoms in patients with PTSD. The 
target mechanism for this intervention is control over amygdala activity following trauma recall. Namely, 
participants will be presented with rt-fMRI data that corresponds to amygdala activity in response to recalled 
trauma in order to help them improve control over this key region in the fear circuit. We hypothesize that 
improved control over the amygdala will reduce the core symptoms of PTSD and initiate a healthier clinical 
trajectory. 
A secondary purpose of this study is to use fMRI as a method for investigating brain function in individuals 
with PTSD. This study approach provides a tool for probing the neurobiology of PTSD by (1) testing the critical role 
of the amygdala in this disorder and (2) examining how amygdala connectivity is related to both amygdala 
regulation and clinical symptoms.
In pursuit of the overarching goals of this study, we aim to:
• determine if our NF intervention increases control over the region of interest (the amygdala) more than sham 
feedback in which participants receive feedback that is unassociated with their PTSD symptoms
• determine if NF results in clinical improvements in PTSD symptoms, relative to sham feedback, and examine 
whether these improvements correlate with improved control over the amygdala
• determine if NF results in changes in resting state connectivity to the amygdala, and whether these changes 
correlate with symptom improvement and an improved ability to regulate the amygdala
Finally, we would like to relate genetic markers to brain patterns in PTSD subjects. Therefore, we have a 
created a separate consent form to allow us to collect, analyze, and relate genetic information to brain function.
2. Probable Duration of Project: State the expected duration of the project, including all follow-up and data 
analysis activities. 
The initial R-61 phase (testing whether, when used by human participants, the proposed intervention 
alters the presumed biological signature/mechanism of action) will last two years. If in the R-61 phase, 
participants who receive NF demonstrate larger improvement in control over their amygdalae than sham 
patients, an R-33 phase (continued testing of the efficacy of the intervention) will be initiated, and last up to 8 
years. 
3. Background: Describe the background information that led to the plan for this project. Provide references to 
support the expectation of obtaining useful scientific data.
MRI methods can detect quite subtle changes in blood flow/oxygenation using T2* weighted images. 
These methods are often used to assess alterations in brain that occur with regional activation in response to 
external stimuli or tasks. The methods, known generally as functional magnetic resonance imaging (fMRI), are 
non-invasive and permit repeated performances of tasks in individuals as well as children. The resolution is 
similar to that of conventional anatomic MRI. There is firm evidence that this approach to the study of brain 
responses provides a higher quality of information, with much better spatial and temporal resolution, 
sensitivity and safety, and without the need for inter-subject averaging, than the best PET or SPECT studies of 
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blood flow. For localization and quantitation of regional responses to stimuli, it is becoming increasingly clear 
that MRI will be the method of choice in experimental neuroscience. The preliminary results from other 
laboratories strongly suggest that this method is capable of providing unique information about the 
magnitude and location of the physiological response of the brain to specific stimuli [1,2].
More recently, there have been publications suggesting that real-time neurofeedback of functional 
imaging data can enable individuals to control brain activity in specific parts of their brain. One recent study 
reported that neurofeedback of anterior cingulate activity resulted in a decrease in pain in patients with 
chronic pain disorders as well as a decrease in the perception of pain associated with a painful stimulus in 
healthy control subjects [3]. Thus, real time neurofeedback of functional imaging data is new method with 
promising applications to many clinical conditions.
In the context of PTSD, real time fMRI neurofeedback may be effective at reducing symptom severity by 
targeting amygdala activity. Amygdala hyperactivity is a hallmark feature of PTSD, with a substantial body of 
literature revealing heightened amygdala responsivity in PTSD during the processing of both trauma-related 
and trauma-unrelated affective information [4]. Amygdala hyperactivity is also positively correlated with 
symptom severity in PTSD, making it an ideal target for neurofeedback aimed at producing clinical 
improvement (see Shin et al. for review) [4]. Moreover, amygdala activation is associated both with the risk of 
developing PTSD and with positive response to treatment, [5, 6], further highlighting the unique role of the 
amygdala in modulating PTSD. This study will target amygdala activity using a script paradigm first piloted by 
other groups [7, 8], in which individual trauma scripts are collected for each subject and later played in the 
scanner. This will allow us to localize and provoke amygdala activity to use as a target in the neurofeedback 
intervention.
One of the popular control conditions for studies using neurofeedback of real-time fMRI data is a form of 
sham feedback in which a subject receives a feedback signal based on a prior subject’s performance during 
their (true) neurofeedback scan. Because the times at which subjects are told to increase or decrease activity 
in their brain are consistent across subjects, this type of sham biofeedback creates the impression in the 
subject that they are somewhat successful in controlling their brain activity. That is, to the extent that the 
previous subject was able to increase activity during increase periods and decrease activity during decrease 
periods, the subject receiving the sham feedback will appear to also be successful. This helps to control 
somewhat for the perception of success which can affect motivation or placebo effects. This form of sham, 
known as a yoked sham, will be used as the control intervention in this study. 
References
1.  Blamire, A., Ogawa, S., Ugurbil, K., et al.
    "Dynamic mapping of human visual cortex by high-speed MRI"
     Proc. Natl. Acad. Sci. 89: 11069 - 11073, 1992.
2. deCharms RC, Maeda F, Glover GH, et al.
    “Control over brain activation and pain learned by using real-time functional MRI.”
     Proceedings of the National Academy of Sciences 102(51):18626-18631, 2005.
3. Turner, R., Jezzard, P., Wen, H., et al.
"Functional mapping of the human visual cortex at 4 and 1.5 Tesla using deoxygenation contrast EPI"
 Magn. Reson. Med. 29: 277 - 279, 1993.
       4. Shin LM, Rauch SL, Pitman RK. 
    “Amygdala, medial prefrontal cortex, and hippocampal function in PTSD.”
      Ann N Y Acad Sci.1071: 67-79, 2006.
5. Admon R, Lubin G, Stern O, et al. 
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   “Human vulnerability to stress depends on amygdala's predisposition and hippocampal plasticity.”
     Proc Natl Acad Sci USA 106(33):14120-14125. 2729030, 2009.
6. Bryant RA, Felmingham K, Kemp A, et al. 
“Amygdala and ventral anterior cingulate activation predicts treatment response to cognitive behaviour                       
therapy for post-traumatic stress disorder.”
    Psychological medicine. 38(4):555-561, 2008.
7. Lanius RA, Williamson PC, Densmore M, et al. 
    “Neural correlates of traumatic memories in posttraumatic stress disorder: a functional MRI investigation.”
     Am J Psychiatry 158(11): 1920-1922, 2001.
8. Pitman RK, Orr SP, Forgue DF, de Jong JB, Claiborn JM. 
    “Psychophysiologic assessment of posttraumatic stress disorder imagery in Vietnam combat veterans.”
      Arch Gen Psychiatry 44(11): 970-975, 1987
4. Research Plan: Summarize the study design and research procedures using non-technical language that can be 
readily understood by someone outside the discipline. Be sure to distinguish between standard of care vs. 
research procedures when applicable, and include any flowcharts of visits specifying their individual times and 
lengths. Describe the setting in which the research will take place.
A.
Screening and Initial Clinical Assessment: 
Prior to participation, subjects will be screened both over the phone and in-person at the West 
Haven campus of the VA Connecticut Health Care System to determine eligibility and to collect 
demographic and personal history data relevant to the study. If deemed eligible and willing to 
participate, subjects will attend an initial clinical assessment (see Figure 1 for flowchart of all patient 
visits). During this assessment, a clinical psychologist with experience with PTSD will evaluate the 
severity of the subject's symptoms of PTSD and other disorders via a structured clinical interview. If it 
would represent a significant burden to the participant to attend an initial in-person screening 
session due to distance or risk of infection by COVID19, a virtual screening will be offered. 
Assessments that may be collected remotely include the neurological and psychiatric evaluation 
interview, assessment of treatment history, and, for eligible subjects only, the scripting of life events 
and the strategy session. If subjects remain eligible after the initial session, they will be invited to 
continue in the study. Using virtual screening sessions will help to reduce burden on potential 
participants and staff, and limit in-person visits to only those subjects already determined to meet the 
psychiatric eligibility criteria. 
In the Initial Clinical Assessment, if the subject meets clinical inclusion criteria for PTSD, the 
clinician will then collect information about the subject's traumas and stressful life events. The 
collection of life events will occur at the West Haven VA or virtually At this visit, participants who 
appear in person will be asked to wear a portable physiotracking watch to record their GSR and Heart 
rate during memory recall (E4 Wristband, Empatica Inc.) The information about events will later be 
used to create two types of provocative auditory stimuli: auditory trauma narratives (scripts) and clips 
of trauma-related noises. Briefly, and in collaboration with the subject, narratives of the subject's six 
most traumatic and stressful life events will be created and ranked from most to least traumatic. 
Then, two different scripts will be written for each trauma memory (i.e., different wordings, 
descriptions). These scripts will be rich in imagery, combining the subject's narrative accounts with 
descriptions of their emotional and physiological state at the time of the trauma (e.g., sweaty hands, 
tense muscles, etc.). Once written, scripts will be recorded by different voices and edited so that each 
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lasts exactly 60 seconds. In addition, for each trauma memory described by the subject, recordings of 
relevant sounds will be collected and combined into 60 second audio clips of trauma-related noises. 
For example, for a veteran whose trauma involves a jeep under fire, we will concatenate jeep sounds, 
gun shots, heavy breathing, skidding sounds, moaning, etc. to create a 60s trauma-related sound clip. 
Both types of minute-long provocative sound files will be played during the scanning runs to provoke 
trauma recall and anxiety. The two different types of provocative sound clips ensure that we have 
many different stimuli so we don’t need to repeat stimuli too many times (which could induce 
habituation or “tuning out” to that particular sound clip). Information regarding how these auditory 
clips are used during scans is outlined in more detail in the following paragraphs.
B.
Strategy Development Session:
After the Initial Clinical Assessment, participants will meet in person or virtually with a clinician to 
take part in a strategy development session, the goal of which is to develop an individualized 
cognitive strategy for the subject that may provide them with some initial control over their amygdala 
activity. While strategies discussed during this session are intended to assist individuals in 
raising/lowering amygdala activity after trauma recall, they are meant only to engender an initial, 
limited ability to control the amygdala – a starting point for the feedback sessions. During the 
feedback sessions, subjects will have the chance to experiment with their cognitive strategies and 
receive direct feedback regarding what is more effective, thereby allowing subjects to develop 
increasing control over the amygdala in the way that best fits her/his individual style of coping. It is 
important to note that because this stage occurs before randomization, all subjects (NF and sham) 
participate in this session. Therefore, learning effects specific to the session are controlled for by 
group comparisons.
Figure 5: Flowchart of study design. All patients are debriefed and unblinded 
after the final Full Clinical Assessment. Those who had the sham intervention 
will be offered the option of also participating in NF, but data obtained from 
unblinded crossover patients will not be used for any of our primary 
analyses. 
 
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C.
MR Imaging:
At this point, subjects are ready to begin the MRI portion of the study, which consists of two in-
magnet assessments and three neurofeedback or sham sessions, all taking place at the Magnetic 
Resonance Research Center in the Anlyan Center in New Haven, CT. The specific in-magnet 
procedures are described in more detail in the following sections i. – iv.
All subjects who take part in MR imaging are screened at each visit, using screening conventions 
that are standard for magnetic resonance studies, to ensure they do not have any metallic implants, 
shrapnel, pacemakers, etc. Subject will be screened to make sure they are not under the influence of 
illicit substances using urine analysis and a breathalyzer. Based on the results of the urine test and 
breathalyzer, the researchers will determine whether to run the participant through the study 
protocol that day or to postpone participation to a later date as to avoid a potential dampening of 
study effectiveness due to intoxication.  Women of child-bearing age will only be included if they 
assure us they are not pregnant. A free urine pregnancy test will be offered to them to use privately if 
they wish. 
Before each in-magnet assessment, subjects also undergo brief clinical assessments at the Yale 
Magnetic Resonance Research Center (MRRC). During these sessions, symptoms of PTSD and 
depression will be collecting using brief self-report checklists. Information regarding any adverse 
event will also be solicited and recorded.
Subjects will be escorted to and from the scanner by research personnel who will remain present 
throughout the entire assessment. Before each in-magnet assessment, participants will be required 
to fill out an MR Safety Questionnaire, endorsing no rule-outs for MR imaging, and walk through a 
metal detector to ensure they have no ferromagnetic metals on or in their person. The United States 
Food and Drug Administration (FDA) guidelines for magnet strength and exposure to radio waves will 
be carefully observed during all scanning sessions. During in-magnet assessments, MR imaging of the 
brain will record the three dimensional anatomy of the brain, using conventional 3D gradient echo 
sequence to obtain high-resolution slices of the brain. Images of the subject’s brain will also be taken 
while subjects engage in a specific task (described in more detail in Section III.B.). Thousands of 
images will be obtained on each subject for each scanning session. This will provide enough 
information to calculate which regions alter their MRI signal during the activation, or to examine 
which regions vary in signal level in a correlated manner. We may also collect diffusion tensor imaging 
(DTI) data which is most commonly used to examine the integrity of white matter tracts. The total 
imaging time in a single scanning session will not exceed 90 minutes for any subject. During MR scans, 
components of the Siemens Physiologic Monitoring Unit will be used to take recordings of the 
subject’s pulse (via a pulse-oximeter placed on their finger), respiration (via a pneumatic belt), and 
galvanic skin response (via sensors on the fingers). This equipment is designed to be completely MR 
compatible. The records of pulse and respiration will be used during data processing to remove 
physiologic noise from the images. In order to minimize subject head motion during the MR scans, we 
may place tape across the subject’s forehead or chin. This provides tactile feedback about head 
motion. 
Over the course of this procedure, subjects will be asked to report various aspects of their 
experience – this will include responding to questions regarding their perceived control over their 
brain activity.
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i.
In-Magnet Assessment 1: MPRAGE, Resting State, Initial Control Runs, and Localizer. If time 
allows, DTI data will also be collected.
 During the first in-magnet assessment, a high resolution structural image will be 
collected using an MPRAGE sequence. Functional resting state data will be collected, as well 
four control runs. During the resting state sessions spontaneous pupil dilation will be 
measured using a Eyelink 1000 system. As seen in Figure 2, control runs involve a resting 
period, exposure to a provocative audio clip, a period of down-regulation where participants 
try to bring down their amygdala activity, and a final resting period. In order to minimize 
anticipation and rumination regarding the upcoming or preceding stressor, resting periods 
are separated from the provocative audio clip and subsequent period of down-regulation by 
a 1-back memory task (seen in Figure 2 as “1-bk”). These memory tasks provide a cognitively-
engaging distraction for the subject, preventing anticipatory and spill-over amygdala activity 
during resting periods and allowing for a more valid baseline to be established.  
Three localizer runs will also be performed during this session. As seen in Figure 3, 
the localizer runs will involve a resting period, exposure to a provocative audio clip, and a 
final resting period. As in the control run, to ensure that resting periods are not affected by 
the symptom provocation, subjects will perform a 1-back working memory task between the 
rest periods and the provocative audio clips. In order to identify the part of the amygdala 
involved in trauma-related anxiety, activation during the trauma exposure will be compared 
to activity during the resting periods. The area of the amygdala located during this session 
will be used as the target for the brain activity that will be shown to subjects in future NF 
runs. As such, we must be able to identify adequate activation in the amygdala for NF to be 
possible – if no such activation can be identified, the subject will no longer be eligible for 
continuation of the study.
ii.
Randomization
Figure 3: Illustration of a localizer run. Activity will be 
contrasted between provocation and rest blocks to identify 
region of peak amygdala activity.
Figure 2: Schematic illustration of a control task run. Control 
assessed based on activity in the target region of the amygdala 
in the down-regulate blocks (relative to rest)
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All subjects who remain eligible following the localizer will be randomized to receive 
either NF or sham feedback, subject to the restriction that there must always be at least as 
many subjects in the NF group as in the sham group. We will not explicitly describe the sham 
feedback procedure to subjects – rather, all subjects will be told that they will be randomly 
assigned to receive either an experimental intervention (that we hope will help symptoms, 
but that has not yet been demonstrated to be effective) or a control intervention (that we do 
not believe can help symptoms). Subject will be blind to their condition until study 
completion, at which point we will tell them which intervention they received. At that point, 
those who received the control intervention (sham) will be given the option of trying the 
experimental intervention (NF). 
It is important to note that all clinical assessments performed after randomization 
are carried out by a clinical psychologist who is blind to subject assignment. 
iii.
Neurofeedback and Sham Feedback
After randomization, subjects will undergo a total of 18 NF or sham feedback runs, 
carried out over three separate sessions one half of a week apart from one another. Each 
session tends to be composed of 6 NF or sham runs. However, extenuating circumstances 
(e.g., technical errors, subjects’ schedules) may necessitate the 18 NF or sham runs to be 
spread out over more than three sessions. 
In NF runs, an arrow at the top of the screen indicates the subject’s current goal. A 
red arrow pointing upward prompts the subject to listen to the provocative auditory clip and 
not try to control their brain activity pattern. A blue arrow pointing downward prompts the 
subject to try to decrease activity in the target area. A white arrow pointing to the right 
indicates a rest period. In all blocks, a color-coded feedback line is presented below the 
arrow. The line is updated every 2 seconds throughout the scan to indicate activity in their 
target area. During the red block, a provocative audio clip is playing. Subjects are instructed 
not to try to control their activity during this period. The provocative auditory stimulus ends 
when the blue block begins, but subjects often have high activity in this period due to 
rumination. Their goal is to decrease this activity during the blue period. Before engaging in 
this task, subjects are given instructions about what to do during each block, and are 
informed that there is a 6-8 second delay between changes in activity in their target brain 
area and changes in the line graph due to the slow blood flow response and processing 
delays.
The sham feedback is identical to the NF, except for the fact that the feedback line 
displayed to the subject is taken from the amygdala time-course of a previous subject who 
received NF, rather than from the current level of amygdala activity of the present subject. 
This allows the sham subject to get a similar impression of success (or lack thereof) compared 
to the NF subject they were matched to, without receiving any true neurofeedback. While 
this does involve a degree of deception (as subjects will believe that the feedback they are 
receiving is based on their brain activity), subjects in the sham condition will be told at the 
end of the study that the feedback they received was a control intervention and will be 
offered the chance to receive the experimental neurofeedback intervention. It is important 
to note that although the feedback line in the sham condition comes from a past subject, the 
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audio clips in sham runs will still be based on the sham subject's personal memories, and the 
onset and offset of provocative sound files is time-locked across subjects.
iv.
In-Magnet Assessment 2: Resting State, Post-Intervention Control Runs, DTI (if time allows).
Upon completion of all 18 NF or sham runs, subjects will take part in a second in-magnet 
assessment where resting state data will again be collected and they will also complete four 
more control runs. During the resting state sessions spontaneous pupil dilation will be 
measured. These runs are identical in design to the initial control runs described in Section 
C.i. These final control runs will allow us to see how much control subjects gain over their 
amygdalae in the sham versus NF conditions. If time allows, DTI data may also be collected in 
this session.
v.
Follow-Up Scan: Resting State, Long-Term Follow-Up Control Runs, DTI.
One month after the completion of In-Magnet Assessment 2, subjects will take part in an approximately 
hour-long scan where they will perform additional control task runs and where resting state and DTI data will be 
collected. During the resting state sessions spontaneous pupil dilation will be measured.
D.
Clinical Assessments
During brief clinical assessments, symptoms of depression, PTSD, and other clinical conditions 
common in this population, such as tinnitus, will be collected using brief self-report measures. Subjects will 
also respond to a clinician-administered PTSD scale and will be queried regarding adverse events. These 
follow-ups do not always require the subject to be physically present, and will often be carried out over the 
phone or Zoom video conferencing. At 1 and 2 month/s post completion of the final feedback session, 
subjects will undergo a full clinical assessment. Similar measures will be collected during these assessments, 
in addition to the Clinician Administered PTSD Scale for DSM-V (CAPS-5).
E.
Genetic Testing
Adult PTSD patients will be asked via a separate consent form (see below for more details) to provide 
DNA and RNA samples. Both DNA and RNA will be collected in order to conduct sequencing of DNA and RNA. 
Analyses will focus on genes best supported by the PTSD literature at the time of analysis. Genetic data 
collected may be related to the imaging data to examine, for example, whether genetic markers are 
associated with learning over the course of the neurofeedback protocol. See below for more details on 
genetic testing. The genetic component of the present study will occur in collaboration with a pre-existing 
protocol that examines the genetics of neuropsychiatric disorders (HIC0301024156; “Genetic and molecular 
studies of developmental neuropsychiatric disorders associated with cognitive and behavioral impairment”). 
All participants who choose to provide DNA and RNA samples will be consented under this protocol, and all 
genetic data collected by these means will be shared with personnel associated with this protocol.
5. Genetic Testing (continued)
A.   Describe
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i.
the types of future research to be conducted using the materials, specifying if immortalization of 
cell lines, whole exome or genome sequencing, genome wide association studies, or animal 
studies are planned.
Both DNA and RNA will be collected in order to conduct sequencing of DNA and RNA. 
Analyses will focus on genes best supported by the PTSD literature at the time of analysis. 
Genetic data collected may be related to the imaging data to examine, for example, whether 
genetic markers are associated with learning over the course of the neurofeedback protocol. On 
the genetics-specific consent form associated with HIC0301024156, subjects will be able to 
choose whether they want their specimen to be stored for future testing.
ii.
the plan for the collection of material or the conditions under which material will be received. 
Genetic data will be collected in accordance with HIC0301024156. Participants will be 
consented under this protocol using a separate, genetics-specific consent form.
iii. the types of information about the donor/individual contributors that will be entered into a 
database.
Both DNA and RNA will be collected in order to conduct sequencing of DNA and RNA. As 
outlined in HIC0301024156, subjects will also be asked to give permission to their health care 
providers to release copies of their relevant medical and psychiatric records.
iv. the methods to uphold confidentiality.
Any identifiable information that is obtained in connection with this study will remain 
confidential and will be disclosed only with the permission of the subject or as required by U.S. or 
State law. The personal information obtained from subjects will be de-identified at the earliest 
reasonable time after it is received. The principal investigator will keep a link that matches 
subjects to their coded information, and this link will be kept secure and available only to the PI 
or selected members of the research team. The link to any personal information will be kept only 
until the study is complete and all data analyses have been conducted and published, after which 
time the link will be destroyed and the data will become anonymous.
B. What are the conditions or procedures for sharing of materials and/or distributing for future research 
projects? 
The genetic data collected in association with this study will be shared with the PI and research 
personnel of HIC0301024156. This data may also be shared with the U.S. Department of Health and 
Human Services (DHHS) agencies, representatives from Yale University/the Yale Human Research 
Protection Program/the Yale Human Investigation Committee, co-investigators and other investigators, 
study coordinators and members of the research team, and Data and Safety Monitoring Boards and 
others authorized to monitor the conduct of the study. Any transfer of data will occur in a HIPAA-
compliant manner using a secure network and encryption when necessary. De-identified data, including 
data on participant sex/gender, race, ethnicity, and age, may be included in reports to NIH, in 
manuscripts, or on websites, or made otherwise publicly available. Subjects will be asked to allow their 
de-identified genetic data and questionnaire data to be submitted to the NIH dbGaP (database of 
Genotypes and Phenotypes) and/or similar restricted-access scientific databases. The research data 
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collected in the database(s) will be used by scientists for the benefit of medical research. All information 
will be de-identified prior to submission to the NIH dbGaP and/or other similar restricted-access scientific 
database(s). Information that will be sent may include: age at sample collection, gender, race, relevant 
clinical diagnosis and laboratory values.
All health care providers subject to HIPAA are required to protect the privacy of subject information. 
The research staff at the Yale School of Medicine, the West Haven VA, and the Connecticut Mental Health 
Center are required to comply with HIPAA and to ensure the confidentiality of subject information. Some 
of the individuals or agencies listed above may not be subject to HIPAA and therefore may not be 
required to provide the same type of confidentiality protection. They could use or disclose subject 
information in ways not mentioned in this protocol. However, to better protect subject health 
information, agreements are in place with these individuals and/or companies that require that they keep 
subject information confidential.
C. Is widespread sharing of materials planned? 
Not the genetic data. Although other data collected in this study may be uploaded to the National 
Database for Clinical Trials, genetic data will not be included in the upload. Other de-identified data, 
including data on participant sex/gender, race, ethnicity, and age, may be included in reports to NIH, in 
manuscripts, or on websites, or made otherwise publicly available. Subjects will be asked to allow their 
de-identified genetic data and questionnaire data to be submitted to the NIH dbGaP (database of 
Genotypes and Phenotypes) and/or similar restricted-access scientific databases. The research data 
collected in the database(s) will be used by scientists for the benefit of medical research. All information 
will be de-identified prior to submission to the NIH dbGaP and/or other similar restricted-access scientific 
database(s). Information that will be sent may include: age at sample collection, gender, race, relevant 
clinical diagnosis and laboratory values.
As mentioned previously, genetic data will also be shared with the collaborating HIC0301024156 – 
the protocol under which genetic material will be collected.
D. When and under what conditions will materials be stripped of all identifiers?
The personal information obtained from participants will be de-identified at the earliest reasonable 
time after it is received. If subjects do not opt in to long-term storage of their genetic material, their 
sample will be destroyed after the genetic information about PTSD-relevant genes has been determined.
E. Can donor-subjects withdraw their materials at any time, and/or withdraw the identifiers that connect 
them to their materials?
Subjects can withdraw their material at any time before the link to their personal information has 
been destroyed, after which it will not be possible for study staff to identify their material for withdrawal. 
i.
How will requests to withdraw materials be handled (e.g., material no longer identified: that is, 
anonymized) or material destroyed)?
The principal investigator will keep a link that matches subjects to their coded information, 
and this link will be kept secure and available only to the PI or selected members of the research 
team. If the subject requests their material be withdrawn from the study while this link exists, 
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their material will be discarded, and any records of their genetic information destroyed. The link 
to any personal information will be kept only until the study is complete and all data analyses 
have been conducted and published, after which time the link will be destroyed and the data will 
become anonymous.
F. Describe the provisions for protection of participant privacy.
As mentioned above, any identifiable information that is obtained in connection with this study will 
remain confidential and will be disclosed only with participant permission or as required by U.S. or State 
law. The personal information obtained from participants will be de-identified at the earliest reasonable 
time after it is received. The principal investigator will keep a link that matches subjects to their coded 
information, and this link will be kept secure and available only to the PI or selected members of the 
research team. The link to any personal information will be kept only until the study is complete and all 
data analyses have been conducted and published, after which time the link will be destroyed and the 
data will become anonymous. Any information sent to the NIH dbGaP or any other restricted-access 
scientific database will be de-identified prior to submission.
G. Describe the methods for the security of storage and sharing of materials.
Genetic samples will be stored in a locked cabinet that only the necessary research staff have 
access to, and will only have coded study number information on them, no personally identifying 
information. When the material is taken out to be analyzed for genetic information, there will never be 
personal information attached, only study numbers. A record associating patient names and study 
numbers will be kept confidentially in paper form in a locked file cabinet to be seen only by the 
researchers. Personal information obtained from subjects during screening will be kept only on paper in a 
locked file cabinet. Electronically stored information regarding genetic information will be stored on a 
secure, encrypted server with a study number rather than any personal identifiers. As mentioned above, 
any transfer of data will occur in a HIPAA-compliant manner over a secure network and using encryption 
when necessary.
6. Subject Population: Provide a detailed description of the types of human subjects who will be recruited into this 
study.
This study will seek out subjects of all sexes, ages 18 and up. Inclusion criteria include an active and primary 
diagnosis of chronic PTSD, as established by the Clinician Administered PTSD Scale for DSM-V (CAPS-5). The subjects 
must be able to give signed, informed consent and follow instructions in English and have normal or corrected-to-
normal vision. Subjects must be unmedicated or on a stable dose of SSRIs for 2 months prior to enrollment in the 
study, and must not have initiated cognitive-behavioral therapy or any other evidence-based therapy for PTSD 
within the past 3 months. What’s more, subjects must have no intention of changing their medication or 
psychotherapy, or enrolling in another research study testing an experimental intervention, during the 2.5-month 
period of the intervention. However, if unforeseen changes in clinical condition occur during the study, we will not 
discourage subjects from withdrawing from the study to seek new treatments. Subjects with any primary psychiatric 
diagnosis of a current mood disorder, psychotic disorder, autism, mental retardation, or DSM-5 substance use 
disorder will be excluded from participation. Subjects with any history of psychosis or mania will also be excluded. 
While comorbid mood and anxiety disorders will be permitted if they are not the primary focus of clinical attention, 
active suicidality within the past year or a history of suicide attempt in the past 2 years will result in exclusion. As 
this study involves MRI, any subjects with contraindications to MR scanning (e.g., pregnancy, ferromagnetic metal 
in body, severe claustrophobia) will be unable to participate.  Finally, any subjects with a history of unstable medical 
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or neurological condition, or history of brain surgery, epilepsy, or other brain injury will be excluded from 
participation.
7. Subject Classification: Check off all classifications of subjects that will be specifically recruited for enrollment in 
the research project. Will subjects who may require additional safeguards or other considerations be enrolled in 
the study? If so, identify the population of subjects requiring special safeguards and provide a justification for 
their involvement.
None of the populations listed below will be specifically recruited for enrollment.
☐Children
☐ Healthy 
☐Fetal material, placenta, or dead fetus
☐Non-English Speaking
☐ Prisoners
☐Economically disadvantaged persons
☐Decisionally Impaired
☐ Employees
☐Pregnant women and/or fetuses
☐Yale Students 
☐ Females of childbearing potential
NOTE: Is this research proposal designed to enroll children who are wards of the state as potential subjects?
Yes ☐  No ☒ 
8. Inclusion/Exclusion Criteria: What are the criteria used to determine subject inclusion or exclusion?
Inclusion:

Ages 18 and up

Diagnosis of chronic PTSD, as established by the Clinician Administered PTSD Scale for DSM-V 
(CAPS-5) Ability to give signed, informed consent in English

Normal or corrected-to-normal vision

Participants who are on a stable dose of SSRI antidepressants for 2 months (3 months if they 
are on sertraline), or who have been un-medicated for at least 2 months, will be allowed to
participate in this study

At the time of recruitment, patients must have no intention of changing their medication or
psychotherapy during the 2.5 month period of the intervention.

Resarch group must be able to identify a trauma-related target region in or immediately 
adjacent to the amygdala
Exclusion:

Any primary psychiatric diagnosis of a current major mood disorder, psychotic disorder, 
autism, mental retardation, or DSM-5 substance use disorder of mild or greater severity (2 or 
more symptoms) in the past 30 days. Comorbid mood and anxiety disorders will be permitted 
if they are not the primary focus of clinical attention.

Any history of psychosis or mania

Active suicidality within past year, or history of suicide attempt in past 2 years

Any contraindication to MRI scanning (severe claustrophobia, ferromagnetic metal in body,
etc.)

Pregnancy

Any unstable medical or neurological condition

Any history of severe past drug dependence (i.e., a focus of clinical attention or a cause of
substantial social or occupational difficulty)

Any history of brain surgery, of penetrating, neurovascular, infectious, or other major brain
injury, of epilepsy, or of other major neurological abnormality (including a history of 
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traumatic brain injury [TBI] with loss of consciousness for more than 24 hours or 
posttraumatic amnesia for more than 7 days).

Significant hearing loss or severe sensory impairment

Any psychotropic medication other than a stable dose of SSRIs

Any change in accepted psychotropic medication within the past 2 months

Active engagement in cognitive-behavioral therapy or any evidence-based PTSD
psychotherapy (CPT, PE, EMDR) initiated within the past 3 months (continuation of 
established maintenance supportive therapy will be permitted)

Enrollment in another research study testing an experimental/clinical/behavioral intervention 
intended to affect symptoms initiated within the last 2 months, or intended enrollment 
within the next 2.5 months
9. How will eligibility be determined, and by whom?
Eligibility will first be determined during a brief phone screen carried out by research personnel, where 
potential subjects will answer questions about diagnosis, symptom, and medication history. Subjects will also 
answer questions regarding any contraindications for MR research. Individuals with obvious exclusion criteria will 
not be invited for an in-person assessment. Following the phone screen, subjects will attend an in-person 
assessment at the West Haven campus of the VA Connecticut Health Care System to determine eligibility and to 
collect demographic and personal history data relevant to the study. During this assessment, a clinical 
psychologist with experience with PTSD will evaluate the severity of the subject's symptoms of PTSD and other 
disorders via a structured clinical interview. This assessment may be conducted remotely via a virtual meeting 
with the study clinician, if an in-person assessment would present a hardship to the participant. 
10. Risks: Describe the reasonably foreseeable risks, including risks to subject privacy, discomforts, or 
inconveniences associated with subjects participating in the research. 
The screening procedure is practically never associated with any risks. However, some of the questions 
participants will be asked to answer will be personal and may be upsetting. 
Magnetic resonance (MR) is a technique that uses magnetism and radio waves – not x-rays – to acquire 
images of the brain. However, there are still some risks associated with this technique due to the size of the 
scanner or the strength of the magnetic field and radio waves. First, some people may feel uncomfortable or 
anxious during the scans due to the tight quarters of the scanner (especially if they have a history of 
claustrophobia) or due to other factors such as the noises that the scanner makes. There are also some very 
minor side effects that stem from exposure to magnetic fields and/or radio waves that can occur on rare 
occasions – some people might feel dizzy, get an upset stomach, have a metallic taste, or feel tingling 
sensations or muscle twitches during scans. However, these sensations are rare and usually go away quickly. 
Subjects will also be able to communicate with research staff about any issues that arise during the course of 
the scan. Because of its use of powerful magnetic fields, MR imaging carries more pressing risks for certain 
people. For example, individuals with pacemakers or other ferromagnetic metal objects inside their bodies 
might be harmed by the magnetic field. To avoid this risk, all subjects will be screened prior to participation 
for any MR contraindications – only individuals with no ferromagnetic metal in or on their person will be able 
to enter the room containing the magnet. Another risk inherent to MR research is the possibility of metal 
objects being pulled into the magnet and hitting research personnel or the subject. To prevent any accidents, 
no metal can be brought into the magnet room at any time.
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Due to the trauma-related stimuli presented to subjects in the scanner, there is a risk that their PTSD 
symptoms will flare-up. These stimuli include personalized scripts and sound effects that relate to the 
subjects’ traumatic experiences (see section I.4. Research Plan for more detail on these audio clips), and are 
intended to provoke subjects’ symptoms. While the subjects’ goal is to learn to control these symptoms with 
the help of neurofeedback, exposure to upsetting audio clips will no doubt be a difficult and stressful 
experience. If subjects feel they are at risk of an intense reaction (such as a panic attack or psychotic episode), 
they are encouraged to let the investigators know immediately. During piloting of this study under a different 
protocol, a clinician was physically present during the scans involving symptom provocation. No adverse 
events occurred during these scans. As such, a clinician will be on-call at all times during the symptom 
provocation sessions rather than physically present. If subjects have a problem following the session, 
whereby they cannot stop thinking and feeling upset about the stimuli, they are encouraged to contact a 
collaborating researcher and clinician during normal work hours or the Biostudies on-call physician for 
emergency treatment after normal work hours.
11. Minimizing Risks: Describe the manner in which the above-mentioned risks will be minimized.
During screening, participants can choose not to answer any questions and can choose to leave the study 
at any time without incurring any sort of penalty. If participants feel upset when asked about military trauma 
during the PTSD assessment (CAPS-5) or while making the trauma narratives, trained study staff will assist. A 
psychologist in the Mental Health Clinic will also be available to speak with the participant. The clinician can 
employ crisis intervention techniques, assist with healthy coping, and provide debriefing and clinical referrals, 
as necessary. During study debriefing, additional resources will be provided, such as the Veterans Crisis Line 
and information about the VA Connecticut PTSD Firm services. In the event that the assessment will indicate 
an acute emotional distress associated with suicidal thoughts, a psychiatrist or psychologist will be readily 
available to evaluate and talk to the participant. If imminent danger to self or other persists it may result in 
psychiatric hospitalization against the participant’s will.  If a subject experiences a significant worsening in their 
psychiatric symptoms during the course of the study but after the subject leaves the site, one of the study 
clinicians will be available to meet with them to address these issues. Subjects will be told that if they have an 
issue following the session, whereby they cannot stop thinking and feeling upset about the stimuli, or if they 
have any other research-related complaints, concerns, or questions, they will be encouraged to call Dr. 
Harpaz-Rotem [(203) 494-5454] during normal work hours. If it is after-hours and the subject is concerned that 
they may have a panic attack or a psychotic episode, they are to contact the Biostudies on-call physician for 
emergency treatment by calling the VACHS operator at (203) 932-5711, extension 0.
In terms of the MRI procedure, the United States Food and Drug Administration (FDA) guidelines for 
magnet strength and exposure to radio waves will be carefully observed during all scanning sessions. Subjects 
will be closely monitored during the scans and will be able to openly communicate with research staff whilst 
in the magnet. Subjects will be able to request to be removed from the scanner at any time during the session 
if they feel uncomfortable for any reason or decide to discontinue participation. All subjects will be 
thoroughly screened for any MR contraindication prior to participation by carefully filling out an MR Safety 
Questionnaire in the presence of research personnel and by passing through a metal detector. To minimize 
the risk of metal objects being pulled into the scanner, all individuals – not just participants – who enter into 
the room with the magnet will first ensure that they have no ferromagnetic material on their person. Once 
the subject is in the scanner, the door to the room containing the scanner will be closed and remain closed 
for the duration of the session. To protect the subject from the loud noises associated with running an MR 
scan, subjects will wear both earplugs and headphones (the latter also allowing subjects to communicate with 
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the research personnel in the adjoining room, as mentioned above, and to hear the auditory stimuli during 
scans).
Although provocation of symptoms in PTSD engenders clinical risks, they are manageable. Exposure 
therapy, which involves extensive symptom provocation, is the first-line intervention recommended by the 
Institute of Medicine (IOM), DoD, and VA. In the context of NF, we have had no clinical issues arise in years of 
symptom provocation for our OCD study. Moreover, in our PTSD pilot studies, all 4 participants tolerated the 
intervention well. For these reasons, we expect participants to tolerate the intervention without adverse 
reactions. However, for the sake of caution, we will always closely monitor the patients’ symptoms and a 
psychiatrist or clinical psychologist will be available to speak with them and intervene should symptom 
exacerbation occur. Namely, if subjects feel they are at risk of an intense reaction (such as a panic attack or 
psychotic episode), they are encouraged to let the investigators know immediately. As previously mentioned, 
during piloting of this study under a different protocol, a clinician was physically present during the scans 
involving symptom provocation. No adverse events occurred during these scans. As such, a clinician will be 
on-call at all times during the symptom provocation sessions rather than physically present. If subjects have a 
problem following the session, whereby they cannot stop thinking and feeling upset about the stimuli, or 
have any other research-related complaints, concerns, or questions, they are encouraged to contact the PI 
(Dr. Ilan Harpaz-Rotem -ilan.harpaz-rotem@yale.edu / (475) 434-2943) during normal work hours. If it is 
after-hours and subjects are concerned that they may have a panic attack or a psychotic episode, they are 
encouraged to contact the Biostudies on-call physician for emergency treatment by calling the VACHS 
operator at (203) 932-5711, extension 0. 
12. Data and Safety Monitoring Plan: Include an appropriate Data and Safety Monitoring Plan (DSMP) based on 
the investigator’s risk assessment stated below. (Note: the HIC will make the final determination of the risk to 
subjects.)
a. 
What is the investigator’s assessment of the overall risk level for subjects participating in this 
study? 
Moderate risk associated with symptom provocation for PTSD patients, other aspects of 
the study involve minimal risk.
b.
If children are involved, what is the investigator’s assessment of the overall risk level for the 
children participating in this study? 
N/A
c.
Include an appropriate Data and Safety Monitoring Plan. Examples of DSMPs are  
available here http://your.yale.edu/policies-procedures/forms/420-fr-01-data-and-safety-
monitoring-plans-templates
Neurofeedback of amygdala activity for PTSD
Data and Safety Monitoring Plan (DSMP)
420 FR.1
Greater Than Minimal Risk DSMP
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1. Personnel responsible for the safety review and its frequency:
Dr. Ilan Harpaz-Rotem (the principal investigator), Dr. Michelle Hampson, and their research personnel 
(postdoctoral and postgraduate associates) will be responsible for monitoring the data, assuring protocol 
compliance, and conducting the safety reviews at a minimum of every 6 months (including when re-approval of 
the protocol is sought). More specifically, Dr. Ilan Harpaz-Rotem will have primary responsibility for patient well-
being during the protocol and for maintaining clinical data in a secure manner. Dr. Michelle Hampson will be 
responsible for maintaining confidentiality of the neuroimaging data in a secure manner and for ensuring safety 
during MR scanning. During the review process, the principal investigator, in consultation with Dr. Hampson, will 
evaluate whether the study should continue unchanged, require modification/amendment, or close to 
enrollment. In addition to the two primary investigators (Drs. Harpaz-Rotem and Hampson) and research 
personnel, an Independent Monitoring Committee has been established to ensure the proposed study’s safety 
and efficacy. This committee consists of two experts in the field of PTSD: Professor Steven Southwick, M.D., and 
Robert Pietrzak, Ph.D. of VACT and Yale School of Medicine. Either of the primary investigators, the IRB, or the 
Independent Monitoring Committee have the authority to stop or suspend the study or require modifications.
2. The risks associated with the current study are deemed greater than minimal but less than high for the 
following reasons: 
1.
We do not view the risks associated with the exposure to trauma-related stimuli as minimal risks.
2.
Although provocation of symptoms in PTSD engenders clinical risks, they are manageable. Exposure 
therapy, which involves extensive symptom provocation, is the first-line intervention recommended by 
the Institute of Medicine (IOM), DoD, and VA. In the context of neurofeedback, we have had no clinical 
issues arise in years of symptom provocation for our OCD study. Moreover, in our PTSD pilot studies, all 4 
participants tolerated the intervention well. For these reasons, we expect participants to tolerate the 
intervention without adverse reactions. As such, given the now-established safety and validity of the 
current experimental treatment in our prior work, we do not view the proposed study as high risk.
Although we have assessed the proposed study as one of greater than minimal risk, the potential exists for 
anticipated and/or unanticipated adverse events, serious or otherwise, to occur since it is not possible to predict 
with certainty the absolute risk in any given individual. Therefore, we provide a plan for monitoring the data and 
safety of the proposed study as follows:
As previously mentioned, Dr. Harpaz-Rotem will have primary responsibility for patient well-being during the 
protocol and for maintaining clinical data in a secure manner. Dr. Hampson will be responsible for maintaining 
confidentiality of the neuroimaging data in a secure manner, and for ensuring safety during MR scanning. Any 
identifiable information that is obtained in connection with this study will remain confidential and will be 
disclosed only with the permission of the subject or as required by U.S. or State law. The personal information 
obtained from subjects will be de-identified at the earliest reasonable time after it is received. The principal 
investigators will keep a link that matches subjects to their coded information, and this link will be kept secure 
and available only to the PIs or selected members of the research team. The link to any personal information will 
be kept only until the study is complete and all data analyses have been conducted and published, after which 
time the link will be destroyed and the data will become anonymous. Personal information obtained from 
subjects during screening will be kept only on paper in a locked file cabinet. Any other data that is collected 
during the study (i.e., DICOM data) will be stored on a secure, encrypted server with a study number rather than 
any personal identifiers. The record associating patient names and study numbers will be kept confidentially in 
paper form in a locked file cabinet to be seen only by the researchers. Any transfer of data will occur in a HIPAA-
compliant manner over a secure network, using encryption when necessary.
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At every clinical assessment, including brief ones, we collect the Beck Depression Index (BDI; Beck et al. 1961), 
which monitors suicidality, as well as information regarding adverse events and worsening of symptoms. These 
assessments are scheduled to occur at approximately half week intervals during the active part of the 
intervention and at month intervals during follow-up. If any issues arise, Dr. Harpaz-Rotem will be notified and will 
review the data. The guidelines of our IRB will be followed in the case of all adverse events. In the case of 
worsening symptoms or endorsement of suicidal ideation on the BDI (as indicated by a score of 2 or higher on 
question 9), Dr. Harpaz-Rotem will arrange an in-person assessment of the participant. As required by law, if 
needed, Dr. Harpaz-Rotem will admit the participant into Yale-New Haven hospital for further monitoring. In the 
case of difficult decisions, Dr. Harpaz-Rotem will consult the Independent Monitoring Committee.
As mentioned above, the Independent Monitering Committee consists of Drs. Southwick and Pietrzak. Every six 
months, the members of this committee will receive reports from the study team about the occurrence of 
adverse events, the progress of recruitment, the demographic characteristics of enrolled participants, the number 
of dropouts and participants’ reasons for dropping out, as well as any protocol amendments. They will also be 
consulted if any difficult situations arise or if there are any serious and unanticipated adverse events that are 
possibly, probably, or definitely related to the study. These two committee members are extremely experienced 
in the assessment and the outpatient and inpatient management of all psychiatric emergencies, with particular 
expertise in PTSD and related disorders. They will be an ideal sounding-board and resource for the resolution of 
any challenging clinical situations that may arise during the conduct of this research. In the unlikely event that Dr. 
Harpaz-Rotem and the committee members have differing opinions as to the appropriate clinical choice for a 
particular patient, decisions made by the committee will be determinative, on the presumption that their external 
perspective will most appropriately weight the patients’ well-being.
3. Attribution of Adverse Events:
Adverse events will be monitored for each subject participating in the study and attributed to the study 
procedures/design by the principal investigators. As previously mentioned, Dr. Harpaz-Rotem will have primary 
responsibility for any adverse events of clinical significance or that involve overall patient well-being. Dr. Hampson 
will be responsible for any adverse events that occur during MR scanning. These events will be attributed to the 
study procedures/design according to the following categories:
a.) Definite: Adverse event is clearly related to investigational procedures(s).
b.) Probable: Adverse event is likely related to investigational procedures(s).
c.) Possible: Adverse event may be related to investigational procedures(s).
d.) Unlikely: Adverse event is likely not to be related to the investigational procedures(s).
e.) Unrelated: Adverse event is clearly not related to investigational procedures(s).
No possibly, probably or definitely related adverse events are expected for this intervention. We will query 
subjects at every clinical assessment for such events. If any occur, we will consult with the Independent 
Monitoring Committee who will have authority to terminate the study, remove patients from participation, etc.
4. Plan for Grading Adverse Events:
The following scale will be used in grading the severity of adverse events noted during the study:
1.
Mild adverse event
2.
Moderate adverse event
3.
Severe adverse event
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5. Plan for Determining Seriousness of Adverse Events:
Serious Adverse Events:
In addition to grading the adverse event, the PIs will determine whether the adverse event meets the criteria for a 
Serious Adverse Event (SAE).  An adverse event is considered serious if it results in any of the following outcomes:
1.
Death;
2.
A life-threatening experience in-patient hospitalization or prolongation of existing hospitalization; 
3.
A persistent or significant disability or incapacity; 
4.
A congenital anomaly or birth defect; OR
5.
Any other adverse event that, based upon appropriate medical judgment, may jeopardize the subject’s 
health and may require medical or surgical intervention to prevent one of the other outcomes listed in 
this definition. 
An adverse event may be graded as severe but still not meet the criteria for a Serious Adverse Event.  Similarly, an 
adverse event may be graded as moderate but still meet the criteria for an SAE.  It is important for the PIs to 
consider the grade of the event as well as its “seriousness” when determining whether reporting to the IRB is 
necessary.
6. Plan for reporting UPIRSOs (including Adverse Events) to the IRB
The principal investigators will report the following types of events to the IRB: 
Any incident, experience or outcome that meets ALL 3 of the following criteria:
1.
Is unexpected (in terms of nature, specificity, severity, or frequency) given (a) the research 
procedures described in the protocol-related documents, such as the IRB-approved protocol and 
informed consent document and (b) the characteristics of the subject population being studied; AND 
2.
Is related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); AND
3.
Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, legal, or social harm) than was previously known or recognized.
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs) may be medical or non-medical in 
nature, and include – but are not limited to – serious, unexpected, and related adverse events and 
unanticipated adverse device effects.  Please note that adverse events are reportable to the IRB as UPIRSOs 
only if they meet all 3 criteria listed above.
These UPIRSOs/SAEs will be reported to the IRB in accordance with IRB Policy 710, using the appropriate forms 
found on the website. All related events involving risk but not meeting the prompt reporting requirements 
described in IRB Policy 710 should be reported to the IRB in summary form at the time of continuing review. If 
appropriate, such summary may be a simple brief statement that events have occurred at the expected frequency 
and level of severity as previously documented.  In lieu of a summary of external events, a current DSMB report 
can be submitted for research studies that are subject to oversight by a DSMB (or other monitoring entity that is 
monitoring the study on behalf of an industry sponsor).
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Adverse events will be reported to Yale University in a timely manner, according to the IRB guidelines. Any serious 
and possibly, probably, or definitely related events as will be reported within 48 hours of discovery to both the 
Yale IRB and the Independent Monitoring Committee. All adverse events (whether possibly related or not) will be 
summarized for NIH in the yearly renewal report.
7. Plan for reporting adverse events to co-investigators on the study, as appropriate the protocol’s research 
monitor(s), e.g., industrial sponsor, Yale Cancer Center Data and Safety Monitoring Committee (DSMC), Protocol 
Review Committee (PRC), DSMBs, study sponsors, funding and regulatory agencies, and regulatory and decision-
making bodies.
For the current study, the following individuals, funding, and/or regulatory agencies will be notified (choose those 
that apply):
x All Co-Investigators listed on the protocol.
□ Yale Cancer Center Data and Safety Monitoring Committee (DSMC)
x National Institutes of Health
□ Food and Drug Administration (Physician-Sponsored IND #_______)
□ Medical Research Foundation (Grant______)
□ Study Sponsor
x Independent Monitoring Committee (as outlined above)
Every 6 months, Drs. Hampson and Harpaz-Rotem will conduct a review of all adverse events. After evaluating the 
frequency and severity of the adverse events, the PIs will determine if modifications to the protocol or consent 
form are required.
References
Beck, A. T., Ward, C.H., Mendelson, M., Mock, J., & Erbaugh, J.  (1961).  An inventory for measuring depression.  
Archives of General Psychiatry, 4, 561-571.
d. For multi-site studies for which the Yale PI serves as the lead investigator:
Not applicable (not a multi-site study)
13. Statistical Considerations: Describe the statistical analyses that support the study design. 
This study will be divided into two phases: the R61 phase, which focuses on testing the mechanism of 
action of an intervention, and the R33 phase, which is contingent on the findings of the R61 phase and focuses on 
testing the associations between a change in the target, mechanisms of treatment response, and clinical 
outcome. The statistical analyses that support the study design are described below using the above two phases 
as organizing principles, including a section that covers offline neuroimaging data analysis that will be performed 
prior to analyses in both phases of the study.
A.
Offline Neuroimaging Data Analyses:
i.
Preprocessing: Data will be motion corrected using SPM (http://www.fil.ion.ucl.ac.uk/spm/) and 
all subsequent analyses will be done using Yale BioImage Suite software package.
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ii.
Registration: The Montreal Neurological Institute (MNI) brain will be used as a reference 
coordinate system. Functional imaging data for all subjects will be transformed to the space of 
the MNI brain via a series of registrations (functional  anatomical  MPRAGE  MNI space) 
that have all been visually inspected.
iii.
Localizer analyses: The localizer run (see section I.4. Research Plan) will be used to define the 
target region for NF. First, a whole brain “t-map” will be computed by calculating voxel-wise t-
tests contrasting activity during the trauma script exposure period to activity in the resting 
periods, after adjusting for hemodynamic delay. This is not a true t-map due to autocorrelation, 
but is useful for identifying the voxels with peak activation in the amygdala. The 30 peak voxels 
(subject to a cluster filter of 4) falling in the amygdala will be defined as the target area.
iv.
Control task activation analyses: Control over the amygdala target region will be computed by 
running voxel-wise regression analyses separately for the two categories of traumas – trained 
(traumas with which the subject engaged in NF) and untrained (traumas that the subject was not 
exposed to during NF). Four regression analyses will be run per subject – one per category from 
each of the two assessment sessions. Regressors will be defined for the task periods using boxcar 
functions convolved with a canonical hemodynamic response function. Three regressors will be 
used, corresponding to the provocation block, the down-regulate blocks of interest, and the 1-
back periods (the lattermost being included to remove the effects of the 1-back periods and 
make contrasts relative to the rest blocks). Resulting maps of beta values for the regulate and 
provocation blocks will be transformed to a common space (see above section I.b.) and masked 
with the target region (also transformed to common space). Average value in the target region 
will be computed separately from beta maps for the provocation and down-regulate blocks to 
yield estimates of activation in the amygdala in each condition of each assessment session for the 
trained and untrained trauma memories. All analyses outlined in the following sections will use 
data from the regulation blocks of the untrained traumas unless otherwise noted.
v.
Resting state analyses: In addition to the offline neuroimaging data analyses described above in 
section I., resting state data collected during each In-Magnet Assessment will be low-pass filtered 
(0.1 Hz), motion parameters, and the average time-courses of the ventricles and white matter will 
be regressed from the data. Seed maps of connectivity to the amygdala will then be computed. 
First, the time-courses of voxels in the target area will be averaged to yield a reference seed 
region time-course. This time-course will be correlated with the time-course of activity measured 
at every voxel in the brain to yield a whole-brain map of r-values. The r-values will be transformed 
to Gaussian variables via Fisher’s transform. The resulting seed region connectivity maps for each 
In-Magnet Assessment of each subject will be entered into group-level analyses after 
transformation to common space (see above section ii.).
B.
R61 Phase:
i.
To determine if NF increases control over amygdala more than sham feedback: Activation in the 
target region of the amygdala in the down-regulate blocks (computed as described in above 
section A.iv.) will be compared across groups to see if mean activation is larger in the NF group 
than the sham feedback group, with an effect size of the group difference d > 1. If so, this will 
satisfy “Go” criteria and the study will proceed to the R61 phase. If not, the decision will be “No 
Go”.
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C.
R33 Phase:
i.
To determine if NF increases control over the amygdala significantly more than sham feedback: 
Activation in the amygdala in the down-regulate blocks (computed as described in above section 
A.iv.) will be entered into a 2x2 ANOVA with factors time-point (2 levels: pre and post) and group 
(2 levels: NF and sham). If there is a significant interaction of group by time-point at a p < 0.05 
level, a two-sample t-test will be used to see if the improvement in control was greater in the NF 
subjects than the sham subjects.
ii.
To determine if NF improves symptoms more than sham feedback and to correlate symptom 
changes with control over the amygdala: A 2x2 ANOVA with factors group (2 levels: NF and sham) 
and time-point (2 levels: pre-intervention and first post-intervention) will be run on the past-
month scores from the clinician-administered symptom checklist collected during the Full Clinical 
Assessment sessions. If there is a significant group-by-time-point interaction and post-hoc t-tests 
reveal a significantly greater improvement in symptoms in the NF group than the sham group, we 
will conclude the NF does improve clinical symptoms more than the sham. The change in score 
will also be correlated across NF subjects with the change in control over the brain area 
(computed as described above in section A.iv.). We hypothesize a decrease in score (indicating 
improvement in PTSD symptoms) will be correlated with an increase in control. A secondary 
analysis will be run using all 3 time points of scores collected (pre, 1 month post, and 2 month 
post intervention) to explore the long-term clinical effects. A linear mixed model analysis with 
group (NF or sham) by time-point (pre, 1 month post, and 2 month post intervention) will be used 
to capture the longitudinal effect of the clinical intervention. Finally, if the intervention does 
appear to reduce symptoms, we will explore whether these changes are greatest for scores on 
PTSD criterion B (intrusion) and criterion E (alteration in arousal reactivity) as these are expected 
to be most closely related to successful amygdala regulation. 
iii.
To determine if NF changes resting connectivity to the amygdala and if these changes are 
correlated with symptom improvement and improved ability to regulate the amygdala: After 
transforming the resting connectivity maps to the reference space (see above section A.v.), we 
will subtract the seed region connectivity map of the resting data collected pre-intervention from 
that collected in the post-intervention to yield a map of change in amygdala connectivity for each 
subject. Two-sample voxel-wise t-tests will be computed across subjects comparing these maps in 
the NF and sham groups. The resulting group difference map will be cluster corrected, using a 
non-parametric permutation test to identify those areas of the brain “rewired” by NF. For each 
locus surviving cluster correction, we will also examine whether the change in amygdala 
connectivity in this locus for each NF subject is correlated with their symptom improvement or 
their improvement in control over the amygdala.
   
SECTION II: RESEARCH INVOLVING DRUGS, BIOLOGICS, RADIOTRACERS, PLACEBOS AND DEVICES
If this section (or one of its parts, A or B) is not applicable, check off N/A and delete the rest of the section.
A.  RADIOTRACERS
☒N/A
 B.  DEVICES
 ☒N/A
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1.
Are there any investigational devices used or investigational procedures performed at Yale-New Haven 
Hospital (YNHH) (e.g., in the YNHH Operating Room or YNHH Heart and Vascular Center)?  ☐Yes   ☒No  
SECTION III: RECRUITMENT/CONSENT AND ASSENT PROCEDURES 
1. Targeted Enrollment: Give the number of subjects…
a.
Targeted for enrollment at Yale for this protocol: 60
b.
If this is a multi-site study, give the total number of subjects targeted across all sites: 60
2. Indicate recruitment methods below.  Attach copies of any recruitment materials that will be used.
☒Flyers
☒ Internet/web postings
☐ Radio
☒ Posters
☐ Mass email solicitation
☐ Telephone
☒ Letter
☒ Departmental/Center website
☐ Television
☐ Medical record review* 
☒ Departmental/Center research boards
☒ Newspaper
☐ Departmental/Center newsletters
☒ Web-based clinical trial registries
☒ Clinicaltrails.gov 
☒ YCCI Recruitment database
☒ Social Media (Twitter/Facebook): 
☒ Other: collaborating sites 
(Connecticut Mental Health Center, 
VA CT Healthcare system, Yale New 
Haven Hospital); bus ads; Trialfacts (a 
company that helps with study 
recruitment)
All recruitment material, including that which is generated by Trialfacts, will be submitted to the IRB as an 
amendment upon creation. Only recruitment material that has passed IRB review will be disseminated.
* Requests for medical records should be made through JDAT as described at 
http://medicine.yale.edu/ycci/oncore/availableservices/datarequests/datarequests.aspx
3. Recruitment Procedures: 
a. Describe how potential subjects will be identified. 
We will recruit participants from four sources: (1) The CT Mental Health Center (CMHC) – the largest 
provider of mental health services in the community; (2) The VA CT Healthcare system, where mental health 
services are provided to those who were exposed to psychological trauma either in an urban war setting or at 
war overseas. We are currently recruiting veterans from the CT VA for two ongoing projects – more than 150 
veterans have already participated in our studies and many have expressed interest in returning for additional 
studies; (3) Yale New Haven Hospital, which serves as a major trauma center for central Connecticut. The 
Hospital treats a large number of individuals exposed to urban trauma such as physical abuse and gunshots; 
(4) As a large number of individuals who are exposed to trauma do not seek mental health treatment, we will 
also recruit from the larger community. We will use flyers and brochures that will be put on bulletin boards in 
the New Haven area, bus advertisements, advertisements in the newspaper and through Craigslist.
 
Additionally, we will commission the services of Trialfacts (trialfacts.com) – a recruitment service for 
research studies, with whom a Business Associate Agreement (BAA) and a Professional Services and 
Consulting Agreement (PSCA) have been reached. Trialfacts will post online advertisements (which will be 
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submitted to the IRB upon creation) that funnel potential subjects into an online pre-screening survey. 
Responses from subjects who pass this survey and are interested in further screening will be shared with the 
investigators via Yale Secure Box, after which point they will be contacted in the manner described below. 
This process has been reviewed and approved by Yale ITS. No subject data obtained as a result of their 
subsequent participation in this study will be shared with Trialfacts.
b. Describe how potential subjects are contacted.
Participants will first express their interest by contacting the phone number or email that are listed on the 
advertisement/recruiting material. The research team will then reach out to them to describe the study in 
more detail and determine whether they would be willing to be contacted for an initial 10 to 15-minute 
phone screen. If so, subjects will be asked to provide a phone number and a good time at which to contact 
them. The research team will then carry out a 10 to 15-minute phone screen that queries for treatment and 
diagnosis history, symptoms of PTSD or other mental disorders, and any MRI contraindications. If there are 
any obvious rule-outs, the patients will be informed that they are not eligible for participation and will be 
given information regarding other possible resources they may be interested in (e.g., if they are seeking 
treatment). All subjects who do not have obvious rule-outs will be contacted and scheduled for an in-person 
screening at the West Haven VA. From this point forward, subjects will follow the procedure outlined in 
section I.4. Research Plan.
c. Who is recruiting potential subjects?
(1) Research personnel at the CT Mental Health Center (CMHC), the VA CT Healthcare system, Yale New 
Haven Hospital; (2) flyers/brochures that will be put on bulletin boards in the New Haven area, bus 
advertisements as well as advertisements in the newspaper, on buses, and on Craigslist; (3) the recruitment 
company Trialfacts (online advertising).
4. Assessment of Current Health Provider Relationship for HIPAA Consideration: Does the Investigator or any 
member of the research team have a direct existing clinical relationship with any potential subject? 
☐Yes, all subjects
☒Yes, some of the subjects
☐No
If yes, describe the nature of this relationship.
It is possible that subjects recruited through the VA CT Healthcare system may have an existing clinical 
relationship with Dr. Ilan Harpaz-Rotem.
5. Request for waiver of HIPAA authorization: (When requesting a waiver of HIPAA Authorization for either the 
entire study, or for recruitment purposes only.  Note: if you are collecting PHI as part of a phone or email screen, 
you must request a HIPAA waiver for recruitment purposes.)
Choose one: 
☐ For entire study 
☒ For recruitment/screening purposes only
☐ For inclusion of non-English speaking subject if short form is being used and there is no translated HIPAA 
research authorization form available on the University’s HIPAA website at hipaa.yale.edu.
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i.
Describe why it would be impracticable to obtain the subject’s authorization for use/disclosure of this 
data: 
Authorization will be obtained for the study itself. However, it would be impracticable to try to 
acquire this information during the brief initial phone screen. Verbal consent will be obtained from 
participants prior to recording PHI. If patients remain eligible following the phone screen, they will 
undergo a more formal authorization process before data collection.
ii.
If requesting a waiver of signed authorization, describe why it would be impracticable to obtain the 
subject’s signed authorization for use/disclosure of this data: 
Signed authorization will be obtained for all participants. Only the brief phone screening of 
potential participants will be conducted without signed authorization (see above).
The investigator assures that the protected health information for which a Waiver of Authorization has been 
requested will not be reused or disclosed to any person or entity other than those listed in this application, except 
as required by law, for authorized oversight of this research study, or as specifically approved for use in another 
study by an IRB.
Researchers are reminded that unauthorized disclosures of PHI to individuals outside of the Yale HIPAA-Covered 
entity must be accounted for in the “accounting for disclosures log”, by subject name, purpose, date, recipients, 
and a description of information provided.  Logs are to be forwarded to the Deputy HIPAA Privacy Officer.
6. Process of Consent/Assent: Describe the setting and conditions under which consent/assent will be obtained, 
including parental permission or surrogate permission and the steps taken to ensure subjects’ independent 
decision-making.
During the initial phone screens, research personnel will give an overview of the nature of the screening 
questions and obtain verbal consent from the subject before beginning the collection of any sensitive 
information/PHI. Subjects will be informed that this information will be put into a database and that they will be 
able to request that this data is removed and destroyed at any point. All subjects enrolled in the study will read 
over and sign full consent forms prior to clinical assessments and scanning sessions, with a member of the 
research team present and available to answer any questions they may have. This will occur at the Connecticut 
VA, the CMHC, or the Magnetic Resonance Research Center. Subjects will be knowledgeable about the study at 
this time and understand its risks and benefits, having had the procedure described to them in detail on both the 
consent form and by a member of the research team. The only part of the procedure that will be actively withheld 
from the subject is their condition (experimental or sham). However, the subject will be informed that they are 
being randomized into one of the two conditions and that their condition will be revealed to them upon study 
completion or termination, at which time subjects in the sham condition will be offered a chance to engage in real 
NF.
7. Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Indicate how the personnel obtaining 
consent will assess the potential subject’s ability and capacity to consent to the research being proposed. 
Research personnel obtaining consent will make sure that the subject is well informed on the research 
process. This means that they will describe the study in detail in largely non-scientific, layman’s terms, making 
sure that the subject understands the procedure, its risks, and its benefits. The research personnel will also 
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answer any questions the subject may have, and offer an ongoing dialogue about the experiment and the 
subject’s role therein. This will ensure that the subject is both informed and motivated to engage in research, and 
is able to understand their role in the process. If the subject is unable to understand the research or changes their 
mind after hearing about the procedure in more detail, they will be deemed unable or unwilling to give consent 
and will not participate further in the study.
8. Non-English Speaking Subjects: Explain provisions in place to ensure comprehension for research involving non-
English speaking subjects. If enrollment of these subjects is anticipated, translated copies of all consent materials 
must be submitted for approval prior to use. 
As per the eligibility criteria, subjects must be able to understand and follow directions in English. This is due 
to the highly instructional nature of neurofeedback. Subjects will be asked to develop strategies, follow detailed 
instructions, and adapt their regulation techniques over the course of the study –  all of which require active 
communication between the subject and researchers. For this reason, subjects must be comfortable with English 
to be able to participate fully in this study. For those who are proficient in English but for whom English may not 
be a first language, research personnel will take extra care to ensure that such subjects understand the nature of 
the study and are able to communicate effectively in English, especially during the consenting process.
As a limited alternative to the above requirement, will you use the short form* for consenting process if you 
unexpectedly encounter a non-English speaking individual interested in study participation and the translation of 
the long form is not possible prior to intended enrollment?  YES ☐  NO ☒
Note* If more than 2 study participants are enrolled using a short form translated into the same language, then 
the full consent form should be translated into that language for use the next time a subject speaking that 
language is to be enrolled.
Several translated short form templates are available on the HRPP website (yale.edu/hrpp) and translated HIPAA 
Research Authorization Forms are available on the HIPAA website (hipaa.yale.edu). If the translation of the short 
form is not available on our website, then the translated short form needs to be submitted to the IRB office for 
approval via modification prior to enrolling the subject.   Please review the guidance and presentation on use of 
the short form available on the HRPP website.
If using a short form without a translated HIPAA Research Authorization Form, please request a HIPAA waiver in 
the section above. 
9. Consent Waiver: In certain circumstances, the HIC may grant a waiver of signed consent, or a full waiver of 
consent, depending on the study. If you will request either a waiver of consent, or a waiver of signed consent for 
this study, complete the appropriate section below.  
☐Not Requesting any consent waivers 
☒Requesting a waiver of signed consent:
☒ Recruitment/Screening only (if for recruitment, the questions in the box below will apply to 
recruitment activities only)
☐ Entire Study (Note that an information sheet may be required.)
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 For a waiver of signed consent, address the following:
Would the signed consent form be the only record linking the subject and the research?  YES ☐  NO ☒ 
Does a breach of confidentiality constitute the principal risk to subjects? YES ☒  NO ☐
 
OR
Does the research pose greater than minimal risk? YES ☐    NO☒ 
Does the research include any activities that would require signed consent in a non-research context? YES ☐   
NO ☒
 ☐ Requesting a waiver of consent:
☐ Recruitment/Screening only (if for recruitment, the questions in the box below will apply to 
recruitment activities only)
☐ Entire Study 
 
For a full waiver of consent, please address all of the following: N/A 

Does the research pose greater than minimal risk to subjects?  
☐ Yes If you answered yes, stop. A waiver cannot be granted.  
☐ No

Will the waiver adversely affect subjects’ rights and welfare? YES ☐    NO☐

Why would the research be impracticable to conduct without the waiver? Write here

Where appropriate, how will pertinent information be returned to, or shared with subjects at a later date? 
Write here
SECTION IV: PROTECTION OF RESEARCH SUBJECTS
    Confidentiality & Security of Data:
1.
What protected health information (medical information along with the HIPAA identifiers) about subjects will 
be collected and used for the research?
      Protected health information collected from the subject will include clinical information acquired during the 
phone screen and in-person assessments (including diagnostic and treatment history, symptom information, etc.). 
Structural and functional brain data will also be collected and used for research. If they consent to the additional 
genetic testing, genetic data will also be collected. 
2.
How will the research data be collected, recorded and stored?
      Any identifiable information that is obtained in connection with this study will remain confidential and will be 
disclosed only with subject permission or as required by U.S. or State law (examples of information that we are 
legally required to disclose include abuse of a child or elderly person, or certain reportable diseases). The personal 
clinical information obtained from subjects during screening will be kept only on paper in a locked file cabinet – the 
one exception being information collected during phone screens which will be kept in a REDcap database accessed 
only on encrypted devices connected to secure servers. Any other data collected during the study (such as structural 
and functional brain data or genetic data) will be de-identified and will be stored with a study number rather than 
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any personal identifiers. A record associating subject name and study number will be kept confidentially in paper 
form in a locked file cabinet to be seen only by members of the research team. The research team will only give this 
coded information to others to carry out aspects of the present study. The link to personal information will be kept 
until the study is complete and all data analyses have been conducted and published, after which time the link will 
be destroyed and the data will become anonymous. The data will be kept in this anonymous form indefinitely.
      De-identified data will be shared with ClinicalTrials.gov and with the NIMH National Database for Clinical Trials 
(NDCT).
3.
How will the digital data be stored? ☒CD  ☒DVD  ☐Flash Drive  ☐Portable Hard  Drive   ☒Secured Server  ☒
Laptop Computer  ☒Desktop Computer  ☒Other – locked-in-place hard drives for backing up data on secure 
servers/encrypted laptops
4.
What methods and procedures will be used to safeguard the confidentiality and security of the identifiable 
study data and the storage media indicated above during and after the subject’s participation in the study? 
      As mentioned above, any identifiable information that is obtained in connection with this study will remain 
confidential and will be disclosed only with subject permission or as required by U.S. or State law. The personal 
clinical information obtained from subjects during screening and collected during study visits will be stored either 
on paper in a locked file cabinet or in a REDCap database accessed only on encrypted devices connected to secure 
servers. Any other data collected during the study (such as structural and functional brain data) will not be stored 
with any personal identifiers, but rather with a study number. A record associating subject name and study number 
will be kept confidentially in paper form in a locked file cabinet to be seen only by members of the research team. 
The research team will only give this coded information to others to carry out aspects of the present study. The link 
to personal information will be kept until the study is complete and all data analyses have been conducted and 
published, after which time the link will be destroyed and the data will become anonymous. The data will be kept 
in this anonymous form indefinitely. All analyses involving personal subject information will be performed on 
encrypted devices connected to a secure network.
All portable devices must contain encryption software, per University Policy 5100.  If there is a technical reason a 
device cannot be encrypted please submit an exception request to the Information Security, Policy and Compliance 
Office by clicking on url http://its.yale.edu/egrc or email it.compliance@yale.edu
5.
What will be done with the data when the research is completed? Are there plans to destroy the identifiable 
data? If yes, describe how, by whom and when identifiers will be destroyed. If no, describe how the data and/or 
identifiers will be secured.
      
      The link to personal information will be kept in a locked file cabinet until the study is complete and all data 
analyses have been conducted and published, after which time the link will be destroyed by members of the 
research team and the data will become anonymous. The data will be kept in this anonymous form indefinitely. 
All analyses involving personal subject information will be performed on encrypted devices connected to a 
secure network.
6.
If appropriate, has a Certificate of Confidentiality been obtained? Yes.
SECTION V: POTENTIAL BENEFITS
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Potential Benefits: Identify any benefits that may be reasonably expected to result from the research, either to 
the subject(s) or to society at large. (Payment of subjects is not considered a benefit in this context of the risk 
benefit assessment.) 
It is important to note that this study was not designed to benefit the subject directly. Rather, this study 
will allow us to explore the neurobiological mechanisms of PTSD. If we are successful in identifying a target 
mechanism of action that works in treating PTSD, this study could open the door to the development of other 
interventions and potential treatments for what can be a highly debilitating disorder.
This study also seeks to validate neurofeedback as a feasible intervention for PTSD. A growing body of 
literature points to the efficacy of NF across multiple disorders, and this study could help to expand on past 
knowledge of both NF as a technique and of PTSD as a disorder. NF is a cutting-edge intervention that can bridge 
the gap between patients and technology by actively putting a powerful tool (fMRI) in the hands of the individual. 
In other words, rather than acting as a diagnostic tool, MRI in the context of a NF-based treatment would be able 
to be implemented as a patient-driven treatment in its own right. Due to the engaging and empowering nature of 
NF, adherence to a NF-based treatment may be better than other interventions. NF may also prove to be an 
effective alternative for individuals who don’t respond to interventions such as exposure therapy, as it is designed 
to engage an independent mechanism of clinical improvement: a strengthening of emotion regulation circuitry via 
feedback learning. Therefore, if this intervention proves effective, it has potential as a frontline treatment for 
PTSD.
While this study was not designed to directly benefit the subject, subjects may gain some control over 
their emotion regulation circuitry and may see improvement in their clinical symptoms. While this improvement is 
by no means guaranteed, it is hypothesized that individuals in the experimental group (who are receiving real NF) 
will, on average, receive some benefit from the intervention. Subjects in the sham feedback group are not 
expected to receive any benefits, but will be invited to engage in real NF upon completion of the study.
         SECTION VI: RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS
1. Alternatives: What other alternatives are available to the study subjects outside of the research? 
Subjects who are seeking treatment for their PTSD or other disorders will be referred to meet with the 
appropriate clinicians in a non-research environment, if they so choose. The research personnel will facilitate 
discussions with subjects and individuals who reach out about study regarding treatment options, ranging 
from psychoeducation, psychotherapy, to medication. Any subjects interested in research who are not 
eligible for the present study will be matched to other research studies if possible, and/or referred to other 
research groups if the subject so chooses.
2. Payments for Participation (Economic Considerations): Describe any payments that will be made to subjects, 
the amount and schedule of payments, and the conditions for receiving this compensation.
 Subjects will be paid $80.00 per scan, $20.00 per strategy development session, $20.00 per hour for 
clinical assessments, and $50.00 per hour for the script collection sessions. Subjects will be paid the 
corresponding amount at the end of each visit, in cash. Subjects who complete assessments over the phone 
or Zoom will have the option to either receive compensation via Visa or Amazon gift card, or have the 
appropriate amount of money held for them to pick up either at the MR center or the West Haven VA. As 
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payments are made at the end of each visit, subjects who are unable to complete the entire study will be paid 
in an amount proportional to their participation. 
3, Costs for Participation (Economic Considerations): Clearly describe the subject’s costs associated with 
participation in the research, and the interventions or procedures of the study that will be provided at no cost to 
subjects. 
Subjects are responsible for transportation to the appropriate facilities. This may incur costs due to 
gas, bus tickets, and the like. In special circumstances (e.g., subjects traveling from NYC), travel 
reimbursement may be offered. 
4. In Case of Injury: This section is required for any research involving more than minimal risk, and for minimal risk 
research that presents the potential for physical harm (e.g., research involving blood draws).
a.
Will medical treatment be available if research-related injury occurs?
Yes.
b.
Where and from whom may treatment be obtained? 
Participants may contact a clinician (contact information provided in new attachment with title 
“Contact Information for Neurofeedback of Amygdala Activity for PTSD” that we would like to give 
to patients at consent time). Patients will not be charged for phone consultation. If more care is 
needed, the clinician they have phoned will refer them to either the CMHC or the emergency 
room of the Yale-New Haven Hospital, or, for veterans enrolled through the VA, to a VA medical 
facility.
c.
Are there any limits to the treatment being provided?
Only what is limited by the subject’s ability to pay for the costs of care provided. For veterans 
enrolled through the VA, the following text in the VA protocol applies: “If you are injured as a 
direct result of your participation in this research study, VA will provide necessary medical 
treatment at no cost to you. Except in very limited circumstances, this medical treatment will be 
provided in a VA Medical facility. There are no plans to provide compensation for your disability or 
other losses occurring over the long term or if any injury becomes apparent after your 
participation in the study has ended. However, by agreeing to participate in this research study, 
you are not waiving or giving up any legal rights to seek compensation.”
d.
Who will pay for this treatment?
For veterans enrolled through the VA, costs will be covered by the VA (as described above). For 
other participants with PTSD, the subject and/or the subjects’ insurance will p ay.
e.
How will the medical treatment be accessed by subjects?
They will be referred by a study clinician (or via the crisis/acute service hotlines).
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IMPORTANT REMINDERS
Will this study have a billable service?  Yes ☐ 
 No☒
A billable service is defined as any service rendered to a study subject that, if he/she was not on a study, would 
normally generate a bill from either Yale-New Haven Hospital or Yale Medical Group to the patient or the patient’s 
insurer. The service may or may not be performed by the research staff on your study, but may be provided by 
professionals within either Yale-New Haven Hospital or Yale Medical Group (examples include x-rays, MRIs, CT 
scans, specimens sent to central labs, or specimens sent to pathology). Notes: 1. There is no distinction made 
whether the service is paid for by the subject or their insurance (Standard of Care) or by the study’s funding 
mechanism (Research Sponsored). 2. This generally includes new services or orders placed in EPIC for research 
subjects. 
If answered, “yes”, this study will need to be set up in OnCore, Yale’s clinical research management system, for 
Epic to appropriately route research related charges. Please contact oncore.support@yale.edu
Are there any procedures involved in this protocol that will be performed at YNHH or one of its affiliated entities?   
Yes ☐  No ☒ 
IMPORTANT REMINDER ABOUT RESEARCH AT YNHH 
Please note that if this protocol includes Yale-New Haven Hospital patients, including patients at the HRU, the 
Principal Investigator and any co-investigators who are physicians or mid-level practitioners (includes PAs, APRNs, 
psychologists and speech pathologists) who may have direct patient contact with patients on YNHH premises 
must have medical staff appointment and appropriate clinical privileges at YNHH. If you are uncertain whether 
the study personnel meet the criteria, please telephone the Physician Services Department at 203-688-2615. By 
submitting this protocol as a PI, you attest that you and any co-investigator who may have patient contact has a 
medical staff appointment and appropriate clinical privileges at YNHH.
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