Real-time Functional MRI and Neurofeedback of Brain Networks Mediating Trauma Memory Recall in PTSD
Phase: NA
Conditions: Stress Disorders, Post-Traumatic
Sponsor: University of Arkansas

 
 
Protocol Title:  
Real-time fMRI and Neurofeedback of Brain Networks Mediating 
Trauma Memory Recall in PTSD 
 
Principal 
Investigator: 
Keith Bush, PhD  
Department:  
Brain Imaging Research Center; Department of Psychiatry 
Address: 
4301 W. Markham # 554 
Telephone: 
526-8347 
FAX: 
526-8199 
E-mail: 
KABush@uams.edu  
 
Sub- Investigator: 
Clint Kilts, Ph.D. 
Department: 
Brain Imaging Research Center; Department of Psychiatry 
Address: 
4301 W. Markham # 554 
Telephone: 
526-8163 
FAX: 
526-8199 
E-mail: 
CDKilts@uams.edu  
 
Sub- Investigator: 
Andy James, Ph.D. 
Department: 
Brain Imaging Research Center; Department of Psychiatry  
Address: 
4301 W. Markham # 554 
Telephone: 
526-8345 
FAX: 
526-8199 
E-mail: 
GAJames@uams.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Location(s) of 
Study:  
 
Brain Imaging Research Center 
Department of Psychiatry 
University of Arkansas for Medical Sciences 
4301 W. Markham # 554 
Little Rock, AR 72205 

Title: Real-time fMRI and Neurofeedback of Brain States Mediating  Trauma Memory Recall in PTSD 
PI: Keith Bush, PhD 
 
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Date: 08/24/2017 
Page: 2 
 
Table of Contents 
Section 
Description 
Page  
I 
Abbreviations 
3 
II 
Protocol Summary 
3 
III 
Background and Rationale 
3 
IV 
Hypothesis or Research Question/Specific Aims 
3 - 4 
V 
Trial Design 
4 - 7 
VI 
Study Population 
7 - 8 
VII 
Investigational Plan 
8 - 10 
VIII 
Adverse Events: Adverse Events Reporting and Evaluation 
10 - 11 
IX 
Risks and Benefits 
12 - 13 
X 
Outcome Measures 
13 
XI 
Data Handling and Recordkeeping 
13 – 14 
XII 
Statistical Plan 
14 
XIII 
Dissemination of Data 
14 
XIV 
References 
14 - 16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Title: Real-time fMRI and Neurofeedback of Brain States Mediating  Trauma Memory Recall in PTSD 
PI: Keith Bush, PhD 
 
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Date: 08/24/2017 
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I. 
Abbreviations  
 
 
 
 
 
 
 
 
 
II. 
Protocol Summary 
State of the art treatments for posttraumatic stress disorder (PTSD) are only associated with 
success rates of ~60% (Foa, et al., 1999; Foa, Rothbaum, Riggs, & Murdock, 1991; Schnurr, et 
al., 2007). The goal of this project is to test a novel means of boosting efficacy of exposure-
based therapy for PTSD.  
III. 
Background and Rationale  
PTSD is characterized by intense emotional distress upon exposure to trauma reminders and 
avoidance of people and places that can trigger the trauma memory. Neurocircuitry models of 
PTSD that seek to explain symptoms of heightened emotional reactivity, hypervigilance for 
threat, and avoidance (Patel, Spreng, Shin, & Girard, 2012; Rauch, Shin, & Phelps, 2006) 
suggest abnormal activity of neural regions involved in emotional reactivity (e.g., amygdala) and 
cognitive control of emotional responding (e.g., ventral medial prefrontal cortex, anterior 
cingulate cortex). While knowledge exists about neurobiological abnormalities associated with 
PTSD, these data are cross-sectional in nature and ignore individual differences in both neural 
encoding and subjective aspects of the trauma itself (e.g., whether it elicits fear vs guilt vs 
disgust). Additionally, the manner by which existing psychological treatments alter these neural 
mechanisms mediating core PTSD symptoms is unknown. This is problematic, given that state-
of-the-art treatment for PTSD is only effective ~60% of the time (Foa et al., 1991; Schnurr et al., 
2007).  
Here, we propose to utilize a novel computational modeling approach combined with state-
of-the-art fMRI-based neurofeedback(S. LaConte, Strother, Cherkassky, Anderson, & Hu, 2005; 
S. M. LaConte, 2011; S. M. LaConte, Peltier, & Hu, 2007) to directly identify and modulate the 
idiosyncratic neural network encoding the trauma memory. Successful pursuit of these aims 
would 1) provide scientific support for the hypothesis that a distributed network including the 
amygdala, hippocampus, mediap PFC, lateral PFC, and anterior insula mediates emotional 
responding upon trauma memory recall, and 2) provide proof-of-concept evidence that 
neurofeedback modulation of this network can boost existing therapy efficacy.  
 
IV. 
Hypothesis or Research Question /Specific Aims 
AFNI  
Analysis of Functional Images  
BIRC  
Brain Imaging Research Center  
fMRI  
 
PFC 
PTSD 
SCR 
Functional Magnetic Resonance 
Imaging  
Prefrontal Cortex 
Posttraumatic Stress Disorder 
Skin Conductance Response 
 

Title: Real-time fMRI and Neurofeedback of Brain States Mediating  Trauma Memory Recall in PTSD 
PI: Keith Bush, PhD 
 
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Overall research goals: The overall goals of this research plan are to:  
1) Develop a computational model that identifies idiosyncratic neural networks mediating 
emotional responding upon trauma memory recall. Hypothesis: Co-activation between 
amygdala, hippocampus, mediap PFC, lateral PFC, and anterior insula mediates 
emotional responding upon trauma memory recall.  
2) Demonstrate that real-time fMRI neurofeedback of the identified idiosyncratic brain 
network modulates the activity of the brain network, which in turn corresponds with 
expected changes in objective measures of emotional arousal. Hypothesis: 
Neurofeedback increases or decreases activity of the identified neural network, resulting 
in increases or decreases in emotional arousal, respectively. 
 
V. 
Trial Design 
Overview 
There are two stages to this experimental protocol: Pilot Stage and Implementation Stage. In 
the pilot stage, we would recruit healthy adult women (n=10). In the implementation stage, we 
would recruit adult women with a history of physical or sexual assault or trauma (n=17). The 
pilot stage will be used to refine the methodology prior to enrolling the more vulnerable assault 
sample in the implementation stage. All procedures between the different stages would be 
conceptually identical.  
Participants would have two visits to the BIRC. On day 1, participants would undergo a 
structured clinical interview to assess trauma history and mental health diagnoses. Participants 
would also complete assessments and a standardized form for generating idiosyncratic 
trauma/stress scripts. Participants would return on Day 2 in order to complete the MRI scan. 
The MRI scan will consist of a resting state scan and neurofeedback scans. The neurofeedback 
scans will consist of two phases: model building and neurofeedback phases. During the model 
building phase, participants would be presented their stress/trauma scripts in concurrent visual 
and oral formats during fMRI while undergoing simultaneous measurement of physiological 
arousal (SCR). A computational model would be fit to this initial data to identify the brain regions 
that correspond with heightened emotional arousal during the stress/trauma script. Participants 
would then be given three neurofeedback phases (3 minutes each), during which they are given 
feedback to decrease, increase, and decrease activity in this network. A more detailed 
description is included in the following section.  
fMRI Procedures 
Prior to the MRI scan, subjects may have a training session in the MRI simulator to help 
habituate and train them to the MRI environment and MRI tasks.  During this training session, 
subjects will also be allowed to practice some of the computer tasks.  Per the MRI Policies and 
Procedures, the decision of who will be acclimated in the MRI Simulator will be made by the 
Research Coordinators and PI on a case-by-case basis.  The PI for the study will have final say 
in this decision.   

Title: Real-time fMRI and Neurofeedback of Brain States Mediating  Trauma Memory Recall in PTSD 
PI: Keith Bush, PhD 
 
Version: 9 
Date: 08/24/2017 
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Before the MRI scan, participants will be given an explanation of the study’s procedures and 
screened with the MRI Safety Form for metal objects and claustrophobia.  Participants will also 
be screened with the SAFESCAN® ferromagnetic detector according to MRI Policy and 
Procedures. The participant will then lie supine in the scanner. Participants will wear noise-
cancelling headphones for communication and view visual stimuli through a mirror attached to 
the imaging head coil. Participants will undergo an anatomic scan in addition to functional scans 
to facilitate alignment of images.  
 
 
Script generation. Numerous studies have used script-guided imagery to induce emotional 
states, including creation of stress scripts, neutral scripts, and trauma scripts to induce generic 
emotional distress or emotiona distress specific to trauma memory recall vs neutral scripts 
(Cisler, et al., 2014; Orr, et al., 1998; Orr, Pitman, Lasko, & Herz, 1993; Pitman, Orr, Forgue, de 
Jong, & Claiborn, 1987; Rauch, et al., 1996; Shalev, Orr, & Pitman, 1992, 1993; Sinha, Garcia, 
Paliwal, Kreek, & Rounsaville, 2006; Sinha, Lacadie, Skudlarski, & Wexler, 2004). Here, we 
would use this standardized methodology to activate a stress memory (pilot stage participants 
only) or a  trauma memory (implementation stage participants only)) during fMRI. During the 
Day 1 assessments, participants will be asked to write a short narrative (including about 500 
words) describing a stressfull/traumatic event using standardized methodology. This narrative 
will be displayed both on screen and via audio recording through headphones during the MRI 
scan. The pilot stage participants would create a non-traumatic stress script based on selecting 
a recent real-life stressful experience, while the implementation stage participants would create 
a trauma script describing their primary traumatic event. These procedures are consistent with 
our previous IRB approved protocols (133973 and 202715).  
 
Real-time fMRI and neurofeedback.  
Modeling building phase. The first phase of the MRI acquisition would consist of a single 
3 min presentation of the stress/trauma script followed by a 3 min presentation of the neutral 
script (with the order counterbalanced across participants). In between the stress/trauma script 
and neutral script, there would be an emotion rating period, during which the participants 
indicate on a 9 pt Likert scale their anxiety and vividness of the imagery. Skin conductance 
response (SCR) will be recorded using BIOPAC’s psychophysiological monitoring equipment. A 
series of electrodes placed on the participant’s skin will measure SCR and provide an objective 
measure of physiological arousal. A subsequent reinforcement learning algorithm, fitted Q 
learning, would be applied to these joint fMRI and SCR data to identify distributed patterns of 
co-activated brain regions that specifically encode high emotional arousal (i.e,. high SCR) to the 
stress/trauma memory. The resulting idiosyncratic brain map would inform the neurofeedback 
phase in the next three runs. This phase will take approximately 6 minutes.  
Neurofeedback phase. In this phase, participants would undergo three additional 3 min 
presentations of the stressful/traumatic script; however, they would also concurrently be given 
neurofeedback to up- or down-modulate the identified brain network. In this neurofeedback 
phase, participants would be given visual feedback of the current state of their brain with 

Title: Real-time fMRI and Neurofeedback of Brain States Mediating  Trauma Memory Recall in PTSD 
PI: Keith Bush, PhD 
 
Version: 9 
Date: 08/24/2017 
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respect to the desired brain state (based on the computational model). In order to demonstrate 
a causal relationship between the brain state and emotional arousal, we would alternate 
between instructions to decrease the brain state (during which we expect to see decreased 
SCR), increase the brain state (during which we expect to see heightened SCR), and then 
decrease the brain state again. The sequence of manipulations would always be decrease – 
increase – decrease so that participants always end during a phase attempting to decrease 
emotional arousal. Also note that other experiments have used neurofeedback to modulate pain 
and both increase and decrease pain in order to demonstrate experimental control of pain 
through manipulation of the identified brain regions (deCharms, et al., 2005). This phase will 
take approximately 18 minutes.  
 
The visual representation of the brain network will be presented using each participant’s 
stress/trauma stress. The script will be typed and presented to the participant whil laying in the 
scanner. During Run 1 (initial acquisition), participants will be instructed to focus on the memory 
and any thoughts or feelings associated with it. During Runs 2, 3, and 4, participants will be 
instructed to either increase or decrease emotional arousal, based on instructions given to 
them. The script will increase or decrease in brightness as activation of the brain state increases 
or decreases. Participants learn to control activation of their brain state, and thus the brightness 
of the script, through trial and error on their own. Figure 2 provides an overview of the 
experimental design while participants undergo fMRI.  
 
 
 fMRI scanner  
 
 Image acquisition is performed by a Philips Achieva 3T X-series MRI.  
 
Assessments 
Participants will complete several interviews and questionnaires to determine psychological and 
medical history, current life functioning, history of drug use, stress experiences, individual traits, 
family functioning, and demographic variables.    
 
Structured Clinical Interview for DSM-IV: measures current psychological functioning and drug 
use history (First et al., 2002). 
 
Figure 2. Diagram depicting Model-building and Neurofeedback Phases 

Title: Real-time fMRI and Neurofeedback of Brain States Mediating  Trauma Memory Recall in PTSD 
PI: Keith Bush, PhD 
 
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Date: 08/24/2017 
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Data Collection Form: internal form used to collect study specific information such as 
handedness, age, race/ethnicity, medications, etc. 
 
National Survey of Adolescent Trauma Assessment: assesses assaultive event exposure and 
other types of childhood adversity history and chronology (Kilpatrick, et al. 2000, Kilpatrick, et al. 
2003). 
 
Beck's Depression Inventory: measures the severity of current depression (Beck et al., 1961). 
 
Childhood Trauma Questionnaire: measures histories of abuse and neglect during childhood 
(Bernstein, et al. 2003). 
 
Difficulty in Emotion Regulation Scale: assesses multiple aspects of emotion dysregulation 
(Gratz & Roemer, 2004).  
NEO Five-factor Inventory: measure of the Big Five personality traits (Goodwin and Friedman 
2006). 
Positive and Negative Affect Scale: measure of current (at this moment) affect (Watson et al., 
1988). 
Posttraumatic Stress Disorder Checklist- 5: assesses the 20 DSM-5 symptoms of PTSD 
(Weather et al., 2013).  
Strategies to Increase and Decrease Emotions: provides information about various strategies 
participants may use to increase or decrease activation of brain states.  
Stress Script Generating Forms: create narrative description of stressful/traumatic events 
(Pitman et al., 1987). This form is identical to forms used in previously approved projects (IRB#: 
113160, 133973, and 202715).  
 
VI. 
Study Population 
Participant recruitment  
We plan to enroll a total of 27 healthy adults (all women), aged 21-50, into this study: 10 healthy 
women for the pilot stage and 17 women with a history of physical or sexual assault for the 
implementation stage. Given known sex differences in brain reactivity to stress and in neural 
correlates of PTSD (Felmingham, et al., 2010; Seo, et al., 2011), we focus on only women to 
maximize statistical power. In order to achieve these enrollment goals, up to 110 adults could be 
recruited and screened for eligibility. The participants would be recruited from local 
advertisements and flyers in public places. Additionally, we may recruit participants from 
previous or ongoing IRB-approved BIRC studies, provided they have consented to be 
recontacted for other studies by the study team.  
 

Title: Real-time fMRI and Neurofeedback of Brain States Mediating  Trauma Memory Recall in PTSD 
PI: Keith Bush, PhD 
 
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Date: 08/24/2017 
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Inclusion criteria for the healthy pilot stage participants will be no current Axis I psychological 
diagnoses, between the ages of 21-50, English speaking (due to lack of validated measures for 
non-English speaking populations), and medically healthy. Participants endorsing any of the 
following conditions will be excluded from the study: 1) current serious medical condition, 2) any 
internal metal objects, 3) under the age of 21 or over the age of 50, and 4) any current 
psychological disorder or psychiatric medication including acute suicidality or major depression. 
Any subjects that are at high risk or unstable (e.g. self-cutting, comorbid addiction) will also be 
excluded from the study. 
 
Inclusion criteria for the implementation stage participants will be a history of physical or sexual 
assault, between the ages of 21-50, and medically healthy. Participants endorsing any of the 
following conditions will be excluded from the study: 1) current serious medical condition, 2) any 
internal metal objects, 3) under the age of 21 or over the age of 50, and 4) a psychotic disorder 
or developmental disorder including acute suicidality or major depression. Any subjects that are 
at high risk or unstable (e.g. self-cutting, comorbid addiction) will also be excluded from the 
study. 
 
Due to safety concerns, participants with these conditions will be ineligible to participate:  
• 
Claustrophobia, or the inability to lie still in a confined space  
• 
Major medical disorders (e.g., HIV, cancer) 
• 
Magnetic metallic implants (such as screws, pins, shrapnel remnants, aneurysm clips, 
artificial heart valves, inner ear (cochlear) implants, artificial joints, and vascular stents), 
as these may heat, pull, or twist in the strong magnetic field of the MRI scanner  
• 
Electronic or magnetic implants, such as pacemakers, as these may stop working  
• 
Permanent makeup or tattoos with metallic dyes  
• 
A positive pregnancy test (for females), since the effect of strong magnetic fields on the 
developing fetus remains unknown and inconclusive. (We will conduct a pregnancy test 
for all female participants of childbearing potential on the day of the MRI scan.)  
• 
A self-reported history of loss of consciousness (greater than 10 minutes)  
• 
Physical disabilities that prohibit task performance (such as blindness or deafness)  
• 
Psychotic disorders (e.g., schizophrenia) 
• 
Any other condition that the investigator believes might put the participant at risk  
 
Due to their effects on image quality, participants with the following MAY be ineligible to 
participate per Principal Investigator’s judgment: 
• 
Medications which may affect image quality (e.g., water pills) 
• 
Nonremovable dental implants, such as braces or upper permanent retainers, as these 
will distort the MRI images we collect (note: filings, crowns, and silver or gold teeth are 
OK) 
• 
Any other condition, medication, or implant that the investigator believes would degrade 
image quality or render data unusable 
 
VII. 
Investigational Plan 

Title: Real-time fMRI and Neurofeedback of Brain States Mediating  Trauma Memory Recall in PTSD 
PI: Keith Bush, PhD 
 
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Date: 08/24/2017 
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Participant screening, consenting and assessments 
Participant assessment will occur in two parts. First, a phone screening will be conducted to 
ensure a high probability that participants are eligible for the study. This phone screening will 
assess self-report of whether the individual has a current mental health disorder, medical 
disorders, internal metal, claustrophobia, and transportation capability to UAMS. The phone-
screening will be conducted by a trained research coordinator. If the participant meets probable 
inclusion criteria, the research coordinator will schedule the participant for part two of the 
assessment process.  
 
Upon arrival to the BIRC for part two, the participant will first be given a written and verbal 
description of the study and informed consent.  The PI or designated staff will discuss the 
informed consent form with the subject volunteer.  The consent process will take place in a quiet 
and private room.  Subjects may take as much time as needed to make a decision about their 
trial participation and may take the document home if desired.  The person obtaining consent 
will thoroughly explain each element of the document and outline the risks and benefits, 
alternate treatment(s), and follow-up requirements of the study.  Participation privacy will be 
maintained and questions regarding participation will be answered.  No coercion or undue 
influence will be used in the consent process.  No research related procedures will be 
performed prior to obtaining informed consent.  All signatures and dates will be obtained.  A 
copy of the signed consent will be given to the participant.  The informed consent process will 
be documented in each subject’s research record. 
Following the obtainment of consent, part two will entail an in-person interview with a trained 
clinical research coordinator who will administer the BIRC Data Collection form, SCID, trauma 
assessment, questionnaires, and script generation forms. The research coordinator has a 
bachelor’s level education in psychology and has received training in administering structured 
clinical interviews. A Clinical Research Nurse with over 20 years experience in structured 
clinical interviews will train the research coordinator on the SCID. The PI will supervise the 
research coordinator. Participants’ trauma history will be assessed with an adapted version of 
the trauma assessment interview utilized in the National Women’s Study (Resnick et al., 1993) 
and National Survey of Adolescents (Kilpatrick et al., 2000). Participants will additionally 
complete a battery of questionnaires, including the Posttraumatic Stress Disorder Checklist 
(PCL), Beck Depression Inventory (BDI), Childhood Trauma Questionnaire (CTQ), Positive and 
Negative Affect Scale (PANAS), and Difficulty in Emotion Regulation Scale (DERS). Mental 
health functioning will be assessed with the Structured Interview for DSM-IV Disorders (SCID-
IV). This interview is expected to last approximately 3 hours. If the participant meets inclusion 
criteria for the study following the assessment, they will then be asked to complete the 
Stress/Trauma Script Generator Form . If the participant does not meet inclusion criteria 
following the assessment, they will not be allowed to be enrolled in the study, and they will be 
compensated and thanked for their time. For additional information on these forms, see 
Assessments section. 

Title: Real-time fMRI and Neurofeedback of Brain States Mediating  Trauma Memory Recall in PTSD 
PI: Keith Bush, PhD 
 
Version: 9 
Date: 08/24/2017 
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NOTE: Some participants from past BIRC studies or patients of the Women’s Mental Health 
Program (WMHP) may have completed one or more of the clinical interviews used in the current 
project. If the participant has completed these interviews in the past, they may consent to use of 
these forms for the current project, provided the interviews were completed within the past year.  
 
MRI 
Upon arrival to the BIRC for the fMRI scanning session, the participant will be given instructions 
for what they will be asked to do in the scanner. Prior to the scan, participants will complete the 
Strategies to Increase and Decrease Emotions form. Following the training, the participant will 
be screened for internal metal and claustrophobia.  The participant will also be screened using 
the SAFESCAN® ferromagnetic detector per MRI Protocol and Procedures. The fMRI data will 
be acquired on a 3T Achieva X-series head-dedicated MRI scanner (Philips Healthcare, USA).  
The lead MRI coordinator has had extensive experience with high field imaging systems.  
Training on the current system was given to the coordinator by a Philips education specialist. A 
similar training was given to the back-up coordinator as well.  Each MRI session will start with a 
localizer and reference scan to optimize head placement.  Experimental tasks will be 
programmed with commonly used software (Presentation), and the images will be projected 
onto a translucent screen via a projector situated in an adjacent room. Anatomic fMRI scans will 
be acquired on all subjects for image alignment purposes.  
 
Assessing participant well-being: The PI will be present at each scan. A clinical psychologist 
with significant PTSD experience will assess the participant’s emotional well-being in person 
immediately following the scan with a private and informal clinical interview. Referral information 
about treatment options and contact information will be provided to participants who need it. 
Additionally, a trained research coordinator will contact the participants  approximately one 
week later by phone to assess well-being.Referral information about treatment options and 
contact will be given to participants who need it.  This research coordinator will have access to 
the clinical psychologist for questions regarding participants’ clinical status. 
 
Compensation  
Participants will be compensated for their time and participation.  They will receive $25 for the 
interview and $25 for the fMRI scan. Participants will also receive $15 for travel to scheduled 
appointments. Travel will be only compensated one time at the completion of the first visit. 
Participants driving themselves to UAMS for the study will have their parking validated. Bus 
tokens may also be provided to participants utilizing the Central Arkansas Transit (CAT) system. 
 
VIII. 
Adverse Events: Adverse Events Reporting and Evaluation  
 
In adverse event reporting, all areas which mention the investigator refer to the PI and/or the 
PI’s designee. All adverse events occurring during the course of the clinical study will be 
recorded on the Adverse Event Case Report Form. For all adverse events, the investigator must 
provide an assessment of the adverse event, its treatment and resolution, and its relationship to 

Title: Real-time fMRI and Neurofeedback of Brain States Mediating  Trauma Memory Recall in PTSD 
PI: Keith Bush, PhD 
 
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the investigational drug or device. Special reporting procedures are required for certain adverse 
events.  
 
Identification of Adverse Events  
An adverse event is defined as any new medical problem, or exacerbation of an existing 
problem, experienced by a subject while enrolled in the study, whether or not it is considered 
device-related by the investigator.  
 
Serious Adverse Events  
Each adverse event will be assessed for its seriousness using the criteria outlined below. The 
term serious adverse event is not synonymous with a “severe” adverse event, which may be 
used to describe the intensity of an event experienced by the subject. An adverse event will be 
classified as serious if it meets any of the following criteria:  
• Results in, or contributes to, a death  
• Life-threatening (i.e., the subject was, in the opinion of the investigator, at risk of death at the 
time of the event, but it does not include an event that, had it occurred in a more severe form, 
might have caused death)  
• Results in permanent disability or incapacity (i.e., permanent impairment of a body function or 
permanent damage to a body structure)  
• Requires in-subject hospitalization or prolongs hospitalization  
• Necessitates medical or surgical intervention to preclude a permanent disability or incapacity  
• Results in a congenital anomaly or birth defect  
 
Non-serious adverse events are all events that do not meet the criteria for a “serious” adverse 
event. If serious adverse event occurs, the investigator will promptly notify the reviewing IRB of 
such an event as soon as possible, but no later than ten (10) working days after first learning of 
the event.  
 
Severity  
Each adverse event will be assessed for its severity, or the intensity of an event experienced by 
the subject, using the following: 
 
1. Mild: Discomfort noticed, but no disruption to daily activity.  
2. Moderate: Discomfort sufficient to reduce or affect normal daily activity.  
3. Severe: Inability to work or perform normal daily activity.  
 
Deaths  
The investigator will notify the sponsor and IRB as soon as possible, preferably within 24 hours 
but in no event later than 48 hours, of learning of subject’s death, regardless of whether the 
death is related or unrelated to the investigational drug and/or device. The investigator will 
attempt to determine, as conclusively as possible, whether the death is related to the device. 
The cause of death and the investigator’s discussion regarding whether or not the death was 
drug- or device-related will be described in a written report. 

Title: Real-time fMRI and Neurofeedback of Brain States Mediating  Trauma Memory Recall in PTSD 
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Pre-existing conditions  
Pre-existing conditions will not be reported as an adverse event unless there has been a 
substantial increase in the severity or frequency of the problem which has not been attributed to 
natural history.  
 
Annual Reporting to IRB (Continuing Review) 
An annual report will be compiled and sent to the IRB to report on number of subjects enrolled 
in the study, safety events, and accrual schedule.  
 
IX. 
Risks and Benefits 
Potential risks 
Internal metal during MRI scanning: One potential safety concern is participant internal metal 
during MRI scanning, which can be painful and dangerous. 
Assessment of mental health and traumatic event exposure: One potential psychological risk of 
the proposed study is the possibility that some participants might experience distress or become 
offended when asked questions pertaining to victimization and mental health history. Many 
people assume that asking such questions produces substantial distress, particularly in 
research settings. However, the empirical literature suggests that this risk is minimal, and that 
individuals with traumatic event histories actually report obtaining positive benefits from their 
participation in studies where traumatic event history is assessed (Griffin, Resick, Waldrop, & 
Mechanic, 2003; Newman, Walker, & Gefland, 1999).  
Assessment of suicidal ideation: During the clinical interview (SCID) in the depression module, 
questions regarding suicidal ideation are asked. This may elicit distress from participants; 
however, there is a specific protocol should a participant report suicidal ideation, intent, or plan, 
and a protocol to decrease distress, described below. Individuals meeting criteria for current 
major depression will be excluded from the study, further decreasing the likelihood of reported 
suicidal ideation. 
Distress during the stress/trauma imagery task: Another potential risk is that the script-guided 
imagery procedure will elicit anxiety/distress, in addition to the MRI environment itself. 
Participants are able to quit the task at any time by indicating to the MRI coordinator(s) that they 
wish to do so.  
Personal health information/Loss of confidentiality: With all research participation, there is a risk 
that personal information obtained from research participants will be mishandled, and 
confidentiality may be compromised.  
 
Protections Against Risks 

Title: Real-time fMRI and Neurofeedback of Brain States Mediating  Trauma Memory Recall in PTSD 
PI: Keith Bush, PhD 
 
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Date: 08/24/2017 
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This study will be conducted according to good clinical practice (GCP) guidelines and with 
utmost concern for the participant’s well-being. Appropriate safeguards will be used to minimize 
pain or discomfort associated with study participation and involve careful subject screening and 
monitoring. Procedures to minimize risks identified in the previous section are outlined below. 
Internal metal during MRI scanning: The MRI Safety Screening Form will be used to screen for 
any internal or external ferromagnetic objects. If not removable, such objects would represent a 
basis for study exclusion. Participants will also be screened using the SAFESCAN® 
ferromagnetic detector to assure that they have no metal on or in their persons. 
 
Assessment of traumatic event exposure:  Participants will be instructed that they are free to 
refuse to respond to any items if they are not comfortable discussing them Additionally, the 
trauma assessment interview (NSA) is worded with dichotomous questions so that the 
participant only has to answer yes or no to a series of questions. Additionally, if in ascertaining a 
participant’s current condition, the need for clinical intervention is determined, the appropriate 
mental health referral will be arranged.  
Procedures for suicidal participants: Individuals who are actively suicidal, defined as intending to 
hurt or kill themselves in the acute time frame, will be referred to the UAMS ER. The treatment 
response may include hospitalization. These participants will be ineligible for further study 
participation.  
Distress during the stress/trauma imagery task: First, any history of claustrophobia would be 
assessed with participants acclimated to the scanner environment using a MR simulator to 
assess and minimize anxiety. Participants will be instructed that they are free to withdraw from 
study participation at any time, with their refusal to continue having no effect on medical care 
associated with UAMS. Second, numerous past studies have used script-driven imagery 
procedure for generic stress induction or trauma-specific stress induction, and while the protocol 
is successful in inducing either generic or trauma-specific distress, the distress is temporary and 
no adverse events have been noted. Third, participants are instructed that they can stop the 
task at any time without negative consequence to them. 
Personal health information/Loss of confidentiality: To protect the identity of research 
volunteers, contact information will be stored in a separate file and in a locked cabinet from 
experimental data forms. All experimental data will be de-identified using an alphanumeric study 
code rather than a name or other identifying information. All data collection forms will be stored 
in a password-protected cabinet behind a locked office. Computer data records will be stored in 
password-protected network drives. Data will be stripped of all identifiers, including the stripping 
of facial features from the anatomical MRI data. All participants will receive a Notice of Privacy 
Practices, outlining the procedures UAMS investigators use, when they sign informed consent 
and the HIPAA agreement. 
Potential benefits of the proposed research to the subjects and others 

Title: Real-time fMRI and Neurofeedback of Brain States Mediating  Trauma Memory Recall in PTSD 
PI: Keith Bush, PhD 
 
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There are no direct health benefits to participating subjects.  However, the potential benefits of 
this research to society are major in terms of improving the ability to consolidate fear extinction 
learning memories.  
Importance of the Knowledge to be Gained 
The goal of this program of research is to better understand how the brain encodes emotional 
distress upon exposure to trauma reminders and provide proof-of-concept data that 
neurofeedback can modulate this network and potentially boost existing therapy efficacy.  
 
X. 
Outcome Measures 
Data will be collected from living human participants through clinical interview, self-report 
questionnaires, behavioral measures, and MRI scanning. Data for the project will be obtained 
specifically for research purposes.  
 
XI. 
Data Handling and Recordkeeping 
The PI will carefully monitor study procedures to protect the safety of research subjects, the 
quality of the data and the integrity of the study.  All study subject material will be assigned a 
unique identifying code or number.  The key to the code will be kept in a locked file in the 
principal investigator’s office.  Only Drs. Clint Kilts, Andrew James and Keith Bush and the 
appropriate research coordinators will have access to the code and information that identifies 
the subject in this study.   
XII. 
Statistical Plan 
 
Power analysis 
A sample size of 10 for the pilot stage will provide sufficient preliminary data and experience 
implementing this technology to proceed to the implementation stage. Assuming large effect 
sizes, a sample size of 17 during the implementation stage should provide power > .8 to detect 
the hypothesized within-subject effects (i.e,. changes in brain activity and emotional arousal 
between the decrease – increase – decrease neurofeedback phases.  
Data analysis  
Image processing will be performed in AFNI. Standard preprocessing steps (motion correction, 
slice timing correction, noise filtering) will be applied, and then analyses will test hypotheses.  
We would use a data-driven, model-free, approach towards identifying idiosyncratic brain 
mechanisms mediating emotional arousal upon exposure to trauma cues. This would using the  
whole-brain (i.e., voxel-wise) feature space (~50,000 voxels) in the fitting the computational 
model. The fitted Q iteration algorithm (Reidmiller, 2005) would be fit to these data, such that 
the timeseries of activity for each voxel are used as input features with which to predict 
subsequent values of SCR. Cross-validation within- and across-particiapants would identify the 

Title: Real-time fMRI and Neurofeedback of Brain States Mediating  Trauma Memory Recall in PTSD 
PI: Keith Bush, PhD 
 
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Date: 08/24/2017 
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non-linear combination of the voxels whose timecourse of activity scales with the magnitude of 
the concurrent SCR response. In the neurofeedback phase, this fitted model would be 
computed on the observed brain states to provide feedback of the participant’s current brain 
state with respect to the modeled target brain state. We would compare mean brain state 
activation and SCR response during neurofeedback phases using repeated measures GLMs for 
the within-subject manipulation of instruction (decrease – increase – decrease). Cluster level 
thresholding would be used to correct for multiple comparisons during the fMRI analyses, FDR 
would control for multiple comparisons during the SCR analyses.  
 
XIII. 
Dissemination of Data 
All data will be deidentified. Publication of results will only include group level statistics: data will 
not be reported separately for any individual.  
 
XIV. 
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